Comparative Medicine Copyright 2015 by the American Association for Laboratory Animal Science

Vol 65, No 6 December 2015 Pages 499–507

Overview

Rabbit Models for Studying Human Infectious Diseases Xuwen Peng,* John A Knouse, and Krista M Hernon Using an appropriate animal model is crucial for mimicking human disease conditions, and various facets including genetics, anatomy, and pathophysiology should be considered before selecting a model. Rabbits (Oryctolagus cuniculus) are well known for their wide use in production of antibodies, eye research, atherosclerosis and other cardiovascular diseases. However, a systematic description of the rabbit as primary experimental models for the study of various human infectious diseases is unavailable. This review focuses on the human infectious diseases for which rabbits are considered a classic or highly appropriate model, including AIDS (caused by HIV1), adult T-cell leukemia–lymphoma (human T-lymphotropic virus type 1), papilloma or carcinoma (human papillomavirus) , herpetic stromal keratitis (herpes simplex virus type 1), tuberculosis (Mycobacterium tuberculosis), and syphilis (Treponema pallidum). In addition, particular aspects of the husbandry and care of rabbits used in studies of human infectious diseases are described. Abbreviations: CRPV, cottontail rabbit papillomavirus; HPV, human papillomavirus; HSV1, herpes simplex virus type 1; HTLV1, human T-lymphotropic virus type 1

Rodents, especially mice, are the animals most commonly used as models in biomedical research because of their many advantages, including short lifespan, high reproductive rate, cost-effectiveness, ease of genetic manipulation, and the availability of numerous inbred strains with well-defined genetic backgrounds and of a wide variety of reagents for experiments. However, mice and rats are not susceptible to infection by several human pathogens, including HIV1.132 In addition, the causative mutations resulting in human disease sometimes do not cause corresponding pathologic changes in mice,4 and mice are not always suitable for studies due to their small size and phylogenetic features.104 Alternatively, the domestic rabbit (Oryctolagus cuniculus), especially New Zealand white rabbits, has attracted more attention in recent years in biomedical and pharmaceutical research, especially in cardiovascular diseases, because of its intermediate size and phylogenetic proximity to primates.32,44,104 Furthermore, rabbits have served as the primary experimental model for some human infectious diseases because of their susceptibility to infection and the similarity of pathogenesis to that in humans. With the rapid development of rabbit genomics, proteomics, transgenic and knockout lines, and rabbit-specific reagents,12,111,141 the value of rabbits as experimental models in biomedical research likely will increase, especially in their ability to bridge the gap between rodents and the large animal models often required for preclinical and translational research. Because rabbits used in cardiovascular diseases and other traditional studies have been well described Received: 06 Apr 2015. Revision requested: 03 Jun 2015. Accepted: 28 Jun 2015. Department of Comparative Medicine, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania *Corresponding author. Email: [email protected]

elsewhere,5,30,32,104 the current overview focuses on the rabbit models primarily used to study various human infectious diseases.

Rabbit Models for HIV1 Infection and AIDS

The human AIDS complex is a spectrum of conditions that mainly arises due to infection with the retrovirus HIV1, which primarily is transmitted through unprotected sexual contact, contaminated blood transfusions and needles, and from mother to child.115 The virus has a narrow host range for infection, and the restricted species-specific infection in humans is determined by viral entry into target cells, primarily CD4+ T cell helper lymphocytes. This action is mediated by binding of its trimeric envelope spike protein (gp160) to the primary receptor, human CD4,66 followed by binding to specific coreceptors, including human chemokine receptor CCR5.23,130 In addition, the host-specific barriers to HIV1 infection might be related to various antiviral factors that specifically target viruses to restrict their propagation. For example, members of the tripartite-motif–bearing family of proteins have both host- and retrovirus-specific antiviral properties.120,129 All of these characteristics have made the identification and development of a suitable animal model for the study of HIV1 infection extremely difficult. During the last few decades, considerable progress has been made in understanding the HIV1 infection and in the development of animal models of this disease. However, an immunecompetent and infection-susceptible small-animal model is still needed to complement the existing models for studying HIV1 infection and pathogenesis, as well as for evaluating new drugs and developing vaccines. To date, various NHP species serve as the ultimate model of HIV1 infection, but they are either not readily

