Animal models of viral hemorrhagic fever.

AVR 3524

No. of Pages 22, Model 5G

17 October 2014 Antiviral Research xxx (2014) xxx–xxx 1

Contents lists available at ScienceDirect

Antiviral Research journal homepage: www.elsevier.com/locate/antiviral

2

Review

5 4 6

Animal models of viral hemorrhagic fever

7 8 9 10 11 12 1 2 4 7 15 16 17 18 19 20 21 22 23 24 25 26

Q1

Darci R. Smith a,⇑, Michael R. Holbrook b, Brian B. Gowen c a

Southern Research Institute, Frederick, MD 21701, United States Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, United States c Institute for Antiviral Research and Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT 84322, United States b

Q2

a r t i c l e

i n f o

Article history: Received 11 June 2014 Revised 24 September 2014 Accepted 5 October 2014 Available online xxxx Keywords: Animal models Viral hemorrhagic fever Rodents Non-human primates Medical countermeasures

a b s t r a c t The term ‘‘viral hemorrhagic fever’’ (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures. Ó 2014 Published by Elsevier B.V.

28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

44 45 46 47

Contents 1. 2.

48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Animal models of acute arenaviral infection and HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Old World arenaviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Lassa fever rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Lassa fever NHP models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Lujo HF rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. New World arenaviruses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. New World arenavirus rodent infection models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. NHP models of Argentine and Bolivian HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Other rodent models of arenaviral HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bunyavirus HF animal models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Rift Valley fever (RVF). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. RVF rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. RVF NHP models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Crimean-Congo HF (CCHF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. CCHF rodent models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. CCHFV infection of NHPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Hantaviral HF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Hantaviral HF rodent models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Hantaviral HF NHP models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

⇑ Corresponding author at: Southern Research Institute, 431 Aviation Way, Frederick, MD 21701, United States. Tel.: +1 301 228 2191. E-mail address: [email protected] (D.R. Smith). http://dx.doi.org/10.1016/j.antiviral.2014.10.001 0166-3542/Ó 2014 Published by Elsevier B.V.

Please cite this article in press as: Smith, D.R., et al. Animal models of viral hemorrhagic fever. Antiviral Res. (2014), http://dx.doi.org/10.1016/ j.antiviral.2014.10.001

AVR 3524


17 October 2014 2

D.R. Smith et al. / Antiviral Research xxx (2014) xxx–xxx

3.4.

66 67 68 69

4.

70 71 72 73 74 75

5.

76 77 78 79 80 81 82 83 84 85 86 87 88

6. 7.

Severe fever with thrombocytopenia syndrome (SFTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. SFTS rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. SFTS NHP models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Filoviral HF animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Ebola HF (EHF) rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. EHF NHP models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Marburg HF rodent models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. MHF NHP models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Flaviviral HF animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Mosquito-borne flaviviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Dengue HF (DHF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Yellow fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. YF rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. YF NHP model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Tick-borne flaviviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Kyasanur forest disease/Alkhurma hemorrhagic fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Omsk hemorrhagic fever. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. OHF rodent models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.2. OHF NHP models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

89 90

91

1. Introduction

92

Viral hemorrhagic fever (VHF) is a syndrome of acute febrile illness characterized by increased vascular permeability that may lead to shock and coagulation defects that may result in bleeding. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. They range from the well-recognized filoviruses, Ebola (EBOV) and Marburg (MARV) and the flaviviruses yellow fever virus (YFV) and dengue virus (DENV), to more obscure pathogens such as Omsk hemorrhagic fever virus (OHFV) and Sabia virus. Newly emerging HF viruses include Alkhumra virus (AHFV) in Saudi Arabia (Qattan et al., 1996; Zaki, 1997) and severe fever with thrombocytopenia syndrome virus (SFTSV) in China (Yu et al., 2011). With the exception of DENV, which is transmitted among humans by mosquitoes, the HF viruses are maintained in a variety of animal species. Human infections result from direct or indirect contact with the reservoir host or the bite of an arthropod vector. The geographic distribution of each type of VHF therefore reflects the range of its maintenance host, with most being localized to Africa, Southeast Asia or South America. In Europe, VHF is limited to infections by hantaviruses and Crimean-Congo HF virus (CCHFV), while New World hantaviruses are the only cause of VHF in the United States. The various types of VHF differ in their average severity and overall case fatality rate, but all of them are characterized by increased permeability of the endothelial lining of blood vessels (‘‘vascular leak’’) and by coagulation defects that usually produce only minor hemorrhagic phenomena, but in some cases may lead to fatal bleeding (Schnittler and Feldmann, 2003). Major contributing factors to severe infection include viral subversion of the type I interferon response (Basler, 2005) and an uncontrolled proinflammatory cytokine/chemokine response (Bray, 2005). While all types of VHF share a common syndrome, specific pathogenic mechanisms vary by virus and host response. A recent review summarizes current understanding of the pathogenesis of VHF caused by filoviruses, flaviviruses and arenaviruses (Paessler and Walker, 2013). Therapies are available for Lassa fever and for Argentine HF, but there are no approved countermeasures against other types of VHF. The relative infrequency and sporadic occurrence of these zoonotic diseases coupled with ethical considerations constitute a major

93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

impediment to the conduct of human clinical trials, hindering the development of new intervention strategies. Animal models that faithfully reproduce most aspects of human disease are therefore essential for the evaluation of new candidate vaccines and therapeutics. The US Food and Drug Administration (FDA) has developed an ‘‘Animal Rule’’, which allows for the demonstration of drug or vaccine efficacy in laboratory animals instead of humans, when limited frequency and predictability or the severity of a disease makes clinical trials impossible. To satisfy FDA requirements, testing of potential vaccines and therapeutics should be performed using a well-characterized model, ideally employing an immunocompetent animal, a wild-type virus and a realistic challenge dose and route of exposure. Most importantly, the model should recapitulate the principal features of the human disease (FDA, 2009; Snoy, 2010). However, the development of animal models to mimic the full spectrum of HF disease presentation is complex and as discussed in the sections on specific virus families, it is not always possible to use immunocompetent animals, a wild-type virus and a realistic challenge dose and route of exposure. Nonhuman primates (NHPs) are the ‘‘gold standard’’ for evaluating medical countermeasures for several types of VHF, especially for advanced development efforts (Safronetz et al., 2013a). However, because of the cost-prohibitive nature, ethical concerns, and complicated logistical and safety aspects of NHP experiments, rodent models are frequently used for preclinical efficacy studies. The goal of the present article is to review NHP and rodent models currently available to study the pathogenesis of the various types of VHF and test new vaccines and therapies.

131

2. Animal models of acute arenaviral infection and HF

159

2.1. Old World arenaviruses

160

Lassa virus (LASV) causes by far the greatest morbidity and mortality due to infection by arenaviruses that cause hemorrhagic fever (HF). Exposure to LASV and mortality associated with Lassa fever (LF) in hyperendemic areas of West Africa (Fig. 1) are estimated to be as high as 300,000 infections and 10,000 deaths annually, with 15–20% of hospitalized patients succumbing to the disease (McCormick, 1999; McCormick et al., 1987a). LASV is carried by chronically infected rodents (Mastomys species) and human

161


132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158

162 163 164 165 166 167 168

AVR 3524


17 October 2014 D.R. Smith et al. / Antiviral Research xxx (2014) xxx–xxx

3

Fig. 1. The geographic distribution of arenaviral hemorrhagic fevers.

169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205

206 207 208

exposure most often occurs through inhalation of infectious virus particles aerosolized from rodent excreta or direct contact that may result in virus entry through abrasions in the skin (Yun and Walker, 2012). Nosocomial transmission via contact with contaminated medical devices or body fluids during patient care can occur, but is effectively mitigated by barrier nursing (Helmick et al., 1986). Following exposure and a 7–21 day incubation period, LF usually begins as a non-specific illness difficult to distinguish clinically from other febrile diseases (Frame et al., 1970; McCormick et al., 1987b). The clinical manifestations of LF and the disease pathogenesis have been recently reviewed in detail (Moraz and Kunz, 2011; Yun and Walker, 2012). Despite being the most studied of the arenaviral HFs, the events that lead to terminal shock are not well understood. The most consistent and dramatic pathologic findings are varying degrees of liver disease that are generally limited and insufficient to explain the cause of death. What appears to underlie the downfall of those afflicted is unchecked viral replication likely due to deficiencies in cell-mediated immunity, vascular dysfunction and leak, which may not be linked to the overproduction of proinflammatory cytokines, and thrombocytopenia (Fisher-Hoch et al., 1988; Flatz et al., 2010; Mahanty et al., 2001; Schmitz et al., 2002). Actual hemorrhagic manifestations are only observed in a minority of cases (Khan et al., 2008). Southeast of the LF-endemic region of Western Africa, a novel arenavirus, Lujo, was recently isolated from a nosocomial outbreak of HF originating in Lusake, Zambia (Paweska et al., 2009). Four caregivers in Johannesburg, South Africa, also contracted the disease with the index case and 3 of the 4 hospital-acquired cases ultimately resulting in death. The high mortality rate (80%) associated with the Lujo virus (LUJV) outbreak may reflect infection with a particularly pathogenic strain of the virus or exposure to greater infectious doses in the care of severely ill patients. This has also been the case for LF, with higher mortality rates of up to 65% observed with nosocomial outbreaks (Fisher-Hoch et al., 1995). Therefore, challenge dose and route are likely to be important factors in modeling LUJV HF and LF in animals for pathogenesis, antiviral or vaccine studies. 2.1.1. Lassa fever rodent models Consistent with the formidable disease burden associated with LASV infection, substantial work has been done to develop and

characterize small animal models to investigate therapeutic and vaccine intervention strategies and the study of pathogenesis (Table 1). Recent reports have described type I IFN receptor-deficient and MHC-1-deficient or humanized mice that support LASV replication and varying degrees of disease (Flatz et al., 2010; Rieger et al., 2013; Yun et al., 2012). More recently, LASV was shown to cause greater disease severity in STAT-1/ mice basing mortality on weight loss of greater than 20% and hypothermia (Yun et al., 2013). In general, however, adult mice of commonly used laboratory strains are refractory to challenge not involving direct inoculation into the brain (Lukashevich, 1985; Peters et al., 1987). Consequently, the guinea pig has been the principal small animal model in use for the evaluation of experimental therapies (Cashman et al., 2011; Huggins, 1989). A major limitation of the guinea pig model is the requirement for inbred strain 13 animals which are highly susceptible to LASV infection, as the standard Hartley outbred guinea pig strain is far less susceptible to challenge with wild-type virus (Jahrling et al., 1982). Very few strain 13 colonies exist and sufficient numbers of animals are difficult to obtain for the types of numbers required for drug or vaccine efficacy studies. Adaptation of LASV to the Hartley or other commercially available strains of guinea pigs would be advantageous for preclinical product evaluations.

209

2.1.2. Lassa fever NHP models Many of the clinical manifestations and pathologic features of LF are believed to occur in LASV-infected rhesus and cynomolgus macaques, which are considered to be the ‘‘gold standard’’ for modeling LF (Table 2). Important studies with ribavirin in the late 1970s demonstrated the efficacy of the compound in the rhesus macaque model (Jahrling et al., 1980), with ribavirin ultimately being evaluated and showing promise in the treatment of LF in humans (McCormick et al., 1986). More recently, LASV pathogenesis in cynomolgus macaques was investigated in detail and found to recapitulate many of the features of LF in humans (Hensley et al., 2011b). There now appears to be a preference for the use of the cynomolgus macaque model for LF research (Baize et al., 2009; Geisbert et al., 2005; Safronetz et al., 2013c). Other species of NHP have also been shown to be susceptible to lethal infection by LASV. Studies in the late 1980s and early 1990s reported on clinical and pathological findings in hamadryas

232


210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231

233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248

AVR 3524


17 October 2014 4


Table 1 Rodent models of arenavirus infection and disease. Virus

Biocontainment

Disease modeled

Species

Selected references

Old World Lassa

BSL-4

Lassa fever Lassa virus disease Lassa virus replication

Lujo

BSL-3 BSL-2/BSL-2+ BSL-4

Acute arenaviral disease Arenaviral hemorrhagic disease Lujo hemorrhagic fever

Guinea piga STAT-1/ b mouse IFNAR/ c mouse HDDd mouse MHC-1/e mouse Guinea pig NZB mouse FVB mouse Guinea pigf

Walker et al. (1975), Jahrling et al. (1982) Yun et al. (2013) Rieger et al. (2013) Flatz et al. (2010) Flatz et al. (2010) Riviere et al. (1985) (Braccala PNAS paper) Schnell et al. (2012) Bird et al. (2012)

New World Flexal Guanarito

BSL-3 BSL-4

Arenaviral hemorrhagic disease Venezuelan hemorrhagic fever

Hamster Guinea pig

Junín

BSL-4g

Machupo

BSL-4

Argentine hemorrhagic fever Junín virus disease Bolivian hemorrhagic fever Machupo virus disease

Pichindé

BSL-2

Pirital Tacaribe

BSL-3 BSL-2

Guinea pig AG129h mouse Guinea pig STAT-1/b mouse AG129h mouse Guinea pigi Hamster Hamster AG129c mouse

Carlton et al. (2012) Tesh et al. (1994) Hall et al. (1996) Yun et al. (2008) Kolokoltsova et al. (2010) Webb et al. (1975) Bradfute et al. (2011) Patterson et al. (2014) Jahrling et al. (1981), Aronson et al. (1994) Buchmeier and Rawls (1977), Gowen et al. (2010a) Xiao et al. (2001b), Sbrana et al. (2006a) Gowen et al. (2010b), Sefing et al. (in press)

LCM

Acute arenaviral disease Arenaviral hemorrhagic disease Arenaviral hemorrhagic disease Acute arenaviral disease

Lymphocytic choriomeningitis, LCM. a Strain 13, not commercially available. b Signal transducer and activator of transcription 1-deficient. c Type I interferon receptor-deficient. d Expresses a human/mouse chimeric HLA-A2.1 in place of the murine MHC-I. e b2 microglobulin-deficient. f Aged strain 13. g BSL-3+ for vaccinated personnel. h Type I and II interferon receptor-deficient. i Virus adapted to produce lethal disease.

Table 2 Nonhuman primate models of arenaviral hemorrhagic fever. Virus

Biocontainment

Disease modeled

Species

Selected references

Old World Lassa

BSL-4

Lassa fever

LCM

BSL-3

Lassa fever

Rhesus macaque Cynomolgus macaque Marmoset Rhesus macaque

Stephen and Jahrling (1979), Jahrling et al. (19800) Jahrling et al. (1984), Baize et al. (2009), Hensley et al. (2011b) Carrion et al. (2007) Lukashevich et al. (2002)

New World Junín

BSL-4a

Argentine hemorrhagic fever

Machupo

BSL-4

Bolivian hemorrhagic fever

Rhesus macaque Marmoset Rhesus macaque Cynomolgus macaque African green monkey Marmoset

McKee et al. (1985b), Green et al. (1987) Weissenbacher et al. (1979), Gonzalez et al. (1983) Terrell et al. (1973), Kastello et al. (1976) Eddy et al. (1975) Wagner et al. (1977), McLeod et al. (1978) Webb et al. (1975)

Lymphocytic choriomeningitis, LCM. a BSL-3 + for vaccinated personnel. 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264

baboons and African green monkeys (Evseev et al., 1991; Peters et al., 1987), with the baboon model being used to evaluate ribavirin in studies conducted in Russia (Dvoretskaia et al., 1991, 1990). However, several decades have elapsed without further reports. More recently, LASV infection in marmosets was shown to resemble many features observed in human LF (Carrion et al., 2007). The reduced size (350–400 g range) and expense associated with using marmosets make them an attractive alternative to the more costprohibitive macaque experiments (Carrion and Patterson, 2012). However, because of the FDA ‘‘Animal Rule’’, the evaluation of promising countermeasures in the marmoset model would require additional studies in macaques widely considered to most accurately reproduce the human disease. Lymphocytic choriomeningitis virus (LCMV) also causes an acute lethal disease in rhesus macaques serving as a surrogate NHP model for LF requiring a lower biocontainment level (BSL-3)

(Table 1). The LCMV macaque model has been extensively studied to gain insights into the pathogenesis and pathophysiology of severe arenaviral infection (Zapata et al., 2011). However, because the FDA ‘‘Animal Rule’’ would ultimately require efficacy studies in two animal models of LF based on challenge with authentic LASV, it seems unlikely that the LCMV NHP model will prove useful for antiviral drug development, considering the high costs of macaques. Moreover, the use of LCMV is not widely accepted as a model virus for LASV. The susceptibility of a variety of NHP species to LUJV challenge is under investigation and it remains to be seen if the virus can produce lethal disease in macaques, marmosets or other primates, similar to LASV infection.

265

2.1.3. Lujo HF rodent models To date, LUJV has only been shown to cause severe HF-like disease in adult (>1 year old) strain 13 guinea pigs (Bird et al., 2012).

277


266 267 268 269 270 271 272 273 274 275 276

278 279

AVR 3524



295

The infection progresses swiftly compared to LASV and reproduces key features of the few human cases, including diffuse pantropic infection, thrombocytopenia, and coagulation abnormalities (Paweska et al., 2009). Another characteristic marker of severe LUJV HF disease is elevation of liver transaminases, which were only moderately increased in the guinea pig model (Bird et al., 2012). Nevertheless, strain 13 guinea pigs appear to be suitable hosts to model LUJV infection based on limited data in humans. As with the LASV guinea pig model, limited availability of the inbred strain 13 animals presents challenges. Moreover, the requirement for adult animals further complicates matters as the larger guinea pigs are more difficult to obtain, are associated with greater costs for long-term housing and care, and require substantially greater quantities of test compounds which are usually in limited supply for initial antiviral drug development studies. A NHP model of LUJV infection has not been described.

296

2.2. New World arenaviruses

280 281 282 283 284 285 286 287 288 289 290 291 292 293 294

297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342

Of the New World arenaviral HFs endemic in different regions of South America (Fig. 1), Junín virus (JUNV), the etiologic agent of Argentine HF (AHF), causes the greatest morbidity and mortality. AHF cases, although reduced in number, continue to be reported despite the vaccination of individuals with the greatest risk of exposure (Enria et al., 2008). Like LF, HF syndromes caused by New World arenaviruses are also rodent-borne diseases that initially progress gradually and largely indistinguishable from other febrile illnesses. The clinical presentation of the South American HFs is similar to LF; however, prominent thrombocytopenia, disseminated intravascular coagulation, and greater incidence of bleeding are observed in Argentine and Bolivian HF cases, the latter due to Machupo virus (MACV) infection (Geisbert and Jahrling, 2004). The other South American HF virus that has caused a significant number of VHF cases in Venezuela is Guanarito virus (GTOV), which causes a disease very similar to that described for Argentine and Bolivian HF (de Manzione et al., 1998; Salas et al., 1991). The case fatality rate (10–50%) in cases of Argentine, Bolivian, and Venezuelan HF requiring medical attention is significant. Sabiá (Brazil) and Chapare (Bolivia) arenaviruses have been linked to less than a Q3 handful of HF cases (Delgado et al., 2008; Lisieux, 1994), and therefore only limited information is available regarding these agents and their associated diseases. 2.2.1. New World arenavirus rodent infection models Several small animal models have been described for the New World HF arenaviruses (Table 1) to gain insights into their pathogenesis and evaluate antiviral therapies and vaccines, including Candid 1 currently approved for human use to prevent Argentine HF. Aside from studies involving intracerebral inoculation, there are no reports of JUNV challenge causing overt disease in immunocompetent mice, rats or hamsters. Susceptibility of AG129 mice lacking IFN-a/b and c receptors to JUNV (Romero strain) infection was recently reported providing a more cost-effective model for early stage proof-of-concept studies; however, the model is based on defined weight loss criteria of 15–20% as an endpoint (Kolokoltsova et al., 2010). Both strain 13 and commercially available Hartley guinea pigs are exquisitely sensitive to JUNV infection, and thus, infection in guinea pigs is considered to be the best rodent model for AHF. Intraperitoneal challenge with the Romero strain of the virus results in uniform lethality with a clinical presentation very similar to that described for human AHF including fever, tremors, convulsions, thrombocytopenia, elevated aspartate aminotransferase levels and mucosal hemorrhaging (Yun et al., 2008). This model has recently been implemented for antiviral and vaccine studies

5

(Gowen et al., 2013; Salazar et al., 2012; Seregin et al., 2010). The prospect of vaccinated personnel conducting research with pathogenic JUNV strains in Biosafety Level (BSL)-3+ facilities may increase accessibility to this virus, that otherwise requires BSL-4 containment (CDC, 2009). MACV and GTOV are also important HF viruses causing sporadic outbreaks in endemic areas of Bolivia and Venezuela, respectively. In addition to a guinea pig (strain 13) model described more than 30 years ago (Webb et al., 1975), MACV has recently been shown to cause lethal infection in STAT-1- and IFN-ab/c receptor-deficient mice (Bradfute et al., 2011; Patterson et al., 2014) (Table 1). The applicability of the STAT/ model as a tool to evaluate antiviral therapies was demonstrated using ribavirin, for which partial efficacy was observed and is consistent with limited clinical data in humans (Kilgore et al., 1997). Contiguous with the theme of guinea pig susceptibility to the pathogenic clade B New World arenaviruses, GTOV causes lethal disease resembling Venezuelan HF in both Hartley and strain 13 animals. No other rodent models have been described for GTOV, but based on findings with related JUNV and MACV, studies in IFN receptor- or signaling-deficient mice are warranted.

343

2.2.2. NHP models of Argentine and Bolivian HF The rhesus macaque and marmoset models of AHF were originally described in the late 1970s and 1980s (Green et al., 1987; McKee et al., 1987; Weissenbacher et al., 1979); however, several decades have passed since the last published reports (Table 2). Efforts to characterize low-passage clinical isolates of JUNV are in the planning stages to identify a strain of virus that best models the HF syndrome in cynomolgus macaques. This is particularly important, as previous work has demonstrated strain-dependent differences in the type of disease (hemorrhagic vs. neurologic) produced in rhesus macaques (Green et al., 1987; McKee et al., 1987). Modeling neurotropic infections is also of interest since this form of disease is observed in humans, but due to the time required to develop the neurologic disease, studies would be required to extend beyond several months, which increases costs and presents logistical issues. As with LF, the common marmoset JUNV model produces a lethal HF that responds to ribavirin therapy (Gonzalez et al., 1983; Weissenbacher et al., 1986), consistent with limited human clinical data (Enria and Maiztegui, 1994). Several models of Bolivian HF in NHPs have been described (Table 2). Following infection with MACV, rhesus and cynomolgus macaques, African green monkeys and marmosets all develop severe disease that resembles Bolivian HF in humans. Because of their phylogenetic similarity (Briese et al., 2009), findings in existing NHP models of JUNV and MACV infection may extend to GTOV and the less studied Sabiá and Chapare viruses in terms of preclinical drug development.

364

2.3. Other rodent models of arenaviral HF

391

Because the arenaviruses that cause HF require maximum containment facilities, early stage preclinical drug development can be difficult due to limited access and the high expense of efficacy studies in BSL-4. Consequently, a number of useful rodent models have been developed to conduct efficacy testing in BSL-2 and BSL-3 conditions (Table 1). Certain strains of the prototypical Old World arenavirus, LCMV, can cause acute lethal diseases in Hartley outbred guinea pigs (WE strain, BSL-3) (Riviere et al., 1985) and FVB or NZB mice (Clone 13 strain, BSL-2/BSL-2+) (Baccala et al., 2014; Schnell et al., 2012), serving as surrogate models for LF and other types of arenaviral HF. The FVB mouse model demonstrates dramatic hemorrhagic disease manifestations including petechia and tissue hemorrhage more commonly seen with New World arenaviral HF, as opposed to LF (Schnell et al., 2012). Vascular leak, a car-

392


344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363

365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390

393 394 395 396 397 398 399 400 401 402 403 404 405

AVR 3524


17 October 2014 6 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437


dinal feature of VHF, and thrombocytopenia are observed with LCMV infection in NZB mice (Baccala et al., 2014). Several New World arenaviruses, including Pichindé virus (PICV) and Tacaribe virus (TCRV), can be worked with in BSL-2 containment, and have been useful surrogate viruses for antiviral efficacy studies (Gowen and Bray, 2011). PICV infection in both hamsters and guinea pigs with wild-type or adapted viruses, respectively, produces uniformly lethal disease with very low challenge doses. The hamster model has many similarities with AHF, in that diffuse systemic infection triggers proinflammatory cytokines, coagulation abnormalities, and vascular leak just prior to death (Gowen et al., 2010a). Hemorrhagic manifestations in the form of petechia are evident in nearly all PICV-infected hamsters as they become moribund, and bleeding from nasal and oral mucosa is commonly observed. In contrast, guinea pigs do not show clear signs of hemorrhage and vascular leak, but they develop thrombocytopenia and delayed clotting times (Mendenhall et al., 2011). The other arenavirus amenable to BSL-2 containment is TCRV (Gowen et al., 2010b), which can productively infect AG129 mice, culminating in a profound cytokine response, measurable vascular leak, and death (Sefing et al., in press). Thus, both the hamster PICV and TCRV mouse models could be used to evaluate compounds that can mitigate the deleterious vascular leak that likely leads to terminal shock. Two other clade A arenavirus models have been described. Pirital virus (PIRV) produces a lethal infection in hamsters similar to PICV and has been employed for antiviral efficacy testing (Vela et al., 2010). Flexal virus (FLEV) is less pathogenic in hamsters, but can still result in up to 80% lethality (Carlton et al., 2012). Because these models require BSL-3 containment and appear to be less pathogenic in hamsters than PICV, based on the requirement for higher challenge doses, they are considered to be less attractive surrogate models for arenavirus preclinical drug development.

438

3. Bunyavirus HF animal models

439

3.1. Rift Valley fever (RVF)

440

Rift Valley fever virus (genus Phlebovirus) has caused severe epidemics and epizootics throughout Africa and the Arabian peninsula

441

(Fig. 2) (Bird et al., 2009; Meegan and Bailey, 1989). Severe outbreaks have involved tens of thousands of human and livestock cases. Human infections result from the bite of infected mosquitoes or contact with tissues, blood, or fluids from infected animals. After an incubation period of 2–6 days, an abrupt onset of fever, chills, and general malaise ensues. Human disease is usually mild, and recovery occurs without major consequences. About 1–2% of infected individuals develop severe illness, characterized by acute liver disease, delayed-onset encephalitis, retinitis, blindness, or a hemorrhagic syndrome, with a case fatality ratio of 10–20% in hospitalized individuals (Laughlin et al., 1979; Madani et al., 2003; McIntosh et al., 1980).

442

3.1.1. RVF rodent models Several rodent models are available for the evaluation of RVFV infection (Table 3), which has been reviewed in greater detail (Ross et al., 2012). Mice, rats, hamsters, and gerbils have been described as rodent models (Anderson et al., 1991; Anderson et al., 1987, 1988; Gray et al., 2012; Kende et al., 1985; Niklasson et al., 1984; Peters et al., 1986; Peters and Slone, 1982; Smith et al., 2010). Mice are highly susceptible to infection with RVFV by multiple exposure routes. However, different genetic strains of mice have exhibited differences in their susceptibility to RVFV. Infection of BALB/c mice with RVFV strain ZH501 SC or by aerosol resulted in high-titer viremia and demonstrated viral tropism for a variety of tissue and individual cell types on the basis of histopathology, immunohistochemistry, and electron microscopy (Reed et al., 2013, 2012; Smith et al., 2010). For mice exposed by aerosol and SC, a major consequence of infection was overwhelming infection of hepatocytes that subsequently underwent apoptosis. Most BALB/c mice succumbed to RVFV between days 3 and 6 PI which was attributed primarily to severe hepatitis as indicated by the overwhelming infection of hepatocytes and increase in high levels of hepatic enzymes in the blood. The remaining mice were able to effectively clear virus from the liver and blood, but exhibited neuroinvasion and developed lethal panencephalitis. However, the development of neuropathology occurred much earlier and was more severe in mice exposed by aerosol compared to SC exposed mice (Reed et al., 2013).

454

Fig. 2. The geographic distribution of bunyaviral hemorrhagic fevers.


443 444 445 446 447 448 449 450 451 452 453

455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479

AVR 3524


17 October 2014 7

D.R. Smith et al. / Antiviral Research xxx (2014) xxx–xxx Table 3 Principal rodent models for the study of bunyaviral hemorrhagic fevers. Virus

Biocontainment

Genus

Disease modeled

Species

Selected references

Rift Valley

BSL-3+

Phlebovirus

Rift Valley fever

Mouse

Gray et al. (2012), Kende et al. (1985), Peters et al. (1986), Reed et al. (2013), Smith et al. (2010) Anderson et al. (1987, 1991), Bales et al. (2012), Peters and Slone (1982) Niklasson et al. (1984), Peters et al. (1986) Anderson et al. (1988) Anderson et al. (1990), Fisher et al. (2003), Gowen et al. (2006, 2007), Perrone et al. (2007) Tignor and Hanham (1993) Bente et al. (2010), Bereczky et al. (2010), Zivcec et al. (2013) Dowall et al. (2012)

Rat

*

480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511

Punto Toro

BSL-2

Phlebovirus

Rift Valley fever

Crimean-Congo hemorrhagic fever

BSL-4

Nairovirus

Crimean-Congo hemorrhagic fever

Hazara

BSL-2

Nairovirus

Hantaan

BSL-3

Hantavirus

Crimean-Congo hemorrhagic fever Hemorrhagic fever with renal syndrome

Puumala

BSL-3

Hantavirus

Seoul

BSL-3

Hantavirus

Dobrava

BSL-3

Hantavirus

Andes

BSL-4

Hantavirus *

Maporal

BSL-4

Sin Nombre

BSL-4

Hantavirus

Severe fever with thrombocytopenia syndrome

BSL-3

Phlebovirus

Hantavirus

Hemorrhagic fever with renal syndrome Hemorrhagic fever with renal syndrome Hemorrhagic fever with renal syndrome Hantavirus pulmonary syndrome Hantavirus pulmonary syndrome Hantavirus pulmonary syndrome Severe fever with thrombocytopenia syndrome

Hamster Gerbil Hamster Mouse (newborn) Mouse (immunodeficient) Mouse (immunodeficient) Mouse (suckling) Hamster

Hamster

Huggins et al. (1986), McKee et al. (1985a) Hooper et al. (2001), Kamrud et al. (1999), Schmaljohn et al. (1990) Hooper et al. (2001), Kamrud et al. (1999), Sanada et al. (2011), Schmaljohn et al. (1990) Hooper et al. (1999, 2001), Kamrud et al. (1999)

Hamster

Hooper et al. (2001)

Hamster Hamster

Campen et al. (2006), Hooper et al. (2001), WahlJensen et al. (2007) Milazzo et al. (2002)

Hamster

Brocato et al. (2014), Safronetz et al. (2013b)

Mouse (Immunocompetent) Mouse (suckling) Mouse (immunodeficient)

Jin et al. (2012)

Hamster

Chen et al. (2012) Liu et al. (2014)

Previously worked with in BSL-3, but due to biosafety concerns the current recommendation is BSL-4.

Infection of C57BL/6 mice with RVFV strain ZH501 SC results in a similar disease course compared to BALB/c mice except they all succumb by day 4 PI from acute-onset hepatitis with little evidence of pathology in the brain indicating meningoencephalitis (Gray et al., 2012). An analysis of the immune response to RVFV in C57BL/6 mice indicates that the pathogenicity is driven by an unregulated host pro-inflammatory response which results in a significant loss of liver function and the development of neurologic disease (Gray et al., 2012). Another study in C57BL/6 mice infected with RVFV strain ZH548 found that the route of virus inoculation and the presences of Aedes mosquito saliva can potentially affect pathogenicity (Le Coupanec et al., 2013). In contrast to inbred laboratory mouse strains, the wild-derived Mus m. musculus MBT/Pas mice succumbed from RVFV infection several days earlier and developed higher viremias, which was demonstrated to result from the absence of a complete innate immune response (do Valle et al., 2010). Infection of various inbred rat strains with RVFV strain ZH501 also results in different disease manifestations. Wistar-Furth (WF) rats were found to develop severe hepatic disease when inoculated SC whereas August-Copenhagen-Irish (ACI) rats developed encephalitis (Anderson et al., 1987; Bird et al., 2007; Bucci et al., 1981; Peters and Anderson, 1981; Peters and Slone, 1982). In contrast, when Lewis rats were infected SC, little or no mortality was observed, even though the rats became viremic (Anderson et al., 1987; Peters and Slone, 1982). A recent study by Bales et al. assessed the susceptibility of these different inbred rat strains to aerosolized virus and determined that Wistar-Furth and ACI rats developed a similar disease course and outcome when exposed SC and by aerosol. In contrast, they report that Lewis rats developed fatal encephalitis after aerosol infection, but only mild disease following SC exposure (Bales et al., 2012). The breeding

history and supplier of the various rat strains has been shown to affect the resistance or susceptibility to RVFV infection (Ritter et al., 2000), which further complicates the noted differences in disease outcome of inbred rat strains. Other rodent models utilized less frequently in RVFV research include hamsters (Niklasson et al., 1984; Peters et al., 1986) and gerbils (Anderson et al., 1988). Syrian hamsters are more susceptible than BALB/c or C57BL/6 mice and succumb from acute-onset hepatitis within days following SC or IP exposure. The hamster model has relied mainly on experimental infection with the related bunyavirus Punta Toro virus where hepatitis, but not encephalitis is the dominant pathologic feature (Anderson et al., 1990; Fisher et al., 2003). Gerbils infected with RVFV reportedly develop uniformly fatal encephalitis in the absence of significant extraneural lesions (Anderson et al., 1988).

512

3.1.2. RVF NHP models In contrast to most rodent models, infection of NHPs with RVFV does not produce a uniformly fatal disease (Table 4); reviewed more extensively by (Ross et al., 2012). Rhesus macaques historically have been used to evaluate potential vaccines and therapeutics (Peters and Linthicum, 1994). For this model, the rhesus monkeys were usually infected IV, and can be divided into three groups based on the disease course observed with larger cohorts of animals (usually 15–20 monkeys):

527

fatally infected monkeys that developed severe clinical disease and succumbed (18%); clinically ill monkeys that survived (41%); and monkeys that developed very mild or no apparent clinical illness and survived (41%).

536


513 514 515 516 517 518 519 520 521 522 523 524 525 526

528 529 530 531 532 533 534 535

537 538 539 540

AVR 3524


17 October 2014 8


Table 4 Principal NHP models for the study of bunyaviral hemorrhagic fevers. Virus

Biocontainment

Genus

Disease modeled

Species

Selected references

Rift Valley

BSL-3+

Phlebovirus

Rift Valley fever

Rhesus macaque

Hemorrhagic fever with renal syndrome Hantavirus pulmonary syndrome Hantavirus pulmonary syndrome

Marmoset African green monkey Cynomolgus macaque Cynomolgus macaque Rhesus macaque

Hartman et al. (2014), Morrill et al. (1989), Peters et al. (1986, 1988) Hartman et al. (2014), Smith et al. (2012) Hartman et al. (2014) Groen et al. (1995), Klingstrom et al. (2002) McElroy et al. (2002) Safronetz et al. (2014)

Puumala Andes Sin Nombre

BSL-3 BSL-4 BSL-4

Hantavirus Hantavirus Hantavirus

541

570

All of the monkeys develop viremia and have an increase in liver enzymes. Severe disease was accompanied by extensive liver necrosis, evidence of disseminated intravascular coagulation (DIC), and microangiopathic hemolytic anemia (Cosgriff et al., 1989; Morrill et al., 1990; Peters et al., 1988, 1989). More recently, a new model for RVF was described using the common marmoset, which overcomes some of the major limitations of other NHP models. Marmosets were more susceptible to RVFV than rhesus macaques and experienced higher rates of morbidity, mortality, and viremia and marked aberrations in hematological and chemistry values. Depending on the route of exposure, these animals exhibited acute-onset hepatitis, delayedonset encephalitis, and hemorrhagic disease, which are dominant features of severe human RVF (Smith et al., 2012). A recent study described the susceptibility of rhesus macaques, cynomolgus macaques, African green monkeys, and marmosets exposed to RVFV by aerosol (Hartman et al., 2014). Cynomolgus and rhesus macaques developed mild fevers, but no other clinical signs were observed and all the monkeys survived. In contrast, African green monkeys and marmosets were highly susceptible to aerosol infection, and the majority developed fatal encephalitis (Hartman et al., 2014). Collectively, these results indicate the utility of rodent and NHP models of RVF to evaluate potential medical countermeasures because of their ability to mimic different features of severe human disease. However, genetic determinants appear to play an important role in disease outcome as well as the route of virus exposure, which should be taken into account when evaluating vaccines and therapeutics.

571

3.2. Crimean-Congo HF (CCHF)

572

CCHF virus (CCHFV; genus Nairovirus) is thought to be primarily maintained in ticks of the Hyalomma genus of the Ixodidae family with a wide distribution spanning western, central, and southern Africa, the Balkans, the Middle East, southern Russia, and western Asia (Fig. 2) (Ergonul, 2006; Vorou et al., 2007; Whitehouse, 2004). Humans can become infected through tick bites, by contact with a patient during the acute phase of infection, or through exposure to the blood or tissues of viremic livestock (Hoogstraal, 1979; Watts et al., 1988). Human infection with CCHFV is characterized by 4 distinct phases designated the incubation, prehemorrhagic, hemorrhagic, and convalescence. The incubation phase generally lasts 1– 7 days, but can extend longer. The prehemorrhagic phase can last 3–7 days and is characterized by fever, fatigue, cephalagia, dizziness, photophobia, myalgia and in some cases nausea, vomiting, and diarrhea. Severe CCHF progresses to the hemorrhagic phase, which can last 2–3 days and is characterized by petechiae, ecchymosis, epistaxis and hemorrhage. During the hemorrhagic phase the case-fatality rate is approximately 30% (although this can vary by geographical locations) where the main causes of death include severe liver necrosis, shock, and subsequent multiorgan failure (Burt et al., 1997). Predictors of fatal outcome include high viral loads, increased liver enzymes, thrombocytopenia, increased clotting times and

542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569

573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594

cytokines/chemokines (Cevik et al., 2008; Duh et al., 2007; Onguru et al., 2010; Papa et al., 2006, 2007; Saksida et al., 2010; Weber and Mirazimi, 2008; Wolfel et al., 2007; Yesilyurt et al., 2011; Yilmaz et al., 2010). The convalescent phase begins 10– 20 days after onset of symptoms and may be characterized by tachycardia, polyneuritis, breathing impairment, loss of hearing, memory, or vision. The pathogenesis of CCHF remains poorly understood because of limited human pathology data, the need for BSL-4 containment facilities to handle CCHFV, and the lack of an immunocompetent animal model that recapitulates human disease.

595

3.2.1. CCHF rodent models No immunocompetent mammals other than humans are known to develop disease (Table 3). Adult mice, rats, guinea pigs, hamsters, rabbits, sheep, calves, donkeys, NHPs, and other adult animals develop low to undetectable viremia and clear the infection with no signs of illness (Fagbami et al., 1975; Shepherd et al., 1989; Smirnova, 1979). A suckling mouse model has been described in which high viral titers were demonstrated in the blood and liver, with Kupffer cells staining for viral antigen (Tignor and Hanham, 1993). However, virus could not be isolated from the spleen and overall the model does not portray human CCHF. Recently, adult mice with gene knockouts of the signal transducer and activator of transcription 1 (STAT1/) or the interferon a/b receptor (IFNAR/) have been described as lethal CCHF models (Bente et al., 2010; Bereczky et al., 2010). Infection of STAT-1 KO mice was characterized by fever, leukopenia, thrombocytopenia, elevated liver enzymes and proinflammatory cytokine levels, and death within 3 to 5 days. Extensive viral replication in the liver and spleen was associated with necrosis in the liver and lymphocyte depletion in the spleen. However, interstitial pneumonia and intestinal hemorrhage, which are found in lethal human infections, was not apparent (Bente et al., 2010). Infection of IFNAR/ mice resulted in high viral replication in the liver and spleen and death within 2–4 days (Bereczky et al., 2010). A recent study evaluated the sensitivity of IFNAR/ mice and age-matched wild-type mice to multiple exposure routes to CCHFV and analyzed the pathologic, virologic, hematologic, biochemical, and immunologic parameters associated with infection (Zivcec et al., 2013). Wild-type mice cleared CCHFV without developing any sign of disease whereas IFNAR/ mice were susceptible to multiple exposure routes and developed an acute fulminant disease characterized by high viral loads leading to pathology in the liver and lymphoid tissues. Viral replication was detected in antigen-presenting and immune cells, which secreted high levels of chemoattractant and proinflammatory molecules. Severe thrombocytopenia and coagulopathy was also observed in these mice (Zivcec et al., 2013). Therefore, this model mimics the manifestations of severe human CCHF disease (see Table 5). A potential surrogate model for testing antivirals has been described utilizing the closely related Hazara virus, which can be handled at BSL-2. Infection of type I IFN receptor KO mice leads to a lethal disseminated infection with histopathological changes

606


596 597 598 599 600 601 602 603 604 605

607 608 609 610 611 612 613 614 615 616 617 618 619

620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648

AVR 3524


17 October 2014 9

D.R. Smith et al. / Antiviral Research xxx (2014) xxx–xxx Table 5 Principal rodent models for the study of filoviral hemorrhagic fever. Virus

a

Biocontainment

Disease modeled

Species

Ebola

BSL-4

Ebola hemorrhagic fever

Marburg

BSL-4

Marburg hemorrhagic fever

Selected references

a

Mouse Immunodeficient mice Guinea piga Hamster Mousea Immunodeficient mice Guinea piga Hamster

Bray et al. (1999), Gibb et al. (2001) Bray (2001), Raymond et al. (2011) Connolly et al. (1999), Ryabchikova et al. (1999) Lofts et al. (2007), Warfield et al. (2009) Warfield et al. (2007) Hevey et al. (1998), Lofts et al. (2007)

Virus adapted to produce lethal disease.