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available as endangered species or are subject to ethical and high cost concerns. Even among NHP, chimpanzees (Pan troglodytes) and gibbon apes are the only species that are fully susceptible to HIV1 infection.1 However, some macaque species, especially rhesus monkeys, have been used as ‘gold standards’ for testing vaccines because they can be challenged with chimeric SHIV derived from SIV and HIV1.79 SHIV does not produce the same disease in the monkeys as that of HIV1 infection in humans, and it differs from HIV1 in terms of the requirements for effective vaccination.92 Wild-type mice and rats are well known to be nonpermissive for HIV1 infection.131 Even expression of human CD4, the known principal receptor for HIV1, failed to render mouse cells permissive to viral infection.80 In contrast, compared with rodents, rabbits are relatively more susceptible to HIV1 infection, given that both infected normal rabbit cells as well as infected rabbits themselves have been generated.35,43,70,71,133 However, the rabbit infections were much less efficient than those in human lymphocytes, and infected rabbits failed to show consistent clinical signs of AIDS-like disease. Rabbit CD4 may not play the same role as the human molecule in supporting HIV1 infection of cells; instead, rabbits might have additional nonCD4 HIV1 receptors.46 Sequence comparisons of the CD4 molecule cloned from a rabbit thymus cDNA library showed that 6 of the 18 residues implicated in HIV1 binding differ between the human and rabbit proteins, and no correlation between CD4 expression by rabbit cell lines and their ability to support HIV1 infection was seen.46 A subsequent study demonstrated that expression of human CD4 in rabbit PBMC enhanced their infection by HIV1 and resulted in a rapid depletion of the infected cells.78 Furthermore, 2 groups then simultaneously reported the successful generation of transgenic rabbits bearing human CD4.29,117 One of the groups reported that expression of human CD4 in the transgenic rabbits was restricted to lymphocytes that expressed the rabbit homolog, and peripheral blood lymphocytes from the CD4-transgenic rabbits produced greater amounts of HIVq p24 core protein after HIV1 infection in vitro than did similar lymphocytes from nontransgenic rabbits. However, no study describing HIV1 infection of the transgenic rabbits themselves was reported.117 Other in vitro studies similarly demonstrated enhanced susceptibility of lymphocytes derived from the CD4-transgenic rabbits to HIV1 infection.29 Furthermore, in vivo HIV1 infection of the CD4-transgenic rabbits was confirmed through virus isolation, detection of HIV1-specific DNA in peripheral blood lymphocytes, and seroconversion to various HIV1 proteins. However, the infected transgenic rabbits lacked any clinical sign of AIDS-like disease,29 indicating that these animals were not sufficiently susceptible to HIV1 infection for disease development. Various coreceptors are hypothesized to be involved in susceptibility to HIV1 infection, including the β-chemokine receptor CCR5, which is an essential receptor for HIV1 entry into cells.23,41 Cells from a rabbit cell line (SIRC) that expressed the human forms of CD4 and CCR5 were highly permissive for HIV1 infection, and the level of viral replication in the SIRC cells approached that seen in human cells.118 In addition, HIV1 virions produced in SIRC rabbit cells were able to propagate the infection by successfully infecting human PBMC. These findings suggest that transgenic rabbits expressing the human genes for CD4 and CCR5 may accurately reflect HIV1 replication in vivo and serve as a useful small animal model. However, this long-awaited transgenic rabbit model has not yet been reported.

A more recent study showed promise for the development of a rabbit model by demonstrating the considerable natural HIV1 permissivity of rabbit cells.127 In this study, the HIV1 susceptibility of rabbit cells, including primary T cells and macrophages expressing human CD4 and CCR5, was evaluated. The study showed that the rabbit cells, unlike with mouse and rat cells, could support the functions of the regulatory viral proteins Tat and Rev, the processing of the Gag antigen, and the release of HIV1 particles at the levels comparable to those in human cells. It was further demonstrated that viral particles produced by the rabbit T cells were highly infectious. These results suggest that the host-specific factors hampering HIV1 infection could be evaded through receptor complex transgenesis combined with modifications in the HIV1 gag (and possibly vif) genes, potentially rendered rabbits fully permissive to infection by HIV1.127 With increased understanding of the host-specific factors required for HIV1 infection and the ongoing development of new gene-modification techniques, a genetically modified rabbit model that is highly susceptible to HIV1 infection may eventually become possible. This hope is supported by a recent study that described the successful knock-in of the human CD4 and CCR5 homologs into rabbit embryos through the new technique using transcription activator-like effector nuclease (TALEN).125

Rabbit Model for HTLV1 Infection and Adult T-cell Leukemia–Lymphoma

Human T-lymphotropic virus type 1 (HTLV1) was the first human retrovirus isolated in 1979, the virus was obtained from both the fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.40,109 HTLV1 is a single-stranded diploid RNA virus that predominantly affects CD4+ lymphocytes. An estimated 20 million people worldwide are infected with HTLV1.110 Approximately 5% of infected persons develop adult T-cell leukemia– lymphoma, and another 1% to 3% develops the condition known as HTLV-associated myelopathy–tropical spastic paraparesis or various other immune-mediated disorders. In contrast, more than 90% of HTLV1-infected persons remain lifelong asymptomatic, persistent carriers.42 This virus can be transmitted through breast milk, sexual contact, intravenous drug use, blood transfusion, and organ transplantation.42 Research in the last 3 decades was directed at understanding the biologic and pathogenic properties of HTLV1 and to the development of various experimental vaccination and therapeutic strategies against HTLV1 infection. However, a licensed vaccine remains unavailable, and the mechanism underlying the neoplastic pathogenesis in patients with adult T-cell leukemia–lymphoma is not yet completely understood. A variety of animal models have been used to study the early events of HTLV1 infection, including viral transmission, pathogenesis, host immunologic response to the infection and development of novel therapies (see reference 27 for review). Rabbits, rats, and mice are used most commonly among these models, of which rabbits and rats (but not mice) can be infected with HTLV1. Although rats can be infected experimentally, further studies found them to be unreliable models to test the early spread of the virus due to considerable interstrain variation in the response to viral infection.47,63 Consequently, rabbits have been extensively used since the 1980s as a model of HTLV1 infection due to their ease of handling and the consistency of viral infection and transmission.

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Rabbits can be easily infected with HTLV1 after intravenous injection of the MT2 cell line, a T-cell leukemia line derived from a patient with adult T-cell leukemia–lymphoma.89 For studying viral transmission, rabbits inoculated with cell lines are euthanized at defined intervals after infection for the collection of tissue samples, including PBMC, spleen, mesenteric lymph nodes, and gut-associated lymphoid tissues, for further analysis. For example, plasma can be used to detect antibody response by Western blotting, and mononuclear leukocytes can be isolated to detect viral load by real-time PCR analysis or cultured to detect virus expression after exposure.27,53 Rabbits respond similarly to humans infected with HTLV1 in terms of antibody response, and the viral parameters measured in this rabbit model are similar to those used to detect the infection in humans.85,142 Although HTLV1-infected rabbits generally do not develop clinical disease, they simulate the persistent asymptomatic infection manifested by most human patients. Research has shown that persistent HTLV1 infection is determined by a balance between host immune responses and viral spread, and immunomodulatory therapies have been used clinically in HTLV1-infected patients. To understand how the immunosuppressive treatments might influence the host–virus relationship, the effects of cyclosporine (an immunomodulatory drug) was studied in rabbits during early infection of HTLV1.52 The resulting data indicated that immunologic control plays a key role for early HTLV1 spread and has important implications for therapeutic intervention during HTLV1-associated diseases. Collectively, the rabbit model for HTLV1 infection has played indispensable roles in the evaluation of immune responses, parameters of infection, routes of transmission, and viral genetic determinants of infection (by using molecular clones of HTLV1).18,27,51,67,139 The main disadvantage of this model is that the infected rabbits do not spontaneously develop the earlier-described immune-mediated diseases that occur in a small percentage of patients.