Table 6 Principal NHP models for the study of filoviral hemorrhagic fever. Virus

Biocontainment

Disease modeled

Species

Selected references

Ebola

BSL-4

Ebola hemorrhagic fever

Rhesus macaque

Bowen et al. (1978), Bukreyev et al. (2007), Feldmann et al. (2007), FisherHoch et al. (1983, 1985), Geisbert et al. (2003a), Oswald et al. (2007), Warfield et al. (2006) Geisbert et al. (2002, 2003b,d), Jahrling et al. (1996a,b), Jones et al. (2005), Reed et al. (2004), Sullivan et al. (2000) Daddario-DiCaprio et al. (2006b) Daddario-DiCaprio et al. (2006a), Hensley et al. (2011a), Hevey et al. (1998), Jones et al. (2005) Carrion et al. (2011)

Cynomolgus macaque Marburg

BSL-4

Marburg hemorrhagic fever

Rhesus macaque Cynomolgus macaque Marmoset

Table 7 Principal rodent models for the study of flaviviral hemorrhagic fever. Arthropod vector

Virus

Disease modeled

Species

Selected references

Mosquito-borne

Dengue

Neurological

Mouse

Dengue hemorrhagic fever

Mouse Mouse

Yellow fever

Yellow fever

Alkhurma hemorrhagic fever Kyasanur forest disease Omsk hemorrhagic fever

Alkhurma hemorrhagic fever Kyasanur forest disease Omsk hemorrhagic fever

Mouse Hamster No available model Mouse Mouse

An et al. (2004), Blaney et al. (2002), Lin et al. (1998), Shresta et al. (2004) Bente et al. (2005) Grant et al. (2011) Shresta et al. (2006), Tan et al. (2010), Zellweger et al. (2010) Meier et al. (2009) McArthur et al. (2003), Tesh et al. (2001)

Tick-borne

649 650 651 652 653 654 655 656 657

similar to what is described above (Dowall et al., 2012). Therefore, this model could potentially be used for initial evaluations of medical countermeasures; however, this virus has not been reported to cause human disease and may not accurately predict drug or vaccine efficacy for humans. There are obvious limitations for using mouse models with defective IFN responses, but currently these models represent the most appropriate animal disease model of CCHF which can be used for pathogenesis studies and evaluating medical countermeasures.

665

3.2.2. CCHFV infection of NHPs Efforts to develop a NHP model of CCHF that mimics human disease have been unsuccessful thus far. However, studies of CCHFV infection of African green monkeys, baboons, and patas monkeys have been reported (Butenko et al., 1968; Fagbami et al., 1975; Smirnova, 1979). The development of a NHP model that recapitulates human disease would significantly benefit development efforts for medical countermeasures to CCHF.

666

3.3. Hantaviral HF

667

The hantaviruses (family Bunyaviridae, genus Hantavirus) are a large group of viruses that are primarily maintained in specific rodent hosts that dictate their geographic range. At least 23 unique species of hantaviruses are currently recognized by the ICTV and at least half are of medical importance to humans (ICTV, 2013). Han-

658 659 660 661 662 663 664

668 669 670 671

Bhatt et al. (1966), Work and Trapido (1957) Holbrook et al. (2005), Tigabu et al, (2009)

taviruses can cause severe disease in humans that is associated with two clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) with fatality rates as high as 15% and in excess of 40%, respectively (Jonsson et al., 2010). HFRS occurs primarily in Eurasia (Fig. 2) and is generally caused by the Old World hantaviruses Hantaan (HTNV), Seoul (SEOV), Dobrava (DOBV), and Puumala (PUUV) viruses. HPS is confined to the Americas and is most frequently caused by infection with the New World hantaviruses Andes (ANDV) and Sin Nombre (SNV) viruses (Wahl-Jensen et al., 2007) (see Table 6). HFRS mainly affects the kidneys and HPS affects the lungs, while both syndromes are associated with vascular leakage. Although hemorrhage is not seen in HPS, respiratory failure resulting from vas2ular leakage is a prominent feature of the disease (Peters et al., 1999), and therefore, a brief description of animal models of HPS warrants inclusion in this review. Transmission of hantaviruses to humans occurs primarily by inhalation or ingestion of contaminated rodent excreta. Direct transmission through rodent bites and human-to-human transmission have also been documented to occur (Martinez et al., 2005; Padula et al., 1998; St Jeor, 2004; Torres-Perez et al., 2010). Currently, there are no FDA approved medical countermeasures for HFRS and HPS. Therefore, efforts to develop vaccines and antivirals to treat or prevent these diseases are an important area of research (see Table 7).


672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697

AVR 3524


17 October 2014 10


Table 8 Principal NHP models for the study of flaviviral hemorrhagic fevers. Arthropod vector

Virus

Disease modeled

Species

Selected references

Mosquito-borne

Dengue Yellow fever Alkhurma hemorrhagic fever Kyasanur forest disease

Dengue hemorrhagic fever Yellow fever Alkhurma hemorrhagic fever Kyasanur forest disease

Rhesus macaque Rhesus macaque No available model Bonnet macaque

Onlamoon et al. (2010) Monath et al. (1981)

Tick-borne

698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739

740 741 742 743 744 745 746 747 748 749 750 751 752 753

3.3.1. Hantaviral HF rodent models Currently, there is no rodent model that faithfully reproduces human HFRS disease (Table 3). Several small animal models have been described for Old World hantaviruses using mainly suckling mice or natural rodent hosts (reviewed in (Safronetz et al., 2012)). Infection of suckling, juvenile and adult mice with certain strains of HTNV and by certain routes of infection results in lethal disease. However, the primary disease manifestations are neurological or pulmonary, which differs from HFRS in humans (Ebihara et al., 2000; Kurata et al., 1983; McKee et al., 1985a; Seto et al., 2012; Tamura et al., 1989; Wichmann et al., 2002). Despite this limitation, these lethal models have provided a means to evaluate potential antivirals for HFRS (Huggins et al., 1986; Murphy et al., 2001). Syrian hamster models have been described for HTNV, PUUV, SEOV and DOBV, which have been useful for evaluating vaccine candidates (Hooper et al., 1999, 2001; Kamrud et al., 1999; Safronetz et al., 2012; Sanada et al., 2011; Schmaljohn et al., 1990). Development of animal models for HPS (Table 2) is more limited due to the need for high containment facilities for experimental infections with the New World hantaviruses (reviewed in (Safronetz et al., 2012)). Syrian hamsters appear to provide the best small animal HPS model to date. Infection of hamsters with ANDV results in a uniformly fatal disease in which the animals develop pulmonary dysfunction similar to what is described for the human disease (Hooper et al., 2001; Safronetz et al., 2011). When hamsters are infected with Maporal virus (MPRLV) it is reportedly less lethal (Milazzo et al., 2002). Hamsters are susceptible to infection with other New World hantaviruses (SNV and Choclo virus), but show no signs of illness (Eyzaguirre et al., 2008; Hooper et al., 2001; Wahl-Jensen et al., 2007). Safronetz et al. repeatedly passaged SNV in hamsters in an effort to create a lethal disease model. This model demonstrated increased dissemination of the virus, but no signs of disease were observed and no animals succumbed from infection (Safronetz et al., 2013b). Brocato et al. recently described a lethal SNV disease model in immunosuppressed Syrian hamsters (Brocato et al., 2014). Infection with SNV resulted in a mean time to death of 13 days, and the animals displayed clinical signs associated with HPS, including pulmonary edema (Brocato et al., 2014). This newly described lethal model will assist efforts to evaluate candidate Q4 medical countermeasures (see Table 8). 3.3.2. Hantaviral HF NHP models Infection of NHPs with Old World hantaviruses does not provide a good model for HFRS (Yanagihara et al., 1988). Although a nonlethal cynomolgus macaque PUUV infection model has been described, it does not reproduce human disease (Groen et al., 1995). Infection of cynomolgus macaques with PUUV leads to a mild disease suggestive of acute nephropathy, which currently provides the most realistic NHP model (Klingstrom et al., 2002; Sironen et al., 2008). Cynomolgus macaques are susceptible to infection with ANDV, but no signs of illness were observed (McElroy et al., 2002). Recently, a novel NHP model of HPS in rhesus macaques was described (Safronetz et al., 2014). Following infection with SNV propagated in deer mice, the animals developed HPS characterized

Kenyon et al. (1992), Webb and Chaterjea (1962), Webb and Rao (1961)

by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. This newly described NHP model will contribute to a greater understanding of the pathogenesis of HPS and the evaluation of medical countermeasures to treat hantaviral diseases.

754

3.4. Severe fever with thrombocytopenia syndrome (SFTS)

759

SFTS virus (SFTSV) is a newly identified Phlebovirus in the family Bunyaviridae that has caused severe disease in humans in China (Yu et al., 2011). Signs and symptoms of SFTS include high fever, gastrointestinal symptoms, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. Neural symptoms, hemorrhages, DIC, and multiorgan failure have been reported in severe human cases (Gai et al., 2012). However, little is known about the pathology of SFTSV infection because autopsies have not been performed on hfatal cases. The host range of SFTSV has yet to be determined, but Haemophysalis longicornis ticks have been described as potential vectors (Yu et al., 2011, 2012) and a high seroprevalence reported in goats (Zhao et al., 2012). A recent study suggests that SFTSV has a wide host range and natural infections occur in several domesticated animal hosts in endemic areas (Niu et al., 2013). SFTSV antibodies and RNA were detected in sheep, cattle, dogs, pigs, and chickens. While RNA was frequently detected in these animals, infectious virus was only isolated from a single sheep, cow and dog during the study (Niu et al., 2013).

760

3.4.1. SFTS rodent models Adult immunocompetent rodents do not appear to be highly susceptible to SFTSV (Chen et al., 2012; Jin et al., 2012; Liu et al., 2014). C57BL/6 and BALB/c mice, Wistar rats, and Syrian hamsters infected by multiple routes did not develop disease or succumb to infection (Chen et al., 2012; Jin et al., 2012). However, a reduction in white blood cells and platelets was observed in C57BL/6 mice suggesting that this model resembles human SFTS disease (Jin et al., 2012). In contrast to adult rodents, newborn Kunming mice and rats were highly susceptible to intracranial infection with SFTSV (Chen et al., 2012). In an effort to create a more realistic lethal model to test medical countermeasures, Liu et al. recently described a mouse model utilizing IFNAR/ mice, which were highly susceptible to subcutaneous infection. All mice succumbed within 3–4 days postinfection. Virus was detected in all tissues except for the lungs; the major target cells appeared to be reticular cells in the lymphoid tissues of the intestine and spleen (Liu et al., 2014). Future work should aim at further characterizing this mouse model to better understand the pathogenesis of this emerging disease.

779

3.4.2. SFTS NHP models No NHP models of SFTS have been described.

799

4. Filoviral HF animal models

801

Ebola hemorrhagic fever (EHF) and Marburg hemorrhagic fever (MHF) are caused by viruses of the genera Ebolavirus (EBOV) and Marburgvirus (MARV), respectively, of the family Filoviridae

802


755 756 757 758

761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778

780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798

800

803 804

AVR 3524



11

Fig. 3. The geographic distribution of filoviral hemorrhagic fevers.

805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840

(Sanchez et al., 2007). These zoonotic viruses are highly pathogenic and have been associated with devastating outbreaks causing case fatality ranging from 25–90% (Feldmann and Geisbert, 2011). Currently, the largest outbreak of EBOV ever recorded is ongoing in West Africa and the number of confirmed cases and deaths continue to rise (Nunes-Alves, 2014). Fruit bats are most likely the reservoir of EBOV and MARV, and the geographical distribution of both viruses appear to be limited to sub-Saharan Africa (Fig. 3) (Leroy et al., 2005; Pourrut et al., 2007; Towner et al., 2007, 2009). However, Reston ebolavirus (REBOV) was identified in the Philippines by positive serology in pig farmers, but was not associated with causing human disease (Barrette et al., 2009; Taniguchi et al., 2011). Outbreaks of EHF and MHF are usually the result of person-to-person transmission that occurs through direct contact with bodily fluids or contaminated clothes or bedding of an infected person (Baron et al., 1983; Bausch et al., 2007; Dowell et al., 1999; Francesconi et al., 2003; Roels et al., 1999). The incubation period for EBOV and MARV infection in humans range from 3–13 days with death occurring during the second week of illness with a median survival of 9 days after the onset of symptoms (Kortepeter et al., 2011). Signs and symptoms include fever, chills, headache, malaise, and myalgia generally occurring within 4 days following infection (1978; Bente et al., 2009; Q5 Bwaka et al., 1999). Respiratory and gastrointestinal symptoms have been reported, along with vascular abnormalities to include conjunctival infection, hypotension, and edema (Centers for Disease Control, 2001, 2005; Formenty et al., 1999). Hemorrhagic manifestations include petechiae on the torso and arms, ecchymoses, bleeding from venipuncture sites and mucous membranes, gingival bleeding, epistaxis, and visceral hemorrhaging (Bente et al., 2009). Currently, there are no FDA-approved vaccines or therapeutics to prevent or treat EBOV or MARV infections and only supportive care or experimental therapeutics are available. Efforts to develop effective vaccines and therapeutics using animal infection models (Table 3) are therefore an active area of research.

841

4.1. Ebola HF (EHF) rodent models

842

Mice and guinea pigs are generally used as rodent models of EHF, but they do not succumb to infection with wild-type virus

843

unless it has been adapted to virulence for these species, or immunodeficient animals are used (Bray et al., 1999; Connolly et al., 1999). Mouse models of EHF have been extensively reviewed (Bradfute et al., 2012). Mice are generally used as the initial models for evaluating potential vaccines and therapeutics and do mimic some of the predominant EHF disease features. Mice develop viremia and high viral titers in multiple tissues to include the spleen and liver. Liver damage results in high levels of liver enzymes being detected in the serum. An early inflammatory cytokine response is apparent along with lymphopenia, thrombocytopenia, and neutropenia (Bradfute et al., 2012). One limitation of the mouse model is that the animals do not develop DIC, fibrin deposits, or petechiae, but some coagulation abnormalities are apparent. Guinea pigs offer an additional model for preliminary evaluation of vaccines and therapeutics for EHF. Connolly et al. developed a lethal guinea pig adapted strain that produced disease manifestations similar to those reported in experimentally infected NHPs and human cases (Connolly et al., 1999). Fever and coagulation defects, including a drop in platelet counts and an increase in coagulation time, are apparent, but fibrin deposition and coagulopathy (DIC) are not as marked as that observed in NHPs (Connolly et al., 1999; Reed and Mohamadzadeh, 2007). Similar to mice, a maculopapular rash does not develop in these animals. Another important limitation of the guinea pig model is that bystander lymphocyte apoptosis, which is prevalent in primates and mice, has not been determined in this model. Because of the differences observed in the EHF rodent models, several therapeutics that are effective in mice and guinea pigs fail to protect NHPs challenged with wildQ6 type EBOV (Wahl-Jensen et al., 2012) (see Fig. 4). Recent work has focused on utilizing the Syrian hamster as an alternative to NHPs (Ebihara et al., 2013). Syrian hamsters challenged intraperitoneally or subcutaneously with wild-type EBOV do not develop prominent disease, whereas intraperitoneal infection with mouse-adapted EBOV causes severe coagulopathy, lymphocyte apoptosis, cytokine dysregulation, target organ necrosis and/or apoptosis (lymph node, spleen, liver), and a lethal outcome, suggesting that the Syrian hamster model more faithfully reproduces the features of the human and NHP disease. Therefore, this newly developed model may provide a beneficial alternative for testing medical countermeasures for EHF. The prominent disease features in mice, guinea pigs, hamsters and


844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884

AVR 3524


17 October 2014 12


Fig. 4. The geographic distribution of flaviviral hemorrhagic fevers. 885 886

887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915

NHPs were directly compared in a recent review (Wahl-Jensen et al., 2012). 4.1.1. EHF NHP models NHPs are the ‘‘gold standard’’ for evaluating vaccines and therapeutics for EHF (Shurtleff et al., 2011). Several species are susceptible to infection with EBOV (Fisher-Hoch et al., 1983; Perry et al., 2012; Ryabchikova et al., 1999), but rhesus and cynomolgus macaques have been used most frequently in research, as they reliably mimic human disease (Kortepeter et al., 2011). EBOV-infected NHPs develop a fever, macular rash, petechiae, leukocytosis, lymphopenia, thrombocytopenia, DIC, and a cytokine-associated systemic inflammatory response (Ebihara et al., 2011; Kortepeter et al., 2011). Macrophages and dendritic cells are primary targets of EBOV infection which leads to a rapid systemic viral dissemination, immunosuppression through antagonism of the type I interferon response and induction of lymphocyte apoptosis, infection of hepatocytes and other parenchymal cells, coagulation defects, and increased vascular permeability resulting in terminal shock (Baize et al., 1999; Bowen et al., 1978; Feldmann et al., 1996; Fisher-Hoch et al., 1985; Geisbert et al., 2003b,c,d). EBOV infection of NHPs has been intensively investigated, and the pathogenesis has recently been reviewed in detail (Paessler and Walker, 2013). A recent review (Shurtleff et al., 2012) points out that rhesus macaques have been used preferentially over cynomolgus macaques for evaluating small molecule therapeutics, because of the longer time-frame for rhesus monkeys to develop symptoms and succumb to disease (8 days for rhesus macaques and 6 days for cynomolgus macaques) (Geisbert et al., 2010; Warren et al., 2010; Bente et al., 2009). However, there has been no guidance from the FDA that rhesus macaques are the definitive species for evaluation of candidate therapeutics.

916

4.2. Marburg HF rodent models

917

Similar to EHF, rodent models of infection with wild-type MARV are not available unless the virus has first been adapted to virulence for that species (Table 3) (Lofts et al., 2007; Warfield et al., 2009). Some strains were adapted to severe, combined immunodeficient (SCID) mice by serial passaging to develop lethal models (Warfield et al., 2007). Lethal infection models were also developed

918 919 920 921 922

for guinea pigs (Lofts et al., 2007; Simpson et al., 1968) and hamsters (Simpson, 1969; Zlotnik, 1969) by serial passaging for adaptation to virulence for that species. The hamster is the only rodent model demonstrating neuropathogenicity (Zlotnik, 1969). Similar to EHF, a major limitation of MHF rodent models is that coagulation abnormalities, typical rash development, and hemorrhagic manifestations (particularly in mice) are not as pronounced as in NHPs (Bente et al., 2009; Brauburger et al., 2012; Warfield et al., 2009).

923

4.2.1. MHF NHP models Similar to EHF, NHPs represent the ‘‘gold standard’’ for evaluating vaccines and therapeutics for MHF (Brauburger et al., 2012; Shurtleff et al., 2011). Paessler and Walker recently reviewed the pathogenesis of MHF in detail (Paessler and Walker, 2013). Uniform lethality is observed in cynomolgus and rhesus macaques and African green monkeys (Alves et al., 2010; Fritz et al., 2008; Geisbert et al., 2007; Gonchar et al., 1991; Hensley et al., 2011a; Johnson et al., 1996; Lub et al., 1995; Simpson, 1969; Simpson et al., 1968). Following infection, the animals develop a febrile illness with a high fever, anorexia, weight loss and become lethargic. Death is observed 6–13 days post-infection and thrombocytopenia, lymphopenia, blood coagulation abnormalities and hemorrhages are observed. Other NHP models for MHF include squirrel monkeys (Simpson, 1969) and marmosets (Carrion et al., 2011). Both mimic the features of human MARV infections, except that in marmosets the typical maculopapular rash that is observed in old world NHP species and humans is not observed (Carrion et al., 2011). However, virus was isolated from the brains of infected marmosets, which also showed micro-hemorrhages (Carrion et al., 2011). This suggests that marmosets may provide a good model recapitulating the CNS involvement first described in the initial outbreak in Germany (Brauburger et al., 2012). The development of CNS pathology in other MHF models is unclear, because no brain pathology has been observed in mice (Warfield et al., 2007) or cynomolgus macaques (Alves et al., 2010).

931

5. Flaviviral HF animal models

958

Research on flaviviruses associated with development of HF has been severely limited by the lack of animal models that accurately

959


924 925 926 927 928 929 930

932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957

960

AVR 3524



971

recapitulate human disease. While there have been a number of advances in recent years, in most cases researchers have been required to either adapt a virus to the model system, utilize immunodeficient animals, or both. The use of modified systems raise significant concerns with the value of the research completed, particularly with immunodeficient animals, as it is not clear that measured viral pathogenesis and host immune responses can be translated back to the human condition. The use of rodent models is unreliable as mice do not realistically predict human disease. However, until the past few years there have been no small animal models for some types of flaviviral HF.

972

5.1. Mosquito-borne flaviviruses

973

5.1.1. Dengue HF (DHF) Human infection by dengue virus (DENV) can result in disease ranging from a febrile illness to severe hemorrhagic disease and death. DENV exists as four antigenically similar but distinct serotypes (DENV1–4), which allows for productive infection with viruses from each of the four serotypes due to a lack of cross-protective antibodies. Many primary DENV infections are asymptomatic or develop into dengue fever (DF) when they occur during childhood. However, in some cases, typically in the event of secondary dengue infections with a virus from a different serotype, infection can lead to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) (Kurane, 2007; Whitehorn and Simmons, 2011). Most cases of acute DF have some evidence of vascular leakage, but this is typically limited to a macular or maculopapular rash (i.e. petechiae) that resolves (Kurane, 2007; Whitehorn and Simmons, 2011). In severe cases, increased evidence of plasma leakage and hemorrhage occurs with the loss of vascular volume leading to development of shock and, potentially, death (Kurane, 2007; Whitehorn and Simmons, 2011). The specific mechanisms related to severe vascular leakage in DHF or DSS cases are not well understood, however there appears to be a significant immunological role in the development of vascular leakage and severe disease (Halstead, 2012, 2013; Whitehorn and Simmons, 2011). Currently, DENV research is severely hampered by limited availability of animal models that recapitulate human disease. The majority of the effort focused on understanding the mechanisms of viral pathogenesis following DENV infection uses either human samples or cell culture systems.