Rabbit Models for Human Papillomavirus Infection

Papillomaviruses are a group of small DNA viruses that are associated with infection and neoplasia of cutaneous and mucosal epithelial tissues in both humans and some animal species.13,144 More than 100 types of human papillomavirus (HPV) have been defined genetically. These viruses are classified as either ‘low-risk’ viruses involved in the development of benign genital warts or ‘high risk’ viruses (also called carcinogenic viruses), given their roles in the etiologies of various cutaneous and mucosal cancers, notably cervical cancers.91,144 Among the high-risk HPV16 and HPV18 are the most prevalent HPV associated with cervical cancers. Epidemiologic and molecular studies indicate that, although high-risk (carcinogenic) HPV have been found in more than 90% of cervical cancers, the viruses alone are insufficient to cause malignant transformation; various cofactors (inactivation of tumor suppressor genes, activating mutation of cellular oncogenes, or others) apparently are required.143 In addition, various preliminary studies found that activated H-ras, an oncogene found in many human malignant tumors (including some HPV16- or HPV18-associated cervical cancers),75 was required for malignant transformation of HPV16-immortalized human cervical cells26 and that both HPV16 DNA and EJ-ras were required for transformation of primary cells.88

Due to the restricted species-specificity of these viruses, a natural animal model is not available in which to study the infection and pathogenesis of HPV or to evaluate potential vaccines and therapeutic agents. Current preclinical models of natural papillomaviral infections include those involving rabbits, dogs, and cattle. Because of its similarity in genomic structure and tumorigenesis, cottontail rabbit papillomavirus (CRPV) has long been used as an animal model to study the pathogenesis and development of prophylactic and therapeutic strategies for oncogenic HPV infection.7,10,17,69 The major primary advantages of the CRPV model is the reliable and predictable induction of skin papillomas after treatment with purified CRPV DNA, either applied onto scarified rabbit skin or delivered by gene gun,9,61 thus supporting studies on viral genetics and immunology. To study the interaction between a carcinogenic papillomavirus and potential cofactors in vivo, transgenic rabbits were generated that carried the CRPV genome either alone or with the EJ-ras oncogene.107 Analyses showed that the rabbits that expressed CRPV E6/E7 genes alone developed skin papillomas only, but those expressing both CRPV E6/E7 genes and the EJ-ras oncogene were born with extensive squamous cell carcinomas of the skin.107 In a subsequent study, transgenic rabbits with targeted expression of EJ-ras in the skin due to control by the CRPV upstream regulatory region showed growth of keratoacanthomas during the first week of age.105 The keratoacanthomas were morphologically similar to the tumors in humans and spontaneously regressed at about 2 mo of age. After complete regression of the keratoacanthomas, EJ-ras expression was undetectable, and there was no new tumor growth.105 However, CRPV infection of the skin of 2-mo-old transgenic rabbits (after regression of keratoacanthomas) reinitiated the expression of the EJ-ras transgene and accelerated tumorigenesis compared with that in nontransgenic rabbits.106 Together, these results indicate that an activated oncogene such as EJ-ras might act as a cofactor to increase the tumorigenicity or carcinogenicity of the oncogenic papillomavirus infection. This synergistic effect has been confirmed in the human literature: H-ras mutation was identified in 21% of patients with poorly or moderately differentiated cervical tumors.73 However, the mechanisms underlying the synergistic effect between activated H-ras and oncogenic papillomaviruses during carcinogenesis needs to be elucidated further. To assess host immune response to HPV infection and for preclinical evaluation of initial vaccination and immunotherapeutic testing, animal models of HPV infection are required. However, the narrow species specificity of papillomaviruses makes these studies particularly challenging.34 Species-restrictive barriers prevent the infection by and replication of HPV in all immunocompetent laboratory animals. Among the natural papillomavirus infection models, the CRPV model offers several advantages as a preclinical model for studying host immunity to papillomavirus infection.17 One advantage is that papillomas can be generated by direct infection of skin with naked viral DNA.8,69 This feature provides opportunities for genetic modification of the viral genome by site-directed mutagenesis, which can be used to induce epitopes into the various viral genes for testing specific immunity. The CRPV genome tolerates multiple modifications without losing its ability to induce skin papillomas.56 For example, an HPV16 E7 T-cell epitope can be introduced into the E7 gene of the CRPV genome, such that the modified virus retains full tumorigenicity.59 To assess immune responses to the HPV epitopes in an infection

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model for papillomaviruses, a transgenic rabbit model expressing the HLA-A2.1 gene, a well-characterized human MHC class I gene, has been established.58,59 HLA-A2.1 was expressed and colocalized exclusively with rabbit MHC class I on cell surfaces in all transgenic rabbits. The transgenic rabbits vaccinated with a computer-predicted HLA-A2.1-restricted HPV16 E7 multivalent epitope (amino-acid residues 82 through 90) DNA vaccine showed significant to complete protection against infection with modified CRPV DNA containing an embedded HPV16 E7/82–90 epitope within the CRPV E7 gene.6,59 In addition, these transgenic rabbit models have been used to screen and characterize other computer-predicted HLA-A2.1-restricted epitopes from CRPV E1 as potential DNA vaccines for both protective and therapeutic purposes against CRPV infection.55,57,60 Data from these studies indicate that the HLA-A2.1 transgenic rabbit model might provide opportunities to directly test HLA-A2.1-restricted epitopes of HPV proteins in the context of a human MHC class I gene.

Rabbit Models for Ocular Herpes Infection

Herpes simplex virus type 1 (HSV1) is a double-stranded DNA virus, which is unique in its ability to establish a lifelong latent infection in human hosts.128 Infection with HSV1 frequently is associated with ocular pathology and remains a leading cause of infectious blindness worldwide, with an estimated 40,000 new cases of severe monocular visual impairment or blindness each year.33 Ocular HSV1 is transmitted by close contact and affects about 500,000 people in the United States.33 After initial infection, HSV1 travels by retrograde axonal transport to local sensory ganglia, where it either replicates or establishes latency. When reactivated, the virus travels from the sensory ganglia to the cornea, leading to herpetic stromal keratitis and then infectious blindness mainly due to stromal opacification resulting from tissue damage, edema, and corneal scarring.108 Because ocular herpes infections remain a major health problem and no vaccines have been developed, the current research is focused on understanding the complex immune mechanisms associated with viral reactivation, creating improved therapies, and developing vaccines against both primary and recurrent infections.33 Numerous animal models have been used to investigate the pathogenesis, treatment, and prevention of HSV1-associated diseases for several decades. Although guinea pigs are commonly used for studying genital herpesvirus infection, mice and rabbits are typically used for studies of HSV1 latency, reactivation, and recurrence.134 The advantages and disadvantages for using mice and rabbits in studies of HSV1 infection have been well addressed in a recent review article.134 Rabbits are recognized as a valuable model for studying ocular HSV1 infection, mainly because of their large eyes, thus allowing for easy access to corneal lesions for imaging and quantification by slit-lamp examination and for increased quantities of ocular and neural tissues for assessment. In addition, rabbits have an abundant tear film volume, which facilitates the collection of tears for efficient detection of the infectious virus and DNA.134 Furthermore, herpetic stromal keratitis is reliably induced in rabbits after ocular inoculation with HSV1, and the disease course in rabbits is similar to the human disease, including viral reactivation.48,93,96 Because of these advantages, rabbits have long been used for in vivo experiments in HSV1 latency,97 studies of spontaneous and induced reactivation in the HSV1 latent rabbits, and research on recurrent HSV1-specific corneal lesions and therapeutic in-