961 962 963 964 965 966 967 968 969 970

974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023

5.1.1.1. DHF rodent models. Historically, mice have been used in DENV research for the sole purpose of cultivating virus or evaluating the neuroinvasive properties of different strains. Peripheral challenge of most immunocompetent adult mouse strains with DENV does not result in overt disease. The development of a mouse model for DENV has been an area of significant progress over the past decade and has been reviewed in two recent papers (Plummer and Shresta, 2014; Zompi and Harris, 2012) . The first models for DENV infection utilized SCID mice xenografted with human HuH-7, HepG2 and K562 tumor cells. While the ability of an adult mouse to support productive DENV infection was exciting, these animals have limited utility in evaluating pathogenesis, as DENV infects primarily the engrafted cells before migrating to the brain (An et al., 2004; Blaney et al., 2002; Lin et al., 1998). Subsequent to development of the xenografted SCID mouse model, Shresta et al. utilized intravenous infection of A/J mice with DENV2 and found that neurologic disease occurred in about half of the animals (Shresta et al., 2004; Zompi and Harris, 2012). In each of these mouse models, the development of neurological infection is not representative of human disease and diminishes the enthusiasm for either of these models. A model using NOD-SCID mice xenografted with human CD34+ cells was introduced in 2005 (Bente et al., 2005). When these mice

13

were infected with DENV-2 virus, they developed a disease similar to DHF with evidence of thrombocytopenia, rash and fever (Bente et al., 2005). Unlike SCID mice, in which DENV specifically targets the xenografted cells, in the NOD-SCID mice DENV was found to infect cells in the bone marrow, spleen and liver. More recently, NOD-SCID IL2rc(null) (NSG) mice have been used to demonstrate that engrafted animals can develop B and T cell responses that could make the model useful for testing DEN vaccines (Jaiswal et al., 2012, 2009). Unfortunately, except for the xenografted human tissues, little else in the response to virus infection would fundamentally replicate a human response. In addition, while the NOD-SCID and NSG humanized mouse models appear to reflect human disease, the technical component of reliably generating humanized mice can be challenging and time-consuming. The NOD-SCID mouse model was followed closely by a type I/II interferon receptor (IFNAR)-deficient AG129 mouse model (Shresta et al., 2006; Zellweger et al., 2010). This model initially relied in part on the use of a mouse-adapted DENV2 strain, but it does develop severe disease, including vascular leak, similar to humans with DHF. More recently, the AG129 model has employed a virus that has not been adapted to mice (Grant et al., 2011; Tan et al., 2010). The AG129 mouse model has subsequently been used for a number of studies, including some evaluating potential therapeutic and vaccine interventions for DENV infection (Brewoo et al., 2012; Stein et al., 2011; Watanabe et al., 2012). The AG129 mouse model possibly represents the best small animal model for DENV infection at the current time. The small number of small animal models that accurately recapitulates human disease for evaluating DENV infection has limited progress toward understanding mechanisms of viral pathogenesis. However, as more models become available, perhaps our understanding of this disease will improve.

1024

5.1.1.2. DHF NHP models. While NHPs, including rhesus macaques, cynomolgus macaques and African green monkeys, are used routinely in dengue vaccine research, they do not generally represent a model of severe human disease. In primate vaccine studies, vaccine protection is evaluated by induction of neutralizing antibodies and/or viremia following challenge of vaccinated animals (Li et al., 2013; Osorio et al., 2011). NHPs are generally not considered a useful model for the evaluation of human disease, as healthy animals do not typically develop clear signs of disease or succumb to infection. However, recently Onlamoon et al. have used a very high dose (107 pfu) intravenous virus challenge to induce a disease similar to dengue fever as seen in humans (Onlamoon et al., 2010). In this model, animals developed thrombocytopenia, neutropenia, decreased hemoglobin, elevated D-dimers, petechiae and signs of severe coagulopathy. Unsurprisingly, the viral load in the plasma of these animals was high through 6 days postinfection, but subsequently waned in reverse correlation with an increase in DENVspecific antibody titers. While the development of this new model provides as excellent opportunity to more carefully evaluate pathogenesis, the large intravenous bolus of virus required to induce disease may limit the value of the model in vaccine and therapeutic trials, as one would need to carefully evaluate the impact of the large dose of virus/viral antigen on the efficacy of a vaccine or therapeutic.

1056

5.2. Yellow fever

1080

Yellow fever (YF) is caused by infection with the YF virus (YFV), which is endemic in tropical regions of South America and Africa, where it is thought to infect around 200,000 people per year with some 30,000 deaths (Markoff, 2013). The largest recent documented outbreak of YF occurred in the fall of 2012 in the Darfur

1081


1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055

1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079

1082 1083 1084 1085

AVR 3524


17 October 2014 14 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150


region of Sudan, where approximately 1000 cases and 250 deaths were documented (Markoff, 2013). Infection of humans with YFV can cause disease ranging from a nondescript febrile illness to severe hemorrhagic fever and death. The mechanisms determining severity of disease are unknown, but may be related to specific host susceptibility and immune response (Monath, 2012). YF can present with rapid onset of a high fever and headache which resolves in about 80% of people. The remaining 20% may suffer from a bi-phasic disease, in which the first period of infection is characterized by viremia, high fever, myalgia, bradycardia, nausea and vomiting (Gardner and Ryman, 2010). The period of infection is followed by a 1–2 day period of remission and then the period of intoxication wherein fever, vomiting, nausea, jaundice, hemorrhage and renal failure can occur. The case fatality rate is about 20% with death occurring 6–8 days post-onset (Gardner and Ryman, 2010). Despite the isolation of YFV in 1927, very little is known about the pathogenicity of infection. In part, the lack of knowledge regarding YF is the result of a very effective live-attenuated vaccine (17D) that was first tested in humans in 1936 and provides potentially life-long immunity following a single inoculation (Monath, 2012). The 17D vaccine has significantly limited the spread of YFV, restricted the expansion of outbreaks and contributed to the prevention of YF in urban environments. Despite the success of the 17D vaccine, there are occurrences of vaccine-associated disease without a clearly defined etiology (Monath, 2012). A scientific challenge that has limited our understanding of YFV, and the host factors that may be associated with development of vaccine associated disease, has been the lack of viable small animal models that reliably recapitulate human disease. 5.2.1. YF rodent models The weanling mouse has long been used as a model to demonstrate YFV neurovirulence and neuroinvasiveness, as well as to cultivate virus. Until recently, the adult mouse has not proved to be a useful model for YFV infection, but in 2009 Meier et al. described the use of A129 and STAT129 mice as models wherein infection with wild-type YFV (Asibi and Angola73 strains) was lethal in adult animals following footpad challenge (Meier et al., 2009). Infection of these mouse strains with the vaccine strain 17D-204 did not result in disease, demonstrating selective pathogenicity, similar to what is seen in humans and NHPs. The identification of the A129/STAT129 model has provided an excellent new approach for evaluating therapeutic interventions for the treatment of YFV infection. The value of these models for elucidating mechanisms of YFV pathogenicity in humans remains to be determined, as both mouse strains are deficient in their IFN response which could lead to inappropriate interpretation of data and correlation with human disease. However, the evident restriction of 17D-204 infection in these models also clearly demonstrates a critical role for the IFN response following YFV infection. In the early 2000s a hamster model was developed by two groups as a legitimate model for evaluating YFV pathogenicity (McArthur et al., 2003; Sbrana et al., 2006b; Tesh et al., 2001; Xiao et al., 2001a). In both cases, the model required adaptation of a wild-type YFV strain by serial passage. The first described model was developed using the South American Jimenez strain (isolated from a fatal human case in Panama, 1974) and the second used the Asibi strain, which was isolated in Ghana (non-fatal human case, 1927). The Jimenez model was more completely described, but both adapted strains appear to cause similar disease in hamsters and both recapitulate human disease with reasonable fidelity. Infected hamsters developed hallmarks of YFV infection in humans, including microvesicular steatosis, apoptosis and hepatic necrosis (Tesh et al., 2001). Of note however, is that Councilman bodies, a hallmark of YFV infection in the liver of humans, were

not described in either model. The spleen exhibited lymphoid hyperplasia and evidence of necrosis. Additional analysis identified increased liver enzymes in the serum, increased coagulation times, thrombocytopenia, lymphopenia and vascular leak (Gowen et al., 2010a; McArthur et al., 2003; Sbrana et al., 2006b; Tesh et al., 2001; Xiao et al., 2001a). Immunohistochemical evaluation of viral dissemination identified viral antigen in the liver and spleen, but not in the kidneys (Xiao et al., 2001a). Since the initial description of the hamster model, it has been used for a number of studies evaluating therapeutic interventions for disease (Julander, 2013; Julander et al., 2009, 2010, 2011a,b).

1151

5.2.2. YF NHP model NHPs have been used as models for YF since the discovery of the virus, when rhesus macaques were used for virus isolation and histopathological studies (Hudson, 1928a,b,c; Klotz and Belt, 1930a; Klotz and Belt, 1930b,c; Stokes et al., 1928). Since that time, NHPs have largely been used for vaccine efficacy studies (Marchevsky et al., 2003; Mudd et al., 2010; Neves et al., 2009) or for demonstrating a lack of vaccine virulence during manufacture (Minor, 2011) and are considered the ‘‘gold standard’’ of YF animal models. Despite ecological evidence that howler monkeys are highly susceptible to YFV infection (Holzmann et al., 2010), rhesus macaques are the only species in which pathogenesis has been evaluated extensively in a research setting. Rhesus macaques generally develop a monophasic disease that resembles the toxic (terminal) phase of human disease (Monath et al., 1981). Infected animals develop fever, lethargy, diminished urine output, hypotension and coma, with death occurring approximately 5 days post-infection (Monath et al., 1981). Infected animals also become viremic beginning around 2 days postinfection, peaking at 4–5 days postinfection (Monath et al., 1981). Loss of liver function is evident close to death, as liver enzymes become elevated and coagulation times become extended. Histological evidence of liver disease is evident as necrosis of hepatocytes and Kupffer cells, and evidence of Councilman bodies and Torres bodies, similar to what is seen in humans (Monath et al., 1981).

1162

5.3. Tick-borne flaviviruses

1187

5.3.1. Kyasanur forest disease/Alkhurma hemorrhagic fever Kyasanur forest disease (KFD) and isolation of the causative agent, KFDV, were first described in the late 1950s (Work and Trapido, 1957). KFDV is found in a fairly localized region of southwestern India, where human cases occur annually and large outbreaks are identified with some regularity (Holbrook, 2012; Kasabi et al., 2013). KFDV is transmitted by ticks and has genetic and serological qualities that group the virus within the tick-borne encephalitis serocomplex of flaviviruses. There is serological evidence suggesting that KFDV might be more widespread than has been thought, but confirmed cases outside of the endemic region have not been documented. In the mid-1990s a virus serologically related to KFDV was isolated in the Jeddah region of Saudi Arabia, following the occurrence of several cases of hemorrhagic fever (Zaki, 1997). It was subsequently named Alkhurma hemorrhagic fever (AHF) virus (AHFV) and was shown to be closely related to KFDV genetically (Dodd et al., 2011). AHFV has been found in other areas of southwestern Saudi Arabia, and indirect evidence from exported cases suggests it may also be present in southern Egypt (Carletti et al., 2010). Human disease following infection with either KFDV or AHFV is similar, in that hemorrhagic symptoms can be apparent. Neither virus is typically associated with development of neurological disease although such disease can occur (Holbrook, 2012). The case fatality rate for KFD is estimated at 3–5% while AHF is up to 25%, a number that may be somewhat inflated due to incomplete surveillance.

1188


1152 1153 1154 1155 1156 1157 1158 1159 1160 1161

1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186

1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213

AVR 3524


17 October 2014 D.R. Smith et al. / Antiviral Research xxx (2014) xxx–xxx 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224

5.3.1.1. AHF and KFD rodent models. A rodent model for AHF has not yet been described, although it is expected that rodents infected with AHFV would have a disease process similar to those infected with KFDV. In the case of KFDV, suckling mice were used for the initial isolation of the virus and for development of reagents for diagnostic assays (Bhatt et al., 1966; Work and Trapido, 1957). Sub-adult mice have subsequently been used to test vaccine efficacy as these animals will become infected and succumb to the infection. However, these animals develop a neurological disease, rather than a hemorrhagic or visceral disease, which would more accurately reflect human disease.

1245

5.3.1.2. AHF and KFD NHP models. Shortly after the initial isolation of KFDV, rhesus macaques were used in challenge studies to determine if they were a possible model for human disease. Infected macaques became viremic and developed neutralizing antibodies, but did not demonstrate overt signs of illness (Work, 1958). Subsequent studies in red-faced bonnet macaques (Macaca radiata) found that these animals were quite susceptible to viral infection. Bonnet macaques that have been found dead in the forest within the endemic region of KFDV often herald the onset of human disease. Bonnet macaques infected with KFDV develop signs of disease similar to what is seen in humans including anemia, bradycardia, hypotension, leukopenia and lymphopenia (Kenyon et al., 1992; Webb and Chaterjea, 1962; Webb and Rao, 1961). Postmortem evaluation of the liver and kidneys has identified histological lesions similar to those in humans. M. radiata infected with KFDV may develop neurological disease, with evidence of encephalitis on postmortem examination in one study. While M. radiata may be an excellent model for evaluating KFDV (and possibly AHFV) pathogenesis, a 1978 ban on exportation of these animals from India has limited their availability for scientific research (Johnsen et al., 2012).

1246

5.4. Omsk hemorrhagic fever

1247

Omsk hemorrhagic fever (OHF) virus (OHFV) is found in a localized area of south-central Russia near the Siberian cities of Omsk and Novosibirsk. The isolation of OHFV in 1947 was the result of an investigation into an outbreak of severe disease, characterized by overt hemorrhage from the gastrointestinal tract and mucosa (Chumakov, 1948). OHFV infection of humans causes an acute febrile illness that can progress to severe disease (Ruzek et al., 2010). While OHFV is considered a very dangerous virus and is classified as a BSL-4 pathogen, there have been just over 1200 human cases identified with a relative disappearance of the virus over the past few decades (Ruzek et al., 2010). The principal hosts for OHFV are thought to be small mammals, particularly the water vole (Arvicola amphibius), although ticks may also be involved in maintenance of the virus. Muskrats also harbor OHFV and are thought to be the source of many human cases of OHF, when hunters slaughter the animals for their pelts (Kharitonova and Leonov, 1985; Ruzek et al., 2010).

1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244

1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275

5.4.1. OHF rodent models A number of rodent species have been shown to be susceptible to OHFV infection and develop disease ranging from asymptomatic infection to the fatal neurological disease seen in muskrats (Ruzek et al., 2010). The only established laboratory rodent model is the mouse, which develops a viscerotropic disease with few signs of neurological involvement after peripheral infection (Holbrook et al., 2005). OHFV can be found in the brains of infected mice, and it is possible that overt neurological disease would become apparent if the animals survived longer post challenge. Juvenile hamsters, guinea pigs and weaning or juvenile mice infected by intracerebral challenge will develop neurological disease and suc-

15

cumb to infection. There are no published reports of other rodent models.

1276

5.4.2. OHF NHP models A lethal NHP model has not been established for OHFV or other members of the tick-borne encephalitis serocomplex viruses other than KFDV. Recently, Pripuzova et al. completed infection studies in African green monkeys (Cercopithecus aethiops) and crab-eating macaques (Macaca fascicularis) which found that these animals did not develop overt signs of disease following subcutaneous challenge (Pripuzova et al., 2013). Infection of C. aethiops with OHFV resulted in a hemolytic syndrome represented by anemia, thrombocytopenic purpura and lymphocytopenia. These animals also had evidence of liver disease (increased ALT levels). The limited availability of animal models for KFD and OHF has significantly inhibited progress toward understanding their pathophysiology. Hopefully, over the next few years progress will be made toward identification of models for studying these diseases.

1278

6. Summary

1293

A better understanding of disease pathogenesis and development of effective medical countermeasures for the treatment of VHF is dependent on the accurate modeling of the infection in laboratory animals. Rodent models are essential for providing valuable preclinical information about candidate vaccines and therapeutics prior to advancing into the more costly and restrictive NHP models. Murine models are commonly used for VHF research, but often do not meet the FDA Animal Rule requirements because they do not reproduce important aspects of human disease or the virus must first be adapted to this species. Hamsters and guinea pigs have proven valuable for studying some HFVs, but research involving these species is hampered by the lack of available reagents. Because of these limitations, NHP animal models are generally the ‘‘gold standard’’ for evaluating potential medical countermeasures for several HFVs (Safronetz et al., 2013a) particularly in the advanced development stage leading towards licensure. Most importantly, the animal model used to assess the efficacy of candidate vaccines and therapeutics for HFVs must accurately portray human disease. Future efforts and guidance from the FDA should identify which animal models will successfully meet the Animal Rule requirements.

1294

7. Uncited references

1315

Ergonul et al. (2006), Kaya et al. (2011), Sbrana et al. (2006a), Tigabu et al. (2009), Warfield et al. (2006, 2009), Warren et al. Q7 (2010), World Health Organization (1978).

1316

Acknowledgements

1319

The authors would like to thank Jiro Wada for his illustration work. MRH is an employee of Battelle Memorial Institute under its prime contract with NIAID No. HHSN272200200016I. The information presented here is the responsibility of the authors and does not necessarily represent views or policies of the US Department of Health and Human Services or Battelle Memorial Institute.

1320

References

1326

Alves, D.A., Glynn, A.R., Steele, K.E., Lackemeyer, M.G., Garza, N.L., Buck, J.G., Mech, C., Reed, D.S., 2010. Aerosol exposure to the angola strain of Marburg virus causes lethal viral hemorrhagic fever in cynomolgus macaques. Vet. Pathol. 47, 831–851. An, J., Zhou, D.S., Zhang, J.L., Morida, H., Wang, J.L., Yasui, K., 2004. Dengue-specific CD8+ T cells have both protective and pathogenic roles in dengue virus infection. Immunol. Lett. 95, 167–174.


1277

1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292

1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314

1317 1318

1321 1322 1323 1324 1325

Q8

1327 1328 1329 1330 1331 1332 1333

AVR 3524


17 October 2014 16 1334 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402 1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419


Anderson Jr., G.W., Slone Jr., T.W., Peters, C.J., 1987. Pathogenesis of Rift Valley fever virus (RVFV) in inbred rats. Microb. Pathog. 2, 283–293. Anderson Jr., G.W., Slone Jr., T.W., Peters, C.J., 1988. The gerbil, Meriones unguiculatus, a model for Rift Valley fever viral encephalitis. Arch. Virol. 102, 187–196. Anderson Jr., G.W., Slayter, M.V., Hall, W., Peters, C.J., 1990. Pathogenesis of a phleboviral infection (Punta Toro virus) in golden Syrian hamsters. Arch. Virol. 114, 203–212. Anderson Jr., G.W., Rosebrock, J.A., Johnson, A.J., Jennings, G.B., Peters, C.J., 1991. Infection of inbred rat strains with Rift Valley fever virus: development of a congenic resistant strain and observations on age-dependence of resistance. Am. J. Trop. Med. Hyg. 44, 475–480. Aronson, J.F., Herzog, N.K., Jerrells, T.R., 1994. Pathological and virological features of arenavirus disease in guinea pigs. Comparison of two Pichinde virus strains. Am. J. Pathol. 145, 228–235. Baccala, R., Welch, M.J., Gonzalez-Quintial, R., Walsh, K.B., Teijaro, J.R., Nguyen, A., Ng, C.T., Sullivan, B.M., Zarpellon, A., Ruggeri, Z.M., de la Torre, J.C., Theofilopoulos, A.N., Oldstone, M.B., 2014. Type I interferon is a therapeutic target for virus-induced lethal vascular damage. Proc. Natl. Acad. Sci. U.S.A. 111, 8925–8930. Baize, S., Leroy, E.M., Georges-Courbot, M.C., Capron, M., Lansoud-Soukate, J., Debre, P., Fisher-Hoch, S.P., McCormick, J.B., Georges, A.J., 1999. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat. Med. 5, 423–426. Baize, S., Marianneau, P., Loth, P., Reynard, S., Journeaux, A., Chevallier, M., Tordo, N., Deubel, V., Contamin, H., 2009. Early and strong immune responses are associated with control of viral replication and recovery in lassa virusinfected cynomolgus monkeys. J. Virol. 83, 5890–5903. Bales, J.M., Powell, D.S., Bethel, L.M., Reed, D.S., Hartman, A.L., 2012. Choice of inbred rat strain impacts lethality and disease course after respiratory infection with Rift Valley fever virus. Front. Cell. Infect. Microbiol. 2, 105. Baron, R.C., McCormick, J.B., Zubeir, O.A., 1983. Ebola virus disease in southern Sudan: hospital dissemination and intrafamilial spread. Bull. World Health Organ. 61, 997–1003. Barrette, R.W., Metwally, S.A., Rowland, J.M., Xu, L., Zaki, S.R., Nichol, S.T., Rollin, P.E., Towner, J.S., Shieh, W.J., Batten, B., Sealy, T.K., Carrillo, C., Moran, K.E., Bracht, A.J., Mayr, G.A., Sirios-Cruz, M., Catbagan, D.P., Lautner, E.A., Ksiazek, T.G., White, W.R., McIntosh, M.T., 2009. Discovery of swine as a host for the Reston ebolavirus. Science 325, 204–206. Basler, C.F., 2005. Interferon antagonists encoded by emerging RNA viruses. In: Palese, P. (Ed.), Modulation of Host Gene Expression and Innate Immunity by Viruses. Springer, Dordrecht, pp. 197–220. Bausch, D.G., Towner, J.S., Dowell, S.F., Kaducu, F., Lukwiya, M., Sanchez, A., Nichol, S.T., Ksiazek, T.G., Rollin, P.E., 2007. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J. Infect. Dis. 196 (Suppl 2), S142– 147. Bente, D.A., Melkus, M.W., Garcia, J.V., Rico-Hesse, R., 2005. Dengue fever in humanized NOD/SCID mice. J. Virol. 79, 13797–13799. Bente, D., Gren, J., Strong, J.E., Feldmann, H., 2009. Disease modeling for Ebola and Marburg viruses. Dis. Models Mech. 2, 12–17. Bente, D.A., Alimonti, J.B., Shieh, W.J., Camus, G., Stroher, U., Zaki, S., Jones, S.M., 2010. Pathogenesis and immune response of Crimean-Congo hemorrhagic fever virus in a STAT-1 knockout mouse model. J. Virol. 84, 11089–11100. Bereczky, S., Lindegren, G., Karlberg, H., Akerstrom, S., Klingstrom, J., Mirazimi, A., 2010. Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. J. Gen. Virol. 91, 1473–1477. Bhatt, P.N., Work, T.H., Varma, M.G., Trapido, H., Murthy, D.P., Rodrigues, F.M., 1966. Kyasanur forest diseases. IV. Isolation of Kyasanur forest disease virus from infected humans and monkeys of Shimoga district, Mysore state. Indian J Med Sci 20, 316–320. Bird, B.H., Albarino, C.G., Nichol, S.T., 2007. Rift Valley fever virus lacking NSm proteins retains high virulence in vivo and may provide a model of human delayed onset neurologic disease. Virology 362, 10–15. Bird, B.H., Ksiazek, T.G., Nichol, S.T., Maclachlan, N.J., 2009. Rift Valley fever virus. J. Am. Vet. Med. Assoc. 234, 883–893. Bird, B.H., Dodd, K.A., Erickson, B.R., Albarino, C.G., Chakrabarti, A.K., McMullan, L.K., Bergeron, E., Stroeher, U., Cannon, D., Martin, B., Coleman-McCray, J.D., Nichol, S.T., Spiropoulou, C.F., 2012. Severe hemorrhagic fever in strain 13/N guinea pigs infected with Lujo virus. PLoS Negl. Trop. Dis. 6, e1801. Blaney Jr., J.E., Johnson, D.H., Manipon, G.G., Firestone, C.Y., Hanson, C.T., Murphy, B.R., Whitehead, S.S., 2002. Genetic basis of attenuation of dengue virus type 4 small plaque mutants with restricted replication in suckling mice and in SCID mice transplanted with human liver cells. Virology 300, 125–139. Bowen, E.T., Platt, G.S., Simpson, D.I., McArdell, L.B., Raymond, R.T., 1978. Ebola haemorrhagic fever: experimental infection of monkeys. Trans. R. Soc. Trop. Med. Hyg. 72, 188–191. Bradfute, S.B., Stuthman, K.S., Shurtleff, A.C., Bavari, S., 2011. A STAT-1 knockout mouse model for Machupo virus pathogenesis. Virol. J. 8, 300. Bradfute, S.B., Warfield, K.L., Bray, M., 2012. Mouse models for filovirus infections. Viruses 4, 1477–1508. Brauburger, K., Hume, A.J., Muhlberger, E., Olejnik, J., 2012. Forty-five years of Marburg virus research. Viruses 4, 1878–1927. Bray, M., 2001. The role of the Type I interferon response in the resistance of mice to filovirus infection. J. Gen. Virol. 82, 1365–1373. Bray, M., 2005. Pathogenesis of viral hemorrhagic fever. Curr. Opin. Immunol. 17, 399–403.

Bray, M., Davis, K., Geisbert, T., Schmaljohn, C., Huggins, J., 1999. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J. Infect. Dis. 179 (Suppl 1), S248–258. Brewoo, J.N., Kinney, R.M., Powell, T.D., Arguello, J.J., Silengo, S.J., Partidos, C.D., Huang, C.Y., Stinchcomb, D.T., Osorio, J.E., 2012. Immunogenicity and efficacy of chimeric dengue vaccine (DENVax) formulations in interferon-deficient AG129 mice. Vaccine 30, 1513–1520. Briese, T., Paweska, J.T., McMullan, L.K., Hutchison, S.K., Street, C., Palacios, G., Khristova, M.L., Weyer, J., Swanepoel, R., Egholm, M., Nichol, S.T., Lipkin, W.I., 2009. Genetic detection and characterization of Lujo virus, a new hemorrhagic fever-associated arenavirus from southern Africa. PLoS Pathog. 5, e1000455. Brocato, R.L., Hammerbeck, C.D., Bell, T.M., Wells, J.B., Queen, L.A., Hooper, J.W., 2014. A lethal disease model for hantavirus pulmonary syndrome in immunosuppressed Syrian hamsters infected with Sin Nombre virus. J. Virol. 88, 811–819. Bucci, T.J., Moussa, M.I., Wood, O., 1981. Experimental Rift Valley fever encephalitis in ACI rats. Control Epidemiol. Biostat. 3, 60–67. Buchmeier, M.J., Rawls, W.E., 1977. Variation between strains of hamsters in the lethality of Pichinde virus infections. Infect. Immun. 16, 413–421. Bukreyev, A., Rollin, P.E., Tate, M.K., Yang, L., Zaki, S.R., Shieh, W.J., Murphy, B.R., Collins, P.L., Sanchez, A., 2007. Successful topical respiratory tract immunization of primates against Ebola virus. J. Virol. 81, 6379–6388. Burt, F.J., Swanepoel, R., Shieh, W.J., Smith, J.F., Leman, P.A., Greer, P.W., Coffield, L.M., Rollin, P.E., Ksiazek, T.G., Peters, C.J., Zaki, S.R., 1997. Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis. Arch. Pathol. Lab. Med. 121, 839–846. Butenko, A.M., Chumakov, M.P., Smirnova, S.E., Vasilenko, T.I., Zavodova, T.I., Tkachenko, E.A., Rubin, S.G., Stolbov, D.N., 1968. Isolation and Investigation of Astrakhan Strain (‘‘Drozdov’’) of Crimean Hemorrhagic Fever Virus. Institute of Poliomyelitis and Viral Encephalitides, Materials from the 15th Scientific Session (English translation NAMRU3-T866), pp. 88–90. Bwaka, M.A., Bonnet, M.J., Calain, P., Colebunders, R., De Roo, A., Guimard, Y., Katwiki, K.R., Kibadi, K., Kipasa, M.A., Kuvula, K.J., Mapanda, B.B., Massamba, M., Mupapa, K.D., Muyembe-Tamfum, J.J., Ndaberey, E., Peters, C.J., Rollin, P.E., Van den Enden, E., 1999. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J. Infect. Dis. 179 (Suppl. 1), S1– 7. Campen, M.J., Milazzo, M.L., Fulhorst, C.F., Obot Akata, C.J., Koster, F., 2006. Characterization of shock in a hamster model of hantavirus infection. Virology 356, 45–49. Carletti, F., Castilletti, C., Di Caro, A., Capobianchi, M.R., Nisii, C., Suter, F., Rizzi, M., Tebaldi, A., Goglio, A., Passerini Tosi, C., Ippolito, G., 2010. Alkhurma hemorrhagic fever in travelers returning from Egypt, 2010. Emerg. Infect. Dis. 16, 1979–1982. Carlton, M., Gillespie, R., Garver, J., Draguljic, D., Vela, E.M., 2012. The Syrian golden hamster as a model to study Flexal virus pathogenesis. Arch. Clin. Microbiol. 3, 1–9. Carrion Jr., R., Patterson, J.L., 2012. An animal model that reflects human disease: the common marmoset (Callithrix jacchus). Curr. Opin. Virol. 2, 357–362. Carrion Jr., R., Brasky, K., Mansfield, K., Johnson, C., Gonzales, M., Ticer, A., Lukashevich, I., Tardif, S., Patterson, J., 2007. Lassa virus infection in experimentally infected marmosets: liver pathology and immunophenotypic alterations in target tissues. J. Virol. 81, 6482–6490. Carrion Jr., R., Ro, Y., Hoosien, K., Ticer, A., Brasky, K., de la Garza, M., Mansfield, K., Patterson, J.L., 2011. A small nonhuman primate model for filovirus-induced disease. Virology 420, 117–124. Cashman, K.A., Smith, M.A., Twenhafel, N.A., Larson, R.A., Jones, K.F., Allen 3rd, R.D., Dai, D., Chinsangaram, J., Bolken, T.C., Hruby, D.E., Amberg, S.M., Hensley, L.E., Guttieri, M.C., 2011. Evaluation of Lassa antiviral compound ST-193 in a guinea pig model. Antiviral Res. 90, 70–79. Centers for Disease Control and Prevention, 2001. Outbreak of Ebola hemorrhagic fever-Uganda, August 2000-January 2001. MMWR Morb. Mortal. Wkly Rep. 50, 73–77. Centers for Disease Control and Prevention, 2005. Outbreak of Marburg virus hemorrhagic fever-Angola, October 1, 2004-March 29, 2005. MMWR Morb. Mortal. Wkly Rep. 54, 308–309. Centers for Disease Control and Prevention, 2009. Biosafety in microbiological and biomedical laboratories 5th edition. In: Wilson, D.E., Chosewood, L.C. (Eds.), Centers for Disease Control and Prevention, p. 415. Cevik, M.A., Erbay, A., Bodur, H., Gulderen, E., Bastug, A., Kubar, A., Akinci, E., 2008. Clinical and laboratory features of Crimean-Congo hemorrhagic fever: predictors of fatality. Int. J. Infect. Dis. 12, 374–379. Chen, X.P., Cong, M.L., Li, M.H., Kang, Y.J., Feng, Y.M., Plyusnin, A., Xu, J., Zhang, Y.Z., 2012. Infection and pathogenesis of Huaiyangshan virus (a novel tick-borne bunyavirus) in laboratory rodents. J. Gen. Virol. 93, 1288–1293. Chumakov, M.P., 1948. Results of the study made on Omsk hemorrhagic fever (OH) by an expedition of the Institute of Neurology. Vestn. Akad. Med. Nauk. SSSR 2, 19–26. Connolly, B.M., Steele, K.E., Davis, K.J., Geisbert, T.W., Kell, W.M., Jaax, N.K., Jahrling, P.B., 1999. Pathogenesis of experimental Ebola virus infection in guinea pigs. J. Infect. Dis. 179 (Suppl 1), S203–217. Cosgriff, T.M., Morrill, J.C., Jennings, G.B., Hodgson, L.A., Slayter, M.V., Gibbs, P.H., Peters, C.J., 1989. Hemostatic derangement produced by Rift Valley fever virus in rhesus monkeys. Rev. Infect. Dis. 11 (Suppl 4), S807–814.


1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505

AVR 3524


17 October 2014 D.R. Smith et al. / Antiviral Research xxx (2014) xxx–xxx 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590

Daddario-DiCaprio, K.M., Geisbert, T.W., Geisbert, J.B., Stroher, U., Hensley, L.E., Grolla, A., Fritz, E.A., Feldmann, F., Feldmann, H., Jones, S.M., 2006a. Crossprotection against Marburg virus strains by using a live, attenuated recombinant vaccine. J. Virol. 80, 9659–9666. Daddario-DiCaprio, K.M., Geisbert, T.W., Stroher, U., Geisbert, J.B., Grolla, A., Fritz, E.A., Fernando, L., Kagan, E., Jahrling, P.B., Hensley, L.E., Jones, S.M., Feldmann, H., 2006b. Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment. Lancet 367, 1399–1404. de Manzione, N., Salas, R.A., Paredes, H., Godoy, O., Rojas, L., Araoz, F., Fulhorst, C.F., Ksiazek, T.G., Mills, J.N., Ellis, B.A., Peters, C.J., Tesh, R.B., 1998. Venezuelan hemorrhagic fever: clinical and epidemiological studies of 165 cases. Clin. Infect. Dis. 26, 308–313. do Valle, T.Z., Billecocq, A., Guillemot, L., Alberts, R., Gommet, C., Geffers, R., Calabrese, K., Schughart, K., Bouloy, M., Montagutelli, X., Panthier, J.J., 2010. A new mouse model reveals a critical role for host innate immunity in resistance to Rift Valley fever. J. Immunol. 185, 6146–6156. Dodd, K.A., Bird, B.H., Khristova, M.L., Albarino, C.G., Carroll, S.A., Comer, J.A., Erickson, B.R., Rollin, P.E., Nichol, S.T., 2011. Ancient ancestry of KFDV and AHFV revealed by complete genome analyses of viruses isolated from ticks and mammalian hosts. PLoS Negl. Trop. Dis. 5, e1352. Dowall, S.D., Findlay-Wilson, S., Rayner, E., Pearson, G., Pickersgill, J., Rule, A., Merredew, N., Smith, H., Chamberlain, J., Hewson, R., 2012. Hazara virus infection is lethal for adult type I interferon receptor-knockout mice and may act as a surrogate for infection with the human-pathogenic Crimean-Congo hemorrhagic fever virus. J. Gen. Virol. 93, 560–564. Dowell, S.F., Mukunu, R., Ksiazek, T.G., Khan, A.S., Rollin, P.E., Peters, C.J., 1999. Transmission of Ebola hemorrhagic fever: a study of risk factors in family members, Kikwit, Democratic Republic of the Congo, 1995. Commission de Lutte contre les Epidemies a Kikwit. J. Infect. Dis. 179 (Suppl. 1), S87–91. Duh, D., Saksida, A., Petrovec, M., Ahmeti, S., Dedushaj, I., Panning, M., Drosten, C., Avsic-Zupanc, T., 2007. Viral load as predictor of Crimean-Congo hemorrhagic fever outcome. Emerg. Infect. Dis. 13, 1769–1772. Dvoretskaia, V.I., Evseev, A.A., Bogatikov, G.V., Pshenichnov, V.A., 1990. Comparative evaluation of the antiviral efficacy of virazole and ribamidil in experimental Lassa fever in monkeys. Vopr. Virusol. 35, 151–152. Dvoretskaia, V.I., Bogatikov, G.V., Pshenichnov, V.A., Evseev, A.A., 1991. The therapeutic efficacy of ribamidil and virazole in experimental Lassa fever in monkeys. Vopr. Virusol. 36, 55–57. Ebihara, H., Yoshimatsu, K., Ogino, M., Araki, K., Ami, Y., Kariwa, H., Takashima, I., Li, D., Arikawa, J., 2000. Pathogenicity of Hantaan virus in newborn mice: genetic reassortant study demonstrating that a single amino acid change in glycoprotein G1 is related to virulence. J. Virol. 74, 9245–9255. Ebihara, H., Rockx, B., Marzi, A., Feldmann, F., Haddock, E., Brining, D., LaCasse, R.A., Gardner, D., Feldmann, H., 2011. Host response dynamics following lethal infection of rhesus macaques with Zaire ebolavirus. J. Infect. Dis. 204 (Suppl. 3), S991–999. Ebihara, H., Zivcec, M., Gardner, D., Falzarano, D., LaCasse, R., Rosenke, R., Long, D., Haddock, E., Fischer, E., Kawaoka, Y., Feldmann, H., 2013. A Syrian golden hamster model recapitulating Ebola hemorrhagic fever. J. Infect. Dis. 207, 306– 318. Eddy, G.A., Scott, S.K., Wagner, F.S., Brand, O.M., 1975. Pathogenesis of Machupo virus infection in primates. Bull. World Health Organ. 52, 517–521. Enria, D.A., Maiztegui, J.I., 1994. Antiviral treatment of Argentine hemorrhagic fever. Antiviral Res. 23, 23–31. Enria, D.A., Briggiler, A.M., Sanchez, Z., 2008. Treatment of Argentine hemorrhagic fever. Antiviral Res. 78, 132–139. Ergonul, O., 2006. Crimean-Congo haemorrhagic fever. Lancet. Infect. Dis 6, 203– 214. Ergonul, O., Tuncbilek, S., Baykam, N., Celikbas, A., Dokuzoguz, B., 2006. Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever. J. Infect. Dis. 193, 941–944. Evseev, A.A., Dvoretskaia, V.I., Bogatikov, G.V., Pshenichnov, V.A., Mustafin, R.M., 1991. Experimental Lassa fever in hamadryas baboons. Vopr. Virusol. 36, 150– 152. Eyzaguirre, E.J., Milazzo, M.L., Koster, F.T., Fulhorst, C.F., 2008. Choclo virus infection in the Syrian golden hamster. Am. J. Trop. Med. Hyg. 78, 669–674. Fagbami, A.H., Tomori, O., Fabiyi, A., Isoun, T.T., 1975. Experimantal Congo virus (IbAN 7620) infection in primates. Virologie 26, 33–37. FDA, 2009. Guidance for Industry: Animal Model-Essential Elements to Address Efficacy Under the Animal Rule. Feldmann, H., Geisbert, T.W., 2011. Ebola haemorrhagic fever. Lancet 377, 849–862. Feldmann, H., Bugany, H., Mahner, F., Klenk, H.D., Drenckhahn, D., Schnittler, H.J., 1996. Filovirus-induced endothelial leakage triggered by infected monocytes/ macrophages. J. Virol. 70, 2208–2214. Feldmann, H., Jones, S.M., Daddario-DiCaprio, K.M., Geisbert, J.B., Stroher, U., Grolla, A., Bray, M., Fritz, E.A., Fernando, L., Feldmann, F., Hensley, L.E., Geisbert, T.W., 2007. Effective post-exposure treatment of Ebola infection. PLoS Pathog. 3, e2. Fisher, A.F., Tesh, R.B., Tonry, J., Guzman, H., Liu, D., Xiao, S.Y., 2003. Induction of severe disease in hamsters by two sandfly fever group viruses, Punta toro and Gabek forest (Phlebovirus, Bunyaviridae), similar to that caused by Rift Valley fever virus. Am. J. Trop. Med. Hyg. 69, 269–276. Fisher-Hoch, S.P., Platt, G.S., Lloyd, G., Simpson, D.I., Neild, G.H., Barrett, A.J., 1983. Haematological and biochemical monitoring of Ebola infection in rhesus monkeys: implications for patient management. Lancet 2, 1055–1058.