tervention.134 For example, one of the earliest studies using New Zealand white rabbits inoculated with the McKrae strain showed that HSV1 remains latent in the trigeminal ganglion between attacks of HSV1 ocular disease.97 In addition, experiments using rabbit models demonstrated that adrenergic neural elements act as a trigger to induce HSV1 reactivation during latency.72,74,116 Compared with mice, rabbits are a more suitable model for studying recurrent HSV1 ocular lesions49,65 64 because of the ease of access for slit-lamp examination, as mentioned earlier.134 In addition, a recent study reported the use of a novel humanized HLA-A2.1 transgenic rabbit model for the preclinical evaluation of vaccines against ocular herpes.14 In that study, immunization of humanized HLA-transgenic rabbits with a mixture of 3 human glycoprotein D lipopeptides resulted in the production of HSV1-specific CD8+ T cells, reduced HSV1 ocular replication, and reduced number of corneal lesion after ocular challenge by HSV1. HLA-transgenic rabbits likely will become a powerful model to study protective immunity induced by prophylactic vaccination against HSV1 infection.

Rabbit Models for Tuberculosis

Tuberculosis is a widespread infectious disease caused by Mycobacterium tuberculosis in humans.76 This bacterium is an aerobic, acid-fast, and gram-positive organism that is spread through the air, usually by coughing and sneezing from people with active infection, and that typically attacks the lungs. Owing to its epidemic status in many parts of the world, tuberculosis remains a major cause of morbidity and mortality, especially in some developing countries. The disease has not been controlled efficiently due to the absence of affordable long-term treatments, emergence of drug resistance, and lack of an effective vaccine.77 The World Health Organization estimates that one-third of the world’s population has been infected with M. tuberculosis, and new infections occur in about 1% of the population each year.138 More specifically, an estimated 9 million new cases occurred throughout the world in 2013, resulting in 1.5 million deaths, most of which were in developing countries.138 Moreover, tuberculosis is reported to have caused about 11% of deaths among adults with AIDS.20 In AIDS patients, mortality may be related to multiorgan effects in sites other than primary to lung infection.100 In immunocompetent people, cell-mediated immunity (T lymphocytes and macrophages), through the formation of granulomas, is regarded as the dominant mode of protection against M. tuberculosis.102 In contrast, granulomas are absent or poorly formed in people with weakened immune responses, especially those infected with HIV.76 Bacteria confined inside granulomas can become dormant and thus associated with latent infection. In addition, a cell-mediated response to M. tuberculosis can create cavities filled with caseous necrotic material, due to abnormal cell death.99,100 The most commonly used animal models in the study of tuberculosis are well addressed in a recent review.24 Among the 3 species reviewed (mice, guinea pigs, and rabbits), mice are relatively resistant to tuberculosis infection, followed by rabbits, whereas guinea pigs were more susceptible to infection than were mice and rabbits. Unlike mice and guinea pigs, rabbits are the only model that develops pulmonary cavitation like that in humans; therefore, this model offers a means for studying the factors leading to this form of disease and to bronchial spread of the pathogen.24 Researches have found that delayed-type hypersensitivity and cell-mediated immunity each play a role in rabbits’ ability

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to form cavities after exposure to whole tubercle bacilli or mycobacterial protein and lipid components.22,140 Therefore, the rabbit model provides a greater potential for studying the transmission of tuberculosis than do other animal models.24 Despite the advantage of developing lung cavitation seen in humans, rabbits currently available for use in research are relatively resistant to tuberculosis infection. Unfortunately, an inbred strain that was reported to be susceptible to airborne M. tuberculosis84 no longer exists. However, the relative resistance of rabbits to infection allows them to serve as a spontaneous model for studying latent tuberculosis infection in humans.24,123 In contrast, rabbits are significantly susceptible to bovine mycobacterial infection (M. bovis) due to inhaled bovine tubercle bacilli or bronchoscopic inoculation. The resulting pulmonary pathology more closely resembles human M. tuberculosis infection than that seen in mice and guinea pigs.95 Furthermore, infection of rabbits with different strains of M. tuberculosis might result in varied spectrums of disease.86,122 For example, rabbits infected with M. tuberculosis HN878 (a hypervirulent strain of the W-Beijing lineage) developed progressive cavitary disease similar to that seen in humans with active tuberculosis.87 In contrast, infection with the strain CDC 1551 (a hyperimmunogenic clinical isolate) was confined in rabbit lungs as a latent infection; however, unlike in human latent infection, rabbits infected with CDC 1551 tend not to reactivate disease unless they are experimentally immunosuppressed.87 Further study revealed that the rabbits with latent tuberculosis infection showed early activation of T cells and macrophages, as well as an early peak in the level of TNFα,123 and immunosuppression induced by corticosteroids resulted in reactivation of the disease in the rabbits.87 This corticosteroid model is useful, in that it is the only animal model available for studying the immune reconstitution during tuberculosis infection after immunosuppression. For these reasons, New Zealand white rabbits provide a valuable animal model for studying tuberculosis. Effective use of this model might facilitate the elucidation of mechanisms underlying host protective immunity, development of new vaccines, and evaluation of novel diagnostic and treatments.