17

Fisher-Hoch, S.P., Platt, G.S., Neild, G.H., Southee, T., Baskerville, A., Raymond, R.T., Lloyd, G., Simpson, D.I., 1985. Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola). J. Infect. Dis. 152, 887–894. Fisher-Hoch, S., McCormick, J.B., Sasso, D., Craven, R.B., 1988. Hematologic dysfunction in Lassa fever. J. Med. Virol. 26, 127–135. Fisher-Hoch, S.P., Tomori, O., Nasidi, A., Perez-Oronoz, G.I., Fakile, Y., Hutwagner, L., McCormick, J.B., 1995. Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice. BMJ 311, 857–859. Flatz, L., Rieger, T., Merkler, D., Bergthaler, A., Regen, T., Schedensack, M., Bestmann, L., Verschoor, A., Kreutzfeldt, M., Bruck, W., Hanisch, U.K., Gunther, S., Pinschewer, D.D., 2010. T cell-dependence of Lassa fever pathogenesis. PLoS Pathog. 6, e1000836. Formenty, P., Hatz, C., Le Guenno, B., Stoll, A., Rogenmoser, P., Widmer, A., 1999. Human infection due to Ebola virus, subtype Cote d’Ivoire: clinical and biologic presentation. J. Infect. Dis. 179 (Suppl 1), S48–53. Frame, J.D., Baldwin Jr., J.M., Gocke, D.J., Troup, J.M., 1970. Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. Am. J. Trop. Med. Hyg. 19, 670–676. Francesconi, P., Yoti, Z., Declich, S., Onek, P.A., Fabiani, M., Olango, J., Andraghetti, R., Rollin, P.E., Opira, C., Greco, D., Salmaso, S., 2003. Ebola hemorrhagic fever transmission and risk factors of contacts, Uganda. Emerg. Infect. Dis. 9, 1430– 1437. Fritz, E.A., Geisbert, J.B., Geisbert, T.W., Hensley, L.E., Reed, D.S., 2008. Cellular immune response to Marburg virus infection in cynomolgus macaques. Viral Immunol. 21, 355–363. Gai, Z., Liang, M., Zhang, Y., Zhang, S., Jin, C., Wang, S.W., Sun, L., Zhou, N., Zhang, Q., Sun, Y., Ding, S.J., Li, C., Gu, W., Zhang, F., Wang, Y., Bian, P., Li, X., Wang, Z., Song, X., Wang, X., Xu, A., Bi, Z., Chen, S., Li, D., 2012. Person-to-person transmission of severe fever with thrombocytopenia syndrome bunyavirus through blood contact. Clin. Infect. Dis. 54, 249–252. Gardner, C.L., Ryman, K.D., 2010. Yellow fever: a reemerging threat. Clin. Lab. Med. 30, 237–260. Geisbert, T.W., Jahrling, P.B., 2004. Exotic emerging viral diseases: progress and challenges. Nat. Med. 10, S110–121. Geisbert, T.W., Pushko, P., Anderson, K., Smith, J., Davis, K.J., Jahrling, P.B., 2002. Evaluation in nonhuman primates of vaccines against Ebola virus. Emerg. Infect. Dis. 8, 503–507. Geisbert, T.W., Hensley, L.E., Jahrling, P.B., Larsen, T., Geisbert, J.B., Paragas, J., Young, H.A., Fredeking, T.M., Rote, W.E., Vlasuk, G.P., 2003a. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 362, 1953–1958. Geisbert, T.W., Hensley, L.E., Larsen, T., Young, H.A., Reed, D.S., Geisbert, J.B., Scott, D.P., Kagan, E., Jahrling, P.B., Davis, K.J., 2003b. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am. J. Pathol. 163, 2347–2370. Geisbert, T.W., Young, H.A., Jahrling, P.B., Davis, K.J., Kagan, E., Hensley, L.E., 2003c. Mechanisms underlying coagulation abnormalities in Ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J. Infect. Dis. 188, 1618–1629. Geisbert, T.W., Young, H.A., Jahrling, P.B., Davis, K.J., Larsen, T., Kagan, E., Hensley, L.E., 2003d. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Am. J. Pathol. 163, 2371–2382. Geisbert, T.W., Jones, S., Fritz, E.A., Shurtleff, A.C., Geisbert, J.B., Liebscher, R., Grolla, A., Stroher, U., Fernando, L., Daddario, K.M., Guttieri, M.C., Mothe, B.R., Larsen, T., Hensley, L.E., Jahrling, P.B., Feldmann, H., 2005. Development of a new vaccine for the prevention of Lassa fever. PLoS Med 2, e183. Geisbert, T.W., Daddario-DiCaprio, K.M., Geisbert, J.B., Young, H.A., Formenty, P., Fritz, E.A., Larsen, T., Hensley, L.E., 2007. Marburg virus Angola infection of rhesus macaques: pathogenesis and treatment with recombinant nematode anticoagulant protein c2. J. Infect. Dis. 196 (Suppl 2), S372–381. Geisbert, T.W., Lee, A.C., Robbins, M., Geisbert, J.B., Honko, A.N., Sood, V., Johnson, J.C., de Jong, S., Tavakoli, I., Judge, A., Hensley, L.E., Maclachlan, I., 2010. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet 375, 1896– 1905. Gibb, T.R., Bray, M., Geisbert, T.W., Steele, K.E., Kell, W.M., Davis, K.J., Jaax, N.K., 2001. Pathogenesis of experimental Ebola Zaire virus infection in BALB/c mice. J. Comp. Pathol. 125, 233–242. Gonchar, N.I., Pshenichnov, V.A., Pokhodiaev, V.A., Lopatov, K.L., Firsova, I.V., 1991. The sensitivity of different experimental animals to the Marburg virus. Vopr. Virusol. 36, 435–437. Gonzalez, P.H., Laguens, R.P., Frigerio, M.J., Calello, M.A., Weissenbacher, M.C., 1983. Junin virus infection of Callithrix jacchus: pathologic features. Am. J. Trop. Med. Hyg. 32, 417–423. Gowen, B.B., Bray, M., 2011. Progress in the experimental therapy of severe arenaviral infections. Future Microbiol 6, 1429–1441. Gowen, B.B., Smee, D.F., Wong, M.H., Judge, J.W., Jung, K.H., Bailey, K.W., Pace, A.M., Rosenberg, B., Sidwell, R.W., 2006. Recombinant Eimeria protozoan protein elicits resistance to acute phlebovirus infection in mice but not hamsters. Antimicrob. Agents Chemother. 50, 2023–2029. Gowen, B.B., Wong, M.H., Jung, K.H., Sanders, A.B., Mendenhall, M., Bailey, K.W., Furuta, Y., Sidwell, R.W., 2007. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother. 51, 3168–3176.


1591 1592 1593 1594 1595 1596 1597 1598 1599 1600 1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 1661 1662 1663 1664 1665 1666 1667 1668 1669 1670 1671 1672 1673 1674 1675

AVR 3524


17 October 2014 18 1676 1677 1678 1679 1680 1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761


Gowen, B.B., Julander, J.G., London, N.R., Wong, M.H., Larson, D., Morrey, J.D., Li, D.Y., Bray, M., 2010a. Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever. Virol. J. 7, 240. Gowen, B.B., Wong, M.H., Larson, D., Ye, W., Jung, K.H., Sefing, E.J., Skirpstunas, R., Smee, D.F., Morrey, J.D., Schneller, S.W., 2010b. Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. PLoS One 5, e12760. Gowen, B.B., Juelich, T.L., Sefing, E.J., Brasel, T., Smith, J.K., Zhang, L., Tigabu, B., Hill, T.E., Yun, T., Pietzsch, C., Furuta, Y., Freiberg, A.N., 2013. Favipiravir (T-705) inhibits Junin virus infection and reduces mortality in a guinea pig model of Argentine hemorrhagic fever. PLoS Negl. Trop. Dis. 7, e2614. Grant, D., Tan, G.K., Qing, M., Ng, J.K., Yip, A., Zou, G., Xie, X., Yuan, Z., Schreiber, M.J., Schul, W., Shi, P.Y., Alonso, S., 2011. A single amino acid in nonstructural protein NS4B confers virulence to dengue virus in AG129 mice through enhancement of viral RNA synthesis. J. Virol. 85, 7775–7787. Gray, K.K., Worthy, M.N., Juelich, T.L., Agar, S.L., Poussard, A., Ragland, D., Freiberg, A.N., Holbrook, M.R., 2012. Chemotactic and inflammatory responses in the liver and brain are associated with pathogenesis of Rift Valley fever virus infection in the mouse. PLoS Negl. Trop. Dis. 6, e1529. Green, D.E., Mahlandt, B.G., McKee Jr., K.T., 1987. Experimental Argentine hemorrhagic fever in rhesus macaques: virus-specific variations in pathology. J. Med. Virol. 22, 113–133. Groen, J., Gerding, M., Koeman, J.P., Roholl, P.J., van Amerongen, G., Jordans, H.G., Niesters, H.G., Osterhaus, A.D., 1995. A macaque model for hantavirus infection. J. Infect. Dis. 172, 38–44. Hall, W.C., Geisbert, T.W., Huggins, J.W., Jahrling, P.B., 1996. Experimental infection of guinea pigs with Venezuelan hemorrhagic fever virus (Guanarito): a model of human disease. Am. J. Trop. Med. Hyg. 55, 81–88. Halstead, S.B., 2012. Controversies in dengue pathogenesis. Paediatr. Int. Child Health 32 (Suppl 1), 5–9. Halstead, S.B., 2013. Dengue vascular permeability syndrome: what, no T cells? Clin. Infect. Dis. 56, 900–901. Hartman, A.L., Powell, D.S., Bethel, L.M., Caroline, A.L., Schmid, R.J., Oury, T., Reed, D.S., 2014. Aerosolized rift valley Fever virus causes fatal encephalitis in African green monkeys and common marmosets. J. Virol. 88, 2235–2245. Helmick, C.G., Webb, P.A., Scribner, C.L., Krebs, J.W., McCormick, J.B., 1986. No evidence for increased risk of Lassa fever infection in hospital staff. Lancet 2, 1202–1205. Hensley, L.E., Alves, D.A., Geisbert, J.B., Fritz, E.A., Reed, C., Larsen, T., Geisbert, T.W., 2011a. Pathogenesis of Marburg hemorrhagic fever in cynomolgus macaques. J. Infect. Dis. 204 (Suppl 3), S1021–1031. Hensley, L.E., Smith, M.A., Geisbert, J.B., Fritz, E.A., Daddario-DiCaprio, K.M., Larsen, T., Geisbert, T.W., 2011b. Pathogenesis of Lassa fever in cynomolgus macaques. Virol. J. 8, 205. Hevey, M., Negley, D., Pushko, P., Smith, J., Schmaljohn, A., 1998. Marburg virus vaccines based upon alphavirus replicons protect guinea pigs and nonhuman primates. Virology 251, 28–37. Holbrook, M.R., 2012. Kyasanur forest disease. Antiviral Res. 96, 353–362. Holbrook, M.R., Aronson, J.F., Campbell, G.A., Jones, S., Feldmann, H., Barrett, A.D., 2005. An animal model for the tickborne flavivirus–Omsk hemorrhagic fever virus. J. Infect. Dis. 191, 100–108. Holzmann, I., Agostini, I., Areta, J.I., Ferreyra, H., Beldomenico, P., Di Bitetti, M.S., 2010. Impact of yellow fever outbreaks on two howler monkey species (Alouatta guariba clamitans and A. caraya) in Misiones, Argentina. Am. J. Primatol. 72, 475–480. Hoogstraal, H., 1979. The epidemiology of tick-borne Crimean-Congo hemorrhagic fever in Asia, Europe, and Africa. J. Med. Entomol. 15, 307–417. Hooper, J.W., Kamrud, K.I., Elgh, F., Custer, D., Schmaljohn, C.S., 1999. DNA vaccination with hantavirus M segment elicits neutralizing antibodies and protects against Seoul virus infection. Virology 255, 269–278. Hooper, J.W., Larsen, T., Custer, D.M., Schmaljohn, C.S., 2001. A lethal disease model for hantavirus pulmonary syndrome. Virology 289, 6–14. Hudson, N.P., 1928a. The pathology of experimental yellow fever in Macacus rhesus. III. Comparison with the pathology of yellow fever in man. Am. J. Pathol. 4 (419– 430), 419. Hudson, N.P., 1928b. The pathology of experimental yellow fever in the Macacus rhesus. I. Gross pathology. Am. J. Pathol. 4 (395–405), 391. Hudson, N.P., 1928c. The pathology of experimental yellow fever in the Macacus rhesus. II. Microscopic pathology. Am. J. Pathol. 4, 407–418. Huggins, J.W., 1989. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral drug. Rev. Infect. Dis. 11 (Suppl. 4), S750– S761. Huggins, J.W., Kim, G.R., Brand, O.M., McKee Jr., K.T., 1986. Ribavirin therapy for Hantaan virus infection in suckling mice. J. Infect. Dis. 153, 489–497. ICTV, 2013. Virus Taxonomy. Jahrling, P.B., Hesse, R.A., Eddy, G.A., Johnson, K.M., Callis, R.T., Stephen, E.L., 1980. Lassa virus infection of rhesus monkeys: pathogenesis and treatment with ribavirin. J. Infect. Dis. 141, 580–589. Jahrling, P.B., Hesse, R.A., Rhoderick, J.B., Elwell, M.A., Moe, J.B., 1981. Pathogenesis of a pichinde virus strain adapted to produce lethal infections in guinea pigs. Infect. Immun. 32, 872–880. Jahrling, P.B., Smith, S., Hesse, R.A., Rhoderick, J.B., 1982. Pathogenesis of Lassa virus infection in guinea pigs. Infect. Immun. 37, 771–778. Jahrling, P.B., Peters, C.J., Stephen, E.L., 1984. Enhanced treatment of Lassa fever by immune plasma combined with ribavirin in cynomolgus monkeys. J. Infect. Dis. 149, 420–427.

Jahrling, P.B., Geisbert, J., Swearengen, J.R., Jaax, G.P., Lewis, T., Huggins, J.W., Schmidt, J.J., LeDuc, J.W., Peters, C.J., 1996a. Passive immunization of Ebola virus-infected cynomolgus monkeys with immunoglobulin from hyperimmune horses. Arch. Virol. Suppl. 11, 135–140. Jahrling, P.B., Geisbert, T.W., Jaax, N.K., Hanes, M.A., Ksiazek, T.G., Peters, C.J., 1996b. Experimental infection of cynomolgus macaques with Ebola-Reston filoviruses from the 1989–1990 U.S. epizootic. Arch. Virol. Suppl. 11, 115–134. Jaiswal, S., Pearson, T., Friberg, H., Shultz, L.D., Greiner, D.L., Rothman, A.L., Mathew, A., 2009. Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice. PLoS One 4, e7251. Jaiswal, S., Pazoles, P., Woda, M., Shultz, L.D., Greiner, D.L., Brehm, M.A., Mathew, A., 2012. Enhanced humoral and HLA-A2-restricted dengue virus-specific T-cell responses in humanized BLT NSG mice. Immunology 136, 334–343. Jin, C., Liang, M., Ning, J., Gu, W., Jiang, H., Wu, W., Zhang, F., Li, C., Zhang, Q., Zhu, H., Chen, T., Han, Y., Zhang, W., Zhang, S., Wang, Q., Sun, L., Liu, Q., Li, J., Wang, T., Wei, Q., Wang, S., Deng, Y., Qin, C., Li, D., 2012. Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model. Proc. Natl. Acad. Sci. U.S.A. 109, 10053–10058. Johnsen, D.O., Johnson, D.K., Whitney Jr, R.A., 2012. History of the use of nonhuman primates in biomedical research. In: Abee, C.R., Mansfield, K., Tardif, S., Morris, T. (Eds.), Nonhuman Primates in Biomedical Research: Biology and Management, 2nd ed. Academic Press, New York, pp. 1–34. Johnson, E.D., Johnson, B.K., Silverstein, D., Tukei, P., Geisbert, T.W., Sanchez, A.N., Jahrling, P.B., 1996. Characterization of a new Marburg virus isolated from a 1987 fatal case in Kenya. Arch. Virol. Suppl. 11, 101–114. Jones, S.M., Feldmann, H., Stroher, U., Geisbert, J.B., Fernando, L., Grolla, A., Klenk, H.D., Sullivan, N.J., Volchkov, V.E., Fritz, E.A., Daddario, K.M., Hensley, L.E., Jahrling, P.B., Geisbert, T.W., 2005. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat. Med. 11, 786–790. Jonsson, C.B., Figueiredo, L.T., Vapalahti, O., 2010. A global perspective on hantavirus ecology, epidemiology, and disease. Clin. Microbiol. Rev. 23, 412–441. Julander, J.G., 2013. Experimental therapies for yellow fever. Antiviral Res. 97, 169– 179. Julander, J.G., Shafer, K., Smee, D.F., Morrey, J.D., Furuta, Y., 2009. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106. Antimicrob. Agents Chemother. 53, 202– 209. Julander, J.G., Jha, A.K., Choi, J.A., Jung, K.H., Smee, D.F., Morrey, J.D., Chu, C.K., 2010. Efficacy of 20 -C-methylcytidine against yellow fever virus in cell culture and in a hamster model. Antiviral Res. 86, 261–267. Julander, J.G., Ennis, J., Turner, J., Morrey, J.D., 2011a. Treatment of yellow fever virus with an adenovirus-vectored interferon, DEF201, in a hamster model. Antimicrob. Agents Chemother. 55, 2067–2073. Julander, J.G., Trent, D.W., Monath, T.P., 2011b. Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model. Vaccine 29, 6008–6016. Kamrud, K.I., Hooper, J.W., Elgh, F., Schmaljohn, C.S., 1999. Comparison of the protective efficacy of naked DNA, DNA-based Sindbis replicon, and packaged Sindbis replicon vectors expressing hantavirus structural genes in hamsters. Virology 263, 209–219. Kasabi, G.S., Murhekar, M.V., Sandhya, V.K., Raghunandan, R., Kiran, S.K., Channabasappa, G.H., Mehendale, S.M., 2013. Coverage and effectiveness of Kyasanur forest disease (KFD) vaccine in Karnataka, South India, 2005–10. PLoS Negl. Trop. Dis. 7, e2025. Kastello, M.D., Eddy, G.A., Kuehne, R.W., 1976. A rhesus monkey model for the study of Bolivian hemorrhagic fever. J. Infect. Dis. 133, 57–62. Kaya, A., Engin, A., Guven, A.S., Icagasioglu, F.D., Cevit, O., Elaldi, N., Gulturk, A., 2011. Crimean-Congo hemorrhagic fever disease due to tick bite with very long incubation periods. Int. J. Infect. Dis. 15, e449–452. Kende, M., Alving, C.R., Rill, W.L., Swartz Jr., G.M., Canonico, P.G., 1985. Enhanced efficacy of liposome-encapsulated ribavirin against Rift Valley fever virus infection in mice. Antimicrob. Agents Chemother. 27, 903–907. Kenyon, R.H., Rippy, M.K., McKee Jr., K.T., Zack, P.M., Peters, C.J., 1992. Infection of Macaca radiata with viruses of the tick-borne encephalitis group. Microb. Pathog. 13, 399–409. Khan, S.H., Goba, A., Chu, M., Roth, C., Healing, T., Marx, A., Fair, J., Guttieri, M.C., Ferro, P., Imes, T., Monagin, C., Garry, R.F., Bausch, D.G., 2008. New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral Res. 78, 103–115. Kharitonova, N.N., Leonov, Y.A., 1985. Omsk Hemorrhagic Fever. Amerind Publishing Co., New Delhi. Kilgore, P.E., Ksiazek, T.G., Rollin, P.E., Mills, J.N., Villagra, M.R., Montenegro, M.J., Costales, M.A., Paredes, L.C., Peters, C.J., 1997. Treatment of Bolivian hemorrhagic fever with intravenous ribavirin. Clin. Infect. Dis. 24, 718–722. Klingstrom, J., Plyusnin, A., Vaheri, A., Lundkvist, A., 2002. Wild-type Puumala hantavirus infection induces cytokines, C-reactive protein, creatinine, and nitric oxide in cynomolgus macaques. J. Virol. 76, 444–449. Klotz, O., Belt, T., 1930a. Pathology of the liver in yellow fever. Am. J. Pathol. 6, 663. Klotz, O., Belt, T.H., 1930b. The pathology of the spleen in yellow fever. Am. J. Pathol. 6 (655–662), 653. Klotz, O., Belt, T.H., 1930c. Regeneration of liver and kidney following yellow fever. Am. J. Pathol. 6, 689–697. Kolokoltsova, O.A., Yun, N.E., Poussard, A.L., Smith, J.K., Smith, J.N., Salazar, M., Walker, A., Tseng, C.T., Aronson, J.F., Paessler, S., 2010. Mice lacking alpha/beta


1762 1763 1764 1765 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 1778 1779 1780 1781 1782 1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846