Rabbit Models for Syphilis

A sexually transmitted infectious disease caused by Treponema pallidum (T. pallidum) subspecies pallidum, syphilis remains to be a significant global health problem, with an estimated 12 million new cases of infection each year.137 T. pallidum is a member of the Spirochaetaceae family of spiral-shaped, gram-negative, highly mobile bacteria.31 This bacterium is characterized by a small genome that lacks the ability to encode sufficient metabolic pathways necessary to make most of its macronutrients.37,99 Therefore, this organism cannot be grown in vitro because it must rely heavily on its host for nutrients, and it cannot survive outside of mammalian cells. Humans are the only natural reservoir for the subspecies pallidum. 73,119 Syphilis is transmitted primarily through sexual contact; however, congenital syphilis can occur due to transmission from mother to fetus during pregnancy or at birth.136 Infection is initiated by the penetration of T. pallidum through dermal microabrations or intact mucous membranes, resulting in primary syphilis. Untreated syphilis progresses through stages including secondary, latent, and tertiary disease. Late syphilis can affect the cardiovascular system and central nervous system of infected persons.62,83,103 In addition, pregnant mothers with untreated syphilis can spread the disease through transplacental

transmission of the bacteria to the unborn infants, resulting in the congenital syphilis.112 Nearly half of the children infected with syphilis during fetal development die shortly before or after birth,98 and adults infected with syphilis have an enhanced risk for HIV transmission and acquisition.15 A recent review paper systematically addresses many questions that remain to be studied regarding syphilis, including the biologic basis of the disease and the development of new tools for diagnosis, treatment and prevention.54 Although humans are the only natural hosts of T. pallidum, rabbits are the only mammal to develop naturally occurring syphilis caused by T. paraluis-cuniculi, a bacterium closely related to T. pallidum with antigenic crossreactivity and similar symptoms.2,21,25,45 These characteristics suggest that rabbits might also be susceptible to experimental infection with T. pallidum. The testes of rabbits were shown to be particularly susceptible to T. pallidum infection.135 Because T. pallidum cannot be grown in culture, this unique property led to the use of rabbits as an in-vivo medium for the propagation of T. pallidum and a primary model for studying the pathogenesis and immunity of human syphilis.65,126 Additional studies have found that infection of rabbits by intradermal inoculation with T. pallidum resulted in development of primary lesions, which resemble the chancre of syphilis histologically and morphologically in humans.114 Experimental syphilis in rabbits usually ended after the resolution of the primary lesions, without development of secondary syphilis lesions, especially when the rabbits were infected with the Nichols strain of T. pallidum. However, a different strain of T. pallidum, Melbourne 1, induces secondary syphilis lesions in rabbits.121 In addition, rabbit models for experimental congenital and neurologic syphilis have been created by intravenous administration of the organism. 38,39,126 However, neither the neuroinvasive nor congenital transmission model has been well characterized.103,126 Because the rabbit model closely reflects human infection, it is continually used to study disease pathogenesis,103 explore new therapies,3,81,82 and develop potential vaccines.11,90