AVR 3524



and gamma interferon receptors are susceptible to junin virus infection. J. Virol. 84, 13063–13067. Kortepeter, M.G., Bausch, D.G., Bray, M., 2011. Basic clinical and laboratory features of filoviral hemorrhagic fever. J. Infect. Dis. 204 (Suppl. 3), S810–816. Kurane, I., 2007. Dengue hemorrhagic fever with special emphasis on immunopathogenesis. Comp. Immunol. Microbiol. Infect. Dis. 30, 329–340. Kurata, T., Tsai, T.F., Bauer, S.P., McCormick, J.B., 1983. Immunofluorescence studies of disseminated Hantaan virus infection of suckling mice. Infect. Immun. 41, 391–398. Laughlin, L.W., Meegan, J.M., Strausbaugh, L.J., Morens, D.M., Watten, R.H., 1979. Epidemic Rift Valley fever in Egypt: observations of the spectrum of human illness. Trans. R. Soc. Trop. Med. Hyg. 73, 630–633. Le Coupanec, A., Babin, D., Fiette, L., Jouvion, G., Ave, P., Misse, D., Bouloy, M., Choumet, V., 2013. Aedes mosquito saliva modulates Rift Valley fever virus pathogenicity. PLoS Negl. Trop. Dis. 7, e2237. Leroy, E.M., Kumulungui, B., Pourrut, X., Rouquet, P., Hassanin, A., Yaba, P., Delicat, A., Paweska, J.T., Gonzalez, J.P., Swanepoel, R., 2005. Fruit bats as reservoirs of Ebola virus. Nature 438, 575–576. Li, X.F., Deng, Y.Q., Yang, H.Q., Zhao, H., Jiang, T., Yu, X.D., Li, S.H., Ye, Q., Zhu, S.Y., Wang, H.J., Zhang, Y., Ma, J., Yu, Y.X., Liu, Z.Y., Li, Y.H., Qin, E.D., Shi, P.Y., Qin, C.F., 2013. A chimeric dengue virus vaccine using Japanese encephalitis virus vaccine strain SA14-14-2 as backbone is immunogenic and protective against either parental virus in mice and nonhuman primates. J. Virol. 87, 13694–13705. Lin, Y.L., Liao, C.L., Chen, L.K., Yeh, C.T., Liu, C.I., Ma, S.H., Huang, Y.Y., Huang, Y.L., Kao, C.L., King, C.C., 1998. Study of dengue virus infection in SCID mice engrafted with human K562 cells. J. Virol. 72, 9729–9737. Liu, Y., Wu, B., Paessler, S., Walker, D.H., Tesh, R.B., Yu, X.J., 2014. The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever. J. Virol. 88, 1781–1786. Lofts, L.L., Ibrahim, M.S., Negley, D.L., Hevey, M.C., Schmaljohn, A.L., 2007. Genomic differences between guinea pig lethal and nonlethal Marburg virus variants. J. Infect. Dis. 196 (Suppl 2), S305–312. Lub, M., Sergeev, A.N., P’Iankov, O.V., Petrishchenko, O.G., Kotliarov, V.A., 1995. Certain pathogenetic characteristics of a disease in monkeys in infected with the Marburg virus by an airborne route. Vopr. Virusol. 40, 158–161. Lukashevich, I.S., 1985. Lassa virus lethality for inbred mice. Ann. Soc. Belg. Med. Trop. 65, 207–209. Lukashevich, I.S., Djavani, M., Rodas, J.D., Zapata, J.C., Usborne, A., Emerson, C., Mitchen, J., Jahrling, P.B., Salvato, M.S., 2002. Hemorrhagic fever occurs after intravenous, but not after intragastric, inoculation of rhesus macaques with lymphocytic choriomeningitis virus. J. Med. Virol. 67, 171–186. Madani, T.A., Al-Mazrou, Y.Y., Al-Jeffri, M.H., Mishkhas, A.A., Al-Rabeah, A.M., Turkistani, A.M., Al-Sayed, M.O., Abodahish, A.A., Khan, A.S., Ksiazek, T.G., Shobokshi, O., 2003. Rift Valley fever epidemic in Saudi Arabia: epidemiological, clinical, and laboratory characteristics. Clin. Infect. Dis. 37, 1084–1092. Mahanty, S., Bausch, D.G., Thomas, R.L., Goba, A., Bah, A., Peters, C.J., Rollin, P.E., 2001. Low levels of interleukin-8 and interferon-inducible protein-10 in serum are associated with fatal infections in acute Lassa fever. J. Infect. Dis. 183, 1713– 1721. Marchevsky, R.S., Freire, M.S., Coutinho, E.S., Galler, R., 2003. Neurovirulence of yellow fever 17DD vaccine virus to rhesus monkeys. Virology 316, 55–63. Markoff, L., 2013. Yellow fever outbreak in Sudan. N. Engl. J. Med. 368, 689–691. Martinez, V.P., Bellomo, C., San Juan, J., Pinna, D., Forlenza, R., Elder, M., Padula, P.J., 2005. Person-to-person transmission of Andes virus. Emerg. Infect. Dis. 11, 1848–1853. McArthur, M.A., Suderman, M.T., Mutebi, J.P., Xiao, S.Y., Barrett, A.D., 2003. Molecular characterization of a hamster viscerotropic strain of yellow fever virus. J. Virol. 77, 1462–1468. McCormick, J.B., 1999. Lassa fever. In: Saluzzo, J.F., Dodet, B. (Eds.), Emergence and Control of Rodent-Borne Viral Diseases. Elsevier, pp. 177–195. McCormick, J.B., King, I.J., Webb, P.A., Scribner, C.L., Craven, R.B., Johnson, K.M., Elliott, L.H., Belmont-Williams, R., 1986. Lassa fever. Effective therapy with ribavirin. N. Engl. J. Med. 314, 20–26. McCormick, J.B., King, I.J., Webb, P.A., Johnson, K.M., O’Sullivan, R., Smith, E.S., Trippel, S., Tong, T.C., 1987a. A case-control study of the clinical diagnosis and course of Lassa fever. J. Infect. Dis. 155, 445–455. McCormick, J.B., Webb, P.A., Krebs, J.W., Johnson, K.M., Smith, E.S., 1987b. A prospective study of the epidemiology and ecology of Lassa fever. J. Infect. Dis. 155, 437–444. McElroy, A.K., Bray, M., Reed, D.S., Schmaljohn, C.S., 2002. Andes virus infection of cynomolgus macaques. J. Infect. Dis. 186, 1706–1712. McIntosh, B.M., Russell, D., dos Santos, I., Gear, J.H., 1980. Rift Valley fever in humans in South Africa. S. Afr. Med. J. 58, 803–806. McKee Jr., K.T., Kim, G.R., Green, D.E., Peters, C.J., 1985a. Hantaan virus infection in suckling mice: virologic and pathologic correlates. J. Med. Virol. 17, 107–117. McKee Jr., K.T., Mahlandt, B.G., Maiztegui, J.I., Eddy, G.A., Peters, C.J., 1985b. Experimental Argentine hemorrhagic fever in rhesus macaques: viral straindependent clinical response. J. Infect. Dis. 152, 218–221. McKee Jr., K.T., Mahlandt, B.G., Maiztegui, J.I., Green, D.E., Peters, C.J., 1987. Virusspecific factors in experimental Argentine hemorrhagic fever in rhesus macaques. J. Med. Virol. 22, 99–111. McLeod Jr., C.G., Stookey, J.L., White, J.D., Eddy, G.A., Fry, G.A., 1978. Pathology of Bolivian hemorrhagic fever in the African green monkey. Am. J. Trop. Med. Hyg. 27, 822–826.

19

Meegan, J.M., Bailey, Charles L., 1989. Rift Valley fever. In: Monath, T.P. (Ed.), The Arboviruses: Epidemiology and Ecology. CRC Press, Boca Raton, pp. 51–76. Meier, K.C., Gardner, C.L., Khoretonenko, M.V., Klimstra, W.B., Ryman, K.D., 2009. A mouse model for studying viscerotropic disease caused by yellow fever virus infection. PLoS Pathog. 5, e1000614. Mendenhall, M., Russell, A., Smee, D.F., Hall, J.O., Skirpstunas, R., Furuta, Y., Gowen, B.B., 2011. Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic fever. PLoS Negl. Trop. Dis. 5, e1342. Milazzo, M.L., Eyzaguirre, E.J., Molina, C.P., Fulhorst, C.F., 2002. Maporal viral infection in the Syrian golden hamster: a model of hantavirus pulmonary syndrome. J. Infect. Dis. 186, 1390–1395. Minor, P.D., 2011. Neurovirulence tests of three 17D yellow fever vaccine strains. Biologicals 39, 167–170. Monath, T.P., 2012. Review of the risks and benefits of yellow fever vaccination including some new analyses. Expert Rev. Vaccines 11, 427–448. Monath, T.P., Brinker, K.R., Chandler, F.W., Kemp, G.E., Cropp, C.B., 1981. Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues. Am. J. Trop. Med. Hyg. 30, 431–443. Moraz, M.L., Kunz, S., 2011. Pathogenesis of arenavirus hemorrhagic fevers. Expert Rev. Anti Infect. Ther. 9, 49–59. Morrill, J.C., Knauert, F.K., Ksiazek, T.G., Meegan, J.M., Peters, C.J., 1989. Rift Valley fever infection of rhesus monkeys: implications for rapid diagnosis of human disease. Res. Virol. 140, 139–146. Morrill, J.C., Jennings, G.B., Johnson, A.J., Cosgriff, T.M., Gibbs, P.H., Peters, C.J., 1990. Pathogenesis of Rift Valley fever in rhesus monkeys: role of interferon response. Arch. Virol. 110, 195–212. Mudd, P.A., Piaskowski, S.M., Neves, P.C., Rudersdorf, R., Kolar, H.L., Eernisse, C.M., Weisgrau, K.L., de Santana, M.G., Wilson, N.A., Bonaldo, M.C., Galler, R., Rakasz, E.G., Watkins, D.I., 2010. The live-attenuated yellow fever vaccine 17D induces broad and potent T cell responses against several viral proteins in Indian rhesus macaques–implications for recombinant vaccine design. Immunogenetics 62, 593–600. Murphy, M.E., Kariwa, H., Mizutani, T., Tanabe, H., Yoshimatsu, K., Arikawa, J., Takashima, I., 2001. Characterization of in vitro and in vivo antiviral activity of lactoferrin and ribavirin upon hantavirus. J. Vet. Med. Sci. 63, 637–645. Neves, P.C., Matos, D.C., Marcovistz, R., Galler, R., 2009. TLR expression and NK cell activation after human yellow fever vaccination. Vaccine 27, 5543–5549. Niklasson, B.S., Meadors, G.F., Peters, C.J., 1984. Active and passive immunization against Rift Valley fever virus infection in Syrian hamsters. APMIS 92, 197–200. Niu, G., Li, J., Liang, M., Jiang, X., Jiang, M., Yin, H., Wang, Z., Li, C., Zhang, Q., Jin, C., Wang, X., Ding, S., Xing, Z., Wang, S., Bi, Z., Li, D., 2013. Severe fever with thrombocytopenia syndrome virus among domesticated animals, China. Emerg. Infect. Dis. 19, 756–763. Nunes-Alves, C., 2014. Ebola update. Nat. Rev. Microbiol. 12, 656. Onguru, P., Dagdas, S., Bodur, H., Yilmaz, M., Akinci, E., Eren, S., Ozet, G., 2010. Coagulopathy parameters in patients with Crimean-Congo hemorrhagic fever and its relation with mortality. J. Clin. Lab. Anal. 24, 163–166. Onlamoon, N., Noisakran, S., Hsiao, H.M., Duncan, A., Villinger, F., Ansari, A.A., Perng, G.C., 2010. Dengue virus-induced hemorrhage in a nonhuman primate model. Blood 115, 1823–1834. Osorio, J.E., Brewoo, J.N., Silengo, S.J., Arguello, J., Moldovan, I.R., Tary-Lehmann, M., Powell, T.D., Livengood, J.A., Kinney, R.M., Huang, C.Y., Stinchcomb, D.T., 2011. Efficacy of a tetravalent chimeric dengue vaccine (DENVax) in Cynomolgus macaques. Am. J. Trop. Med. Hyg. 84, 978–987. Oswald, W.B., Geisbert, T.W., Davis, K.J., Geisbert, J.B., Sullivan, N.J., Jahrling, P.B., Parren, P.W., Burton, D.R., 2007. Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. PLoS Pathog. 3, e9. Padula, P.J., Edelstein, A., Miguel, S.D., Lopez, N.M., Rossi, C.M., Rabinovich, R.D., 1998. Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 241, 323–330. Paessler, S., Walker, D.H., 2013. Pathogenesis of the viral hemorrhagic fevers. Annu. Rev. Pathol. 8, 411–440. Papa, A., Bino, S., Velo, E., Harxhi, A., Kota, M., Antoniadis, A., 2006. Cytokine levels in Crimean-Congo hemorrhagic fever. J. Clin. Virol. 36, 272–276. Papa, A., Drosten, C., Bino, S., Papadimitriou, E., Panning, M., Velo, E., Kota, M., Harxhi, A., Antoniadis, A., 2007. Viral load and Crimean-Congo hemorrhagic fever. Emerg. Infect. Dis. 13, 805–806. Patterson, M., Seregin, A., Huang, C., Kolokoltsova, O., Smith, J., Miller, M., Smith, J., Yun, N., Poussard, A., Grant, A., Tigabu, B., Walker, A., Paessler, S., 2014. Rescue of a recombinant Machupo virus from cloned cDNAs and in vivo characterization in interferon (alphabeta/gamma) receptor double knockout mice. J. Virol. 88, 1914–1923. Paweska, J.T., Sewlall, N.H., Ksiazek, T.G., Blumberg, L.H., Hale, M.J., Lipkin, W.I., Weyer, J., Nichol, S.T., Rollin, P.E., McMullan, L.K., Paddock, C.D., Briese, T., Mnyaluza, J., Dinh, T.H., Mukonka, V., Ching, P., Duse, A., Richards, G., de Jong, G., Cohen, C., Ikalafeng, B., Mugero, C., Asomugha, C., Malotle, M.M., Nteo, D.M., Misiani, E., Swanepoel, R., Zaki, S.R., 2009. Nosocomial outbreak of novel arenavirus infection, southern Africa. Emerg. Infect. Dis. 15, 1598–1602. Perrone, L.A., Narayanan, K., Worthy, M., Peters, C.J., 2007. The S segment of Punta toro virus (Bunyaviridae, Phlebovirus) is a major determinant of lethality in the Syrian hamster and codes for a type I interferon antagonist. J. Virol. 81, 884– 892.


1932 1933 1934 1935 1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

AVR 3524


17 October 2014 20 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 2101 2102


Perry, D.L., Bollinger, L., White, G.L., 2012. The Baboon (Papio spp.) as a model of human Ebola virus infection. Viruses 4, 2400–2416. Peters, C.J., Anderson, G.W., 1981. Pathogenesis of Rift Valley fever. Contrib. Epidemiol. Biostat. 3, 21–41. Peters, C.J., Linthicum, K.J., 1994. Rift Valley fever. In: Beran, G.W., Steele, J.H. (Eds.), Handbook of Zoonoses, Section B. Viral, 2nd ed., CRC Press, Boca Raton, FL, pp. 125–138. Peters, C.J., Slone, T.W., 1982. Inbred rat strains mimic the disparate human response to Rift Valley fever virus infection. J. Med. Virol. 10, 45–54. Peters, C.J., Reynolds, J.A., Slone, T.W., Jones, D.E., Stephen, E.L., 1986. Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator. Antiviral Res. 6, 285–297. Peters, C.J., Jahrling, P.B., Liu, C.T., Kenyon, R.H., McKee Jr., K.T., Barrera Oro, J.G., 1987. Experimental studies of arenaviral hemorrhagic fevers. Curr. Top. Microbiol. Immunol. 134, 5–68. Peters, C.J., Jones, D., Trotter, R., Donaldson, J., White, J., Stephen, E., Slone Jr., T.W., 1988. Experimental Rift Valley fever in rhesus macaques. Arch. Virol. 99, 31–44. Peters, C.J., Liu, C.T., Anderson Jr., G.W., Morrill, J.C., Jahrling, P.B., 1989. Pathogenesis of viral hemorrhagic fevers: Rift Valley fever and Lassa fever contrasted. Rev. Infect. Dis. 11 (Suppl. 4), S743–749. Peters, C.J., Simpson, G.L., Levy, H., 1999. Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu. Rev. Med. 50, 531–545. Plummer, E.M., Shresta, S., 2014. Mouse models for dengue vaccines and antivirals. J. Immunol. Methods. Pourrut, X., Delicat, A., Rollin, P.E., Ksiazek, T.G., Gonzalez, J.P., Leroy, E.M., 2007. Spatial and temporal patterns of Zaire ebolavirus antibody prevalence in the possible reservoir bat species. J. Infect. Dis. 196 (Suppl 2), S176–183. Pripuzova, N.S., Gmyl, L.V., Romanova, L., Tereshkina, N.V., Rogova, Y.V., Terekhina, L.L., Kozlovskaya, L.I., Vorovitch, M.F., Grishina, K.G., Timofeev, A.V., Karganova, G.G., 2013. Exploring of primate models of tick-borne flaviviruses infection for evaluation of vaccines and drugs efficacy. PLoS One 8, e61094. Qattan, I., Akbar, N., Afif, H., Abu Azmah, S., Al-Khateeb, T., Zaki, A., et al., 1996. A novel flavivirus: Makkah region 1994–1996. Saudi Epidemiol. Bull. 3, 1–3. Raymond, J., Bradfute, S., Bray, M., 2011. Filovirus infection of STAT-1 knockout mice. J. Infect. Dis. 204 (Suppl 3), S986–990. Reed, D.S., Mohamadzadeh, M., 2007. Status and challenges of filovirus vaccines. Vaccine 25, 1923–1934. Reed, D.S., Hensley, L.E., Geisbert, J.B., Jahrling, P.B., Geisbert, T.W., 2004. Depletion of peripheral blood T lymphocytes and NK cells during the course of Ebola hemorrhagic Fever in cynomolgus macaques. Viral Immunol. 17, 390–400. Reed, C., Steele, K.E., Honko, A., Shamblin, J., Hensley, L.E., Smith, D.R., 2012. Ultrastructural study of Rift Valley fever virus in the mouse model. Virology 431, 58–70. Reed, C., Lin, K., Wilhelmsen, C., Friedrich, B., Nalca, A., Keeney, A., Donnelly, G., Shamblin, J., Hensley, L.E., Olinger, G., Smith, D.R., 2013. Aerosol exposure to Rift Valley fever virus causes earlier and more severe neuropathology in the murine model, which has important implications for therapeutic development. PLoS Negl. Trop. Dis. 7, e2156. Rieger, T., Merkler, D., Gunther, S., 2013. Infection of type I interferon receptordeficient mice with various old world arenaviruses: a model for studying virulence and host species barriers. PLoS One 8, e72290. Ritter, M., Bouloy, M., Vialat, P., Janzen, C., Haller, O., Frese, M., 2000. Resistance to Rift Valley fever virus in Rattus norvegicus: genetic variability within certain ‘inbred’ strains. J. Gen. Virol. 81, 2683–2688. Riviere, Y., Ahmed, R., Southern, P.J., Buchmeier, M.J., Oldstone, M.B., 1985. Genetic mapping of lymphocytic choriomeningitis virus pathogenicity: virulence in guinea pigs is associated with the L RNA segment. J. Virol. 55, 704–709. Roels, T.H., Bloom, A.S., Buffington, J., Muhungu, G.L., Mac Kenzie, W.R., Khan, A.S., Ndambi, R., Noah, D.L., Rolka, H.R., Peters, C.J., Ksiazek, T.G., 1999. Ebola hemorrhagic fever, Kikwit, Democratic Republic of the Congo, 1995: risk factors for patients without a reported exposure. J. Infect. Dis. 179 (Suppl 1), S92–97. Ross, T.M., Bhardwaj, N., Bissel, S.J., Hartman, A.L., Smith, D.R., 2012. Animal models of Rift Valley fever virus infection. Virus Res. 163, 417–423. Ruzek, D., Yakimenko, V.V., Karan, L.S., Tkachev, S.E., 2010. Omsk haemorrhagic fever. Lancet 376, 2104–2113. Ryabchikova, E.I., Kolesnikova, L.V., Luchko, S.V., 1999. An analysis of features of pathogenesis in two animal models of Ebola virus infection. J. Infect. Dis. 179 (Suppl 1), S199–202. Safronetz, D., Zivcec, M., Lacasse, R., Feldmann, F., Rosenke, R., Long, D., Haddock, E., Brining, D., Gardner, D., Feldmann, H., Ebihara, H., 2011. Pathogenesis and host response in Syrian hamsters following intranasal infection with Andes virus. PLoS Pathog. 7, e1002426. Safronetz, D., Ebihara, H., Feldmann, H., Hooper, J.W., 2012. The Syrian hamster model of hantavirus pulmonary syndrome. Antiviral Res. 95, 282–292. Safronetz, D., Geisbert, T.W., Feldmann, H., 2013a. Animal models for highly pathogenic emerging viruses. Curr. Opin. Virol. 3, 205–209. Safronetz, D., Prescott, J., Haddock, E., Scott, D.P., Feldmann, H., Ebihara, H., 2013b. Hamster-adapted Sin Nombre virus causes disseminated infection and efficiently replicates in pulmonary endothelial cells without signs of disease. J. Virol. 87, 4778–4782. Safronetz, D., Strong, J.E., Feldmann, F., Haddock, E., Sogoba, N., Brining, D., Geisbert, T.W., Scott, D.P., Feldmann, H., 2013c. A recently isolated Lassa virus from Mali demonstrates atypical clinical disease manifestations and decreased virulence in cynomolgus macaques. J. Infect. Dis. 207, 1316–1327.

Safronetz, D., Prescott, J., Feldmann, F., Haddock, E., Rosenke, R., Okumura, A., Brining, D., Dahlstrom, E., Porcella, S.F., Ebihara, H., Scott, D.P., Hjelle, B., Feldmann, H., 2014. Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques. Proc. Natl. Acad. Sci. U.S.A. 111, 7114–7119. Saksida, A., Duh, D., Wraber, B., Dedushaj, I., Ahmeti, S., Avsic-Zupanc, T., 2010. Interacting roles of immune mechanisms and viral load in the pathogenesis of Crimean-Congo hemorrhagic fever. Clin. Vaccine Immunol. 17, 1086–1093. Salas, R., de Manzione, N., Tesh, R.B., Rico-Hesse, R., Shope, R.E., Betancourt, A., Godoy, O., Bruzual, R., Pacheco, M.E., Ramos, B., et al., 1991. Venezuelan haemorrhagic fever. Lancet 338, 1033–1036. Salazar, M., Yun, N.E., Poussard, A.L., Smith, J.N., Smith, J.K., Kolokoltsova, O.A., Patterson, M.J., Linde, J., Paessler, S., 2012. Effect of ribavirin on junin virus infection in guinea pigs. Zoonoses Public Health 59, 278–285. Sanada, T., Kariwa, H., Nagata, N., Tanikawa, Y., Seto, T., Yoshimatsu, K., Arikawa, J., Yoshii, K., Takashima, I., 2011. Puumala virus infection in Syrian hamsters (Mesocricetus auratus) resembling hantavirus infection in natural rodent hosts. Virus Res. 160, 108–119. Sanchez, A., Beisbert, T.W., Feldmann, H., 2007. Filoviridae Marburg and Ebola viruses. In: Knipe, D.M., Howley, P.M. (Eds.), Fields Virology. Lippincott Williams Wilkins. Sbrana, E., Mateo, R.I., Xiao, S.Y., Popov, V.L., Newman, P.C., Tesh, R.B., 2006a. Clinical laboratory, virologic, and pathologic changes in hamsters experimentally infected with Pirital virus (Arenaviridae): a rodent model of Lassa fever. Am. J. Trop. Med. Hyg. 74, 1096–1102. Sbrana, E., Xiao, S.Y., Popov, V.L., Newman, P.C., Tesh, R.B., 2006b. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus) III. Clinical laboratory values. Am. J. Trop. Med. Hyg. 74, 1084–1089. Schmaljohn, C.S., Chu, Y.K., Schmaljohn, A.L., Dalrymple, J.M., 1990. Antigenic subunits of Hantaan virus expressed by baculovirus and vaccinia virus recombinants. J. Virol. 64, 3162–3170. Schmitz, H., Kohler, B., Laue, T., Drosten, C., Veldkamp, P.J., Gunther, S., Emmerich, P., Geisen, H.P., Fleischer, K., Beersma, M.F., Hoerauf, A., 2002. Monitoring of clinical and laboratory data in two cases of imported Lassa fever. Microbes Infect. 4, 43–50. Schnell, F.J., Sundholm, S., Crumley, S., Iversen, P.L., Mourich, D.V., 2012. Lymphocytic choriomeningitis virus infection in FVB mouse produces hemorrhagic disease. PLoS Pathog. 8, e1003073. Schnittler, H.J., Feldmann, H., 2003. Viral hemorrhagic fever–a vascular disease? Thromb. Haemost. 89, 967–972. Sefing, E.J., Wong, M.H., Larson, D.P., Hurst, B.L., Van Wettere, A.J., Schneller, S.W., Gowen, B.B., 2013. Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe Arenavirus infection in AG129 mice. Virol. J. (in press). Seregin, A.V., Yun, N.E., Poussard, A.L., Peng, B.H., Smith, J.K., Smith, J.N., Salazar, M., Paessler, S., 2010. TC83 replicon vectored vaccine provides protection against Junin virus in guinea pigs. Vaccine 28, 4713–4718. Seto, T., Nagata, N., Yoshikawa, K., Ichii, O., Sanada, T., Saasa, N., Ozaki, Y., Kon, Y., Yoshii, K., Takashima, I., Kariwa, H., 2012. Infection of Hantaan virus strain AA57 leading to pulmonary disease in laboratory mice. Virus Res. 163, 284–290. Shepherd, A.J., Leman, P.A., Swanepoel, R., 1989. Viremia and antibody response of small African and laboratory animals to Crimean-Congo hemorrhagic fever virus infection. Am. J. Trop. Med. Hyg. 40, 541–547. Shresta, S., Kyle, J.L., Robert Beatty, P., Harris, E., 2004. Early activation of natural killer and B cells in response to primary dengue virus infection in A/J mice. Virology 319, 262–273. Shresta, S., Sharar, K.L., Prigozhin, D.M., Beatty, P.R., Harris, E., 2006. Murine model for dengue virus-induced lethal disease with increased vascular permeability. J. Virol. 80, 10208–10217. Shurtleff, A.C., Warren, T.K., Bavari, S., 2011. Nonhuman primates as models for the discovery and development of ebolavirus therapeutics. Expert Opin. Drug Discov. 6, 233–250. Shurtleff, A.C., Nguyen, T.L., Kingery, D.A., Bavari, S., 2012. Therapeutics for filovirus infection: traditional approaches and progress towards in silico drug design. Expert Opin. Drug Discov. 7, 935–954. Simpson, D.I., 1969. Marburg agent disease: in monkeys. Trans. R. Soc. Trop. Med. Hyg. 63, 303–309. Simpson, D.I., Zlotnik, I., Rutter, D.A., 1968. Vervet monkey disease. Experiment infection of guinea pigs and monkeys with the causative agent. Br. J. Exp. Pathol. 49, 458–464. Sironen, T., Klingstrom, J., Vaheri, A., Andersson, L.C., Lundkvist, A., Plyusnin, A., 2008. Pathology of Puumala hantavirus infection in macaques. PLoS One 3, e3035. Smirnova, S.E., 1979. A comparative study of the Crimean hemorrhagic fever-Congo group of viruses. Arch. Virol. 62, 137–143. Smith, D.R., Steele, K.E., Shamblin, J., Honko, A., Johnson, J., Reed, C., Kennedy, M., Chapman, J.L., Hensley, L.E., 2010. The pathogenesis of Rift Valley fever virus in the mouse model. Virology 407, 256–267. Smith, D.R., Bird, B.H., Lewis, B., Johnston, S.C., McCarthy, S., Keeney, A., Botto, M., Donnelly, G., Shamblin, J., Albarino, C.G., Nichol, S.T., Hensley, L.E., 2012. Development of a novel nonhuman primate model for Rift Valley fever. J. Virol. 86, 2109–2120. Snoy, P.J., 2010. Establishing efficacy of human products using animals: the US food and drug administration’s ‘‘animal rule’’. Vet. Pathol. 47, 774–778. St Jeor, S.C., 2004. Three-week incubation period for hantavirus infection. Pediatr. Infect. Dis. J. 23, 974–975. Stein, D.A., Perry, S.T., Buck, M.D., Oehmen, C.S., Fischer, M.A., Poore, E., Smith, J.L., Lancaster, A.M., Hirsch, A.J., Slifka, M.K., Nelson, J.A., Shresta, S., Fruh, K., 2011.


Q9

2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174 2175 2176 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2188

AVR 3524



Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence. J. Virol. 85, 10154–10166. Stephen, E.L., Jahrling, P.B., 1979. Experimental Lassa fever virus infection successfully treated with ribavirin. Lancet 1, 268–269. Stokes, A., Bauer, J.H., Hudson, N.P., 1928. Experimental transmission of yellow fever to laboratory animals. Am. J. Trop. Med. 8, 103–164. Sullivan, N.J., Sanchez, A., Rollin, P.E., Yang, Z.Y., Nabel, G.J., 2000. Development of a preventive vaccine for Ebola virus infection in primates. Nature 408, 605–609. Tamura, M., Asada, H., Kondo, K., Tanishita, O., Kurata, T., Yamanishi, K., 1989. Pathogenesis of Hantaan virus in mice. J. Gen. Virol. 70 (Pt 11), 2897–2906. Tan, G.K., Ng, J.K., Trasti, S.L., Schul, W., Yip, G., Alonso, S., 2010. A non mouseadapted dengue virus strain as a new model of severe dengue infection in AG129 mice. PLoS Negl. Trop. Dis. 4, e672. Taniguchi, S., Watanabe, S., Masangkay, J.S., Omatsu, T., Ikegami, T., Alviola, P., Ueda, N., Iha, K., Fujii, H., Ishii, Y., Mizutani, T., Fukushi, S., Saijo, M., Kurane, I., Kyuwa, S., Akashi, H., Yoshikawa, Y., Morikawa, S., 2011. Reston Ebolavirus antibodies in bats, the Philippines. Emerg. Infect. Dis. 17, 1559–1560. Terrell, T.G., Stookey, J.L., Eddy, G.A., Kastello, M.D., 1973. Pathology of Bolivian hemorrhagic fever in the rhesus monkey. Am. J. Pathol. 73, 477–494. Tesh, R.B., Jahrling, P.B., Salas, R., Shope, R.E., 1994. Description of Guanarito virus (Arenaviridae: Arenavirus), the etiologic agent of Venezuelan hemorrhagic fever. Am. J. Trop. Med. Hyg. 50, 452–459. Tesh, R.B., Guzman, H., da Rosa, A.P., Vasconcelos, P.F., Dias, L.B., Bunnell, J.E., Zhang, H., Xiao, S.Y., 2001. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus). I. Virologic, biochemical, and immunologic studies. J. Infect. Dis. 183, 1431–1436. Tigabu, B., Juelich, T., Bertrand, J., Holbrook, M.R., 2009. Clinical evaluation of highly pathogenic tick-borne flavivirus infection in the mouse model. J. Med. Virol. 81, 1261–1269. Tignor, G.H., Hanham, C.A., 1993. Ribavirin efficacy in an in vivo model of CrimeanCongo hemorrhagic fever virus (CCHF) infection. Antiviral Res. 22, 309–325. Torres-Perez, F., Wilson, L., Collinge, S.K., Harmon, H., Ray, C., Medina, R.A., Hjelle, B., 2010. Sin Nombre virus infection in field workers, Colorado, USA. Emerg. Infect. Dis. 16, 308–310. Towner, J.S., Pourrut, X., Albarino, C.G., Nkogue, C.N., Bird, B.H., Grard, G., Ksiazek, T.G., Gonzalez, J.P., Nichol, S.T., Leroy, E.M., 2007. Marburg virus infection detected in a common African bat. PLoS One 2, e764. Towner, J.S., Amman, B.R., Sealy, T.K., Carroll, S.A., Comer, J.A., Kemp, A., Swanepoel, R., Paddock, C.D., Balinandi, S., Khristova, M.L., Formenty, P.B., Albarino, C.G., Miller, D.M., Reed, Z.D., Kayiwa, J.T., Mills, J.N., Cannon, D.L., Greer, P.W., Byaruhanga, E., Farnon, E.C., Atimnedi, P., Okware, S., Katongole-Mbidde, E., Downing, R., Tappero, J.W., Zaki, S.R., Ksiazek, T.G., Nichol, S.T., Rollin, P.E., 2009. Isolation of genetically diverse Marburg viruses from Egyptian fruit bats. PLoS Pathog. 5, e1000536. Vela, E.M., Knostman, K.A., Mott, J.M., Warren, R.L., Garver, J.N., Vela, L.J., Stammen, R.L., 2010. Genistein, a general kinase inhibitor, as a potential antiviral for arenaviral hemorrhagic fever as described in the Pirital virus-Syrian golden hamster model. Antiviral Res. 87, 318–328. Vorou, R., Pierroutsakos, I.N., Maltezou, H.C., 2007. Crimean-Congo hemorrhagic fever. Curr. Opin. Infect. Dis. 20, 495–500. Wagner, F.S., Eddy, G.A., Brand, O.M., 1977. The African green monkey as an alternate primate host for studying Machupo virus infection. Am. J. Trop. Med. Hyg. 26, 159–162. Wahl-Jensen, V., Chapman, J., Asher, L., Fisher, R., Zimmerman, M., Larsen, T., Hooper, J.W., 2007. Temporal analysis of Andes virus and Sin Nombre virus infections of Syrian hamsters. J. Virol. 81, 7449–7462. Wahl-Jensen, V., Bollinger, L., Safronetz, D., de Kok-Mercado, F., Scott, D.P., Ebihara, H., 2012. Use of the Syrian hamster as a new model of Ebola virus disease and other viral hemorrhagic fevers. Viruses 4, 3754–3784. Walker, D.H., Wulff, H., Lange, J.V., Murphy, F.A., 1975. Comparative pathology of Lassa virus infection in monkeys, guinea-pigs, and Mastomys natalensis. Bull. World Health Organ. 52, 523–534. Warfield, K.L., Swenson, D.L., Olinger, G.G., Nichols, D.K., Pratt, W.D., Blouch, R., Stein, D.A., Aman, M.J., Iversen, P.L., Bavari, S., 2006. Gene-specific countermeasures against Ebola virus based on antisense phosphorodiamidate morpholino oligomers. PLoS Pathog. 2, e1. Warfield, K.L., Alves, D.A., Bradfute, S.B., Reed, D.K., VanTongeren, S., Kalina, W.V., Olinger, G.G., Bavari, S., 2007. Development of a model for marburgvirus based on severe-combined immunodeficiency mice. Virol. J. 4, 108. Warfield, K.L., Bradfute, S.B., Wells, J., Lofts, L., Cooper, M.T., Alves, D.A., Reed, D.K., VanTongeren, S.A., Mech, C.A., Bavari, S., 2009. Development and characterization of a mouse model for Marburg hemorrhagic fever. J. Virol. 83, 6404–6415. Warren, T.K., Warfield, K.L., Wells, J., Enterlein, S., Smith, M., Ruthel, G., Yunus, A.S., Kinch, M.S., Goldblatt, M., Aman, M.J., Bavari, S., 2010. Antiviral activity of a small-molecule inhibitor of filovirus infection. Antimicrob. Agents Chemother. 54, 2152–2159. Watanabe, S., Rathore, A.P., Sung, C., Lu, F., Khoo, Y.M., Connolly, J., Low, J., Ooi, E.E., Lee, H.S., Vasudevan, S.G., 2012. Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial. Antiviral Res. 96, 32–35.

21

Watts, D.M., Ksiazek, T.G., Linthicum, K.J., Hoogstraal, H., 1988. Crimean-Congo hemorrhagic fever. In: Monath, T.P. (Ed.), The Arboviruses: Epidemiology and Ecology. CRC, Boca Raton, FL. Webb, H.E., Chaterjea, J.B., 1962. Clinico-pathological observations on monkeys infected with Kyasanur forest disease virus, with special reference to the haemopoietic system. Br. J. Haematol. 8, 401–413. Webb, H.E., Rao, R.L., 1961. Kyasanur forest disease: a general clinical study in which some cases with neurological complications were observed. Trans. R. Soc. Trop. Med. Hyg. 55, 284–298. Webb, P.A., Justines, G., Johnson, K.M., 1975. Infection of wild and laboratory animals with Machupo and Latino viruses. Bull. World Health Organ. 52, 493– 499. Weber, F., Mirazimi, A., 2008. Interferon and cytokine responses to Crimean Congo hemorrhagic fever virus; an emerging and neglected viral zonoosis. Cytokine Growth Factor Rev. 19, 395–404. Weissenbacher, M.C., Calello, M.A., Colillas, O.J., Rondinone, S.N., Frigerio, M.J., 1979. Argentine hemorrhagic fever: a primate model. Intervirology 11, 363–365. Weissenbacher, M.C., Calello, M.A., Merani, M.S., McCormick, J.B., Rodriguez, M., 1986. Therapeutic effect of the antiviral agent ribavirin in Junin virus infection of primates. J. Med. Virol. 20, 261–267. Whitehorn, J., Simmons, C.P., 2011. The pathogenesis of dengue. Vaccine 29, 7221– 7228. Whitehouse, C.A., 2004. Crimean-Congo hemorrhagic fever. Antiviral Res. 64, 145– 160. Wichmann, D., Grone, H.J., Frese, M., Pavlovic, J., Anheier, B., Haller, O., Klenk, H.D., Feldmann, H., 2002. Hantaan virus infection causes an acute neurological disease that is fatal in adult laboratory mice. J. Virol. 76, 8890–8899. Wolfel, R., Paweska, J.T., Petersen, N., Grobbelaar, A.A., Leman, P.A., Hewson, R., Georges-Courbot, M.C., Papa, A., Gunther, S., Drosten, C., 2007. Virus detection and monitoring of viral load in Crimean-Congo hemorrhagic fever virus patients. Emerg. Infect. Dis. 13, 1097–1100. Work, T., 1958. Russian spring-summer encephalitis virus in India, Kyasanur forest disease. Prog. Med. Virol. 1, 248–279. Work, T.H., Trapido, H., 1957. Summary of preliminary report of investigations of the virus research centre on an epidemic disease affecting forest villagers and wild monkeys in Shimoga district, Mysore. Indian J. Med. Sci. 11, 340–341. World Health Organization, 1978. Ebola haemorrhagic fever in Sudan, 1976. Report of a WHO/International Study Team 56, 247–270. Xiao, S.Y., Zhang, H., Guzman, H., Tesh, R.B., 2001a. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus). II. Pathology. J. Infect. Dis. 183, 1437–1444. Xiao, S.Y., Zhang, H., Yang, Y., Tesh, R.B., 2001b. Pirital virus (Arenaviridae) infection in the syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever. Am. J. Trop. Med. Hyg. 64, 111–118. Yanagihara, R., Amyx, H.L., Lee, P.W., Asher, D.M., Gibbs Jr., C.J., Gajdusek, D.C., 1988. Experimental hantavirus infection in nonhuman primates. Arch. Virol. 101, 125–130. Yesilyurt, M., Gul, S., Ozturk, B., Kayhan, B.C., Celik, M., Uyar, C., Erdogan, F., 2011. The early prediction of fatality in Crimean Congo hemorrhagic fever patients. Saudi Med. J. 32, 742–743. Yilmaz, G., Koksal, I., Topbas, M., Yilmaz, H., Aksoy, F., 2010. The effectiveness of routine laboratory findings in determining disease severity in patients with Crimean-Congo hemorrhagic fever: severity prediction criteria. J. Clin. Virol. 47, 361–365. Yu, X.J., Liang, M.F., Zhang, S.Y., Liu, Y., Li, J.D., Sun, Y.L., Zhang, L., Zhang, Q.F., Popov, V.L., Li, C., Qu, J., Li, Q., Zhang, Y.P., Hai, R., Wu, W., Wang, Q., Zhan, F.X., Wang, X.J., Kan, B., Wang, S.W., Wan, K.L., Jing, H.Q., Lu, J.X., Yin, W.W., Zhou, H., Guan, X.H., Liu, J.F., Bi, Z.Q., Liu, G.H., Ren, J., Wang, H., Zhao, Z., Song, J.D., He, J.R., Wan, T., Zhang, J.S., Fu, X.P., Sun, L.N., Dong, X.P., Feng, Z.J., Yang, W.Z., Hong, T., Zhang, Y., Walker, D.H., Wang, Y., Li, D.X., 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N. Engl. J. Med. 364, 1523–1532. Yu, X.L., Jiang, X.L., Wang, T., Sun, Y.L., Zhang, S., Li, C., Zhang, Q.F., Liang, M.F., Bi, Z.Q., Li, D.X., 2012. Establishment of minireplicon system for severe fever with thrombocytopenia syndrome bunyavirus. Bing Du Xue Bao 28, 246–251. Yun, N.E., Walker, D.H., 2012. Pathogenesis of Lassa fever. Viruses 4, 2031–2048. Yun, N.E., Linde, N.S., Dziuba, N., Zacks, M.A., Smith, J.N., Smith, J.K., Aronson, J.F., Chumakova, O.V., Lander, H.M., Peters, C.J., Paessler, S., 2008. Pathogenesis of XJ and Romero strains of Junin virus in two strains of guinea pigs. Am. J. Trop. Med. Hyg. 79, 275–282. Yun, N.E., Poussard, A.L., Seregin, A.V., Walker, A.G., Smith, J.K., Aronson, J.F., Smith, J.N., Soong, L., Paessler, S., 2012. Functional interferon system is required for clearance of lassa virus. J. Virol. 86, 3389–3392. Yun, N.E., Seregin, A.V., Walker, D.H., Popov, V.L., Walker, A.G., Smith, J.N., Miller, M., de la Torre, J.C., Smith, J.K., Borisevich, V., Fair, J.N., Wauquier, N., Grant, D.S., Bockarie, B., Bente, D., Paessler, S., 2013. Mice lacking functional STAT1 are highly susceptible to lethal infection with Lassa virus. J. Virol. 87, 10908–10911. Zaki, A.M., 1997. Isolation of a flavivirus related to the tick-borne encephalitis complex from human cases in Saudi Arabia. Trans. R. Soc. Trop. Med. Hyg. 91, 179–181. Zapata, J.C., Pauza, C.D., Djavani, M.M., Rodas, J.D., Moshkoff, D., Bryant, J., Ateh, E., Garcia, C., Lukashevich, I.S., Salvato, M.S., 2011. Lymphocytic choriomeningitis virus (LCMV) infection of macaques: a model for Lassa fever. Antiviral Res. Zellweger, R.M., Prestwood, T.R., Shresta, S., 2010. Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7, 128–139.


2274 2275 2276 2277 2278 2279 2280 2281 2282 2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358

AVR 3524


17 October 2014 22 2359 2360 2361 2362 2363 2364


Zhao, L., Zhai, S., Wen, H., Cui, F., Chi, Y., Wang, L., Xue, F., Wang, Q., Wang, Z., Zhang, S., Song, Y., Du, J., Yu, X.J., 2012. Severe fever with thrombocytopenia syndrome virus, Shandong Province, China. Emerg. Infect. Dis. 18, 963–965. Zivcec, M., Safronetz, D., Scott, D., Robertson, S., Ebihara, H., Feldmann, H., 2013. Lethal Crimean-Congo hemorrhagic fever virus infection in interferon alpha/

beta receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy. J. Infect. Dis. 207, 1909–1921. Zlotnik, I., 1969. Marburg agent disease: pathology. Trans. R. Soc. Trop. Med. Hyg. 63, 310–327. Zompi, S., Harris, E., 2012. Animal models of dengue virus infection. Viruses 4, 62– 82.

2365 2366 2367 2368 2369 2370 2371


Animal models for viral haemorrhagic fever.

Animal models of tick-borne hemorrhagic Fever viruses.

Viral hemorrhagic fever viruses.

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses.

Corrigendum to "Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses".

Diagnostic schemes for reducing epidemic size of African viral hemorrhagic fever outbreaks.

Hospital Preparations for Viral Hemorrhagic Fever Patients and Experience Gained from Admission of an Ebola Patient.

Viral hemorrhagic fever cases in the country of Georgia: Acute Febrile Illness Surveillance Study results.

Spatiotemporal heterogeneity analysis of hemorrhagic fever with renal syndrome in China using geographically weighted regression models.

Diagnosis of Crimean-Congo hemorrhagic fever.

[Viral hemorrhagic fevers in man].

Epidemiology and pathogenesis of Bolivian hemorrhagic fever.

Viral haemorrhagic fever.

Hypertension after hemorrhagic fever with renal syndrome.

Immunosuppression by hemorrhagic fever-causing viruses.

Simian hemorrhagic fever virus: Recent advances.

Treatment of viral hemorrhagic fevers with ribavirin.

Viruses Causing Hemorrhagic Fever. Safety Laboratory Procedures.

Ebolavirus hemorrhagic fever and the obstetric patient.

Acute arthritis in crimean-congo hemorrhagic Fever.

Understanding Rift Valley fever: contributions of animal models to disease characterization and control.

dengue hemorrhagic fever in Malaysia--a retrospective epidemiological study 1973-1987. Part I: Dengue hemorrhagic fever (DHF).

Animal models of atherosclerosis.

Animal models of parkinsonism.