The Husbandry and Care of Rabbits Used to Study Human Infectious Disease

As with all animal models used in research, the husbandry and care of rabbits used to study human infectious diseases requires careful consideration regarding the health status and agent used, unique phenotypes of the animal, handling and restraint, and personnel risk. Rabbits are the most numerous of the research animals covered by the Animal Welfare Act, and their use in research in the United States is regulated by the US Department of Agriculture.131 Owing to its well-established influences on research, the husbandry and care of rabbits is aimed at protecting them from unintended disease exposure and environmental stress.19,101,124 Maintaining an established health status typically minimizes variability in research. In addition to the specific requirements outlined by the Animal Welfare Act for rabbit housing environments and care, the human infectious agents used in a rabbit study dictate additional needs depending on the biosafety level of the agent and the associated animal biosafety level for the in vivo application. This information is concisely outlined in several references, including Biosafety in Microbiologic and Biomedical Laboratories,16 and the agents we have discussed here predominately require Animal Biosafety Level 2 practices.

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With the ongoing development and use of transgenic rabbits in research, attention must be paid to unique phenotypes that are associated with genetic manipulation. These considerations must address not only the overall assessment and housing of the animals but also the methods for handling, restraint, and sampling. Using a calm and confident approach during handling and restraint is most successful and likely will minimize the associated stress and potential for injury. Rabbits have a fragile bone structure that comprises a lightweight skeleton with well-developed, large muscles attached, thus making them prone to fractures or subluxation of the vertebrae.124 To avoid these outcomes, a handler must support both the front and rear ends of a rabbit and prevent it from kicking and struggling. The specific model of human disease and associated study goals also will influence matters of restraint, sampling, and other conditions. For example, rabbit models of HIV1 infection may require the development of specialized restraint devices for blood collection that might be inappropriate or unnecessary for rabbits modeling HPV infection. In addition to the basic risks inherent when working with animal models (for example, allergies and zoonoses, bites and scratches, and ergonomic concerns), additional risks must be assessed when working with human pathogens. All persons working with rabbits should be enrolled in their institution’s occupational health and safety program, to identify and prevent risks to personnel. In addition, they should be appropriately trained in all procedures involved with the animal models and pathogens they might contact. All training and participation in health and safety programs should be documented and updated regularly. More detailed information on this topic can be obtained by using Occupational Health and Safety in the Care and Use of Research Animals.94 Preplanning, training, and using appropriate references and resources are all vital to the successful husbandry and care of rabbits modeling human infectious disease.

Conclusion

In this overview, we have addressed the uses of laboratory rabbits as primary models for studies of several human infectious diseases caused by HIV1, HTLV1, HPV, HSV1, M. tuberculosis, and T. pallidum. As we described earlier, rabbit models have played important roles in elucidating the pathogenesis of these diseases and in the exploration and assessment of therapeutic and protective agents. However, challenges regarding the use of rabbit models remain, especially for immunologic and genetic studies, due to the paucity of immunologic reagents and the as-yet incomplete genomic sequence. Fortunately, considerable progress has been achieved in recent years in light of the genomics and proteomics for this species.12,111 Most interesting, a recent study reported the successful generation of targeted mutations in rabbit embryos and production of knockout rabbits by using a new technique, RNA-guided Cas9 nucleases.141 In addition, the current HLA-A2.1 transgenic rabbits, which have been used successfully in studies of HPV6,58 and HSV1,14 might also be helpful in the testing of vaccines that induce CD8+ cytotoxic T lymphocytes against other human pathogens that are permissive or semipermissive in rabbits, including HTLV1,36,51 adenovirus,113 EBV-like viruses,50 and tuberculosis.28 Rabbit likely will play increasingly important roles in the modeling of human diseases, especially in translational studies, especially upon the completion of the rabbit genomic sequence, increased availability of cytokines and antibodies, and creation of additional lines of genetically modified rabbits.

Acknowledgment

This work was supported by the C Max and Sylvia S Lang Professorship Fund, George T Harrell Professorship Fund, and General Fund in the Department of Comparative Medicine of the Pennsylvania State University College of Medicine. We thank Dr Ronald Wilson for his support of the related work.

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