Reactive oxygen and nitrogen species during viral infections.

Just Accepted by Free Radical Research

Reactive oxygen and nitrogen species during viral infections Claudio Giuseppe Molteni, Nicola Principi, Susanna Esposito 10.3109/10715762.2014.945443

Free Radic Res Downloaded from informahealthcare.com by Memorial University of Newfoundland on 08/01/14 For personal use only.

Abstract Oxygen and nitrogen radicals are frequently produced during viral infections. These radicals are not only a physiological mechanism for pathogen clearance but also result in many pathological consequences. Low concentrations of radicals can promote viral replication; however high concentrations of radicals can also inhibit viral replication and are detrimental to the cell due to their mitogenic activity. We reviewed the detailed mechanisms behind oxygen and nitrogen radical production and focused on how viruses induce radical production. In addition, we examined the effects of oxygen and nitrogen radicals on both the virus and host. We also reviewed enzymatic and chemical detoxification mechanisms and recent advances in therapeutic antioxidant applications. Many molecules that modulate the redox balance have yielded promising results in cell and animal models of infection. This encourages their use in clinical practice either alone or with existing therapies. However, since the redox balance also plays an important role in host defence against pathogens, carefully designed clinical trials are needed to assess the therapeutic benefits and secondary effects of these molecules and whether these effects differ between different types of viral infections.

© 2014 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.

Reactive oxygen and nitrogen species during viral infections

Claudio Giuseppe Molteni1, Nicola Principi1, Susanna Esposito1 1

Pediatric Highly Intensive Care Unit, Department of Pathophysiology and

Correspondence: Susanna Esposito, Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Sforza 35, 20122 Milano, Italy. Tel: +390255032498. Fax: +390250320206. Email: [email protected]

Short title: Reactive oxygen and nitrogen species due to viruses Abstract

ST

AC

CE

Oxygen and nitrogen radicals are frequently produced during viral infections. These radicals are not only a physiological mechanism for pathogen clearance but also result in many pathological consequences. Low concentrations of radicals can promote viral replication; however high concentrations of radicals can also inhibit viral replication and are detrimental to the cell due to their mitogenic activity. We reviewed the detailed mechanisms behind oxygen and nitrogen radical production and focused on how viruses induce radical production. In addition, we examined the effects of oxygen and nitrogen radicals on both the virus and host. We also reviewed enzymatic and chemical detoxification mechanisms and recent advances in therapeutic antioxidant applications. Many molecules that modulate the redox balance have yielded promising results in cell and animal models of infection. This encourages their use in clinical practice either alone or with existing therapies. However, since the redox balance also plays an important role in host defence against pathogens, carefully designed clinical trials are needed to assess the therapeutic benefits and secondary effects of these molecules and whether these effects differ between different types of viral infections.

Keywords: antioxidant, inducible nitric oxide synthase, nitric oxide, oxidation, reactive oxygen species

JU


Ospedale Maggiore Policlinico, Milan, Italy

PT ED

Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda

Introduction Oxygen and nitric oxide (NO•) radicals are generated at different anatomic sites and under different cellular contexts. Viral infections enhance the production of oxygen and NO• radicals, which can lead to both favourable and unfavourable effects for the host or pathogen. Low concentrations of radicals can promote viral replication;

PT ED

however, high concentrations of radicals can also inhibit viral activity [1]. Many human viruses, including human

immunodeficiency virus (HIV), herpes simplex type 1 (HSV-1), hepatitis B virus (HBV), hepatitis C virus (HCV), respiratory

syncytial virus (RSV), and influenza viruses, produce reactive

oxygen species (ROS) [2,3]. ROS are highly diffusible molecules

CE

that are produced by the reduction of oxygen molecules; ROS

include superoxide anions (O2-), hydrogen peroxide (H2O2), and hydroxyls (OH•) [1]. OH•, which is the most reactive ROS, is generated from O2- and H2O2 in the presence of Fe3+ or Cu2+ ions,

AC

which catalyse Fenton’s reaction. NO• is generated during viral infections via inducible nitric oxide synthase (iNOS) with tetrahydrobiopterin as a cofactor [1-3]. iNOS is present as a dimer in macrophages and synthesizes NO• via a two-step oxidation of the

ST

terminal guanidine nitrogen of L-arginine. NO• gives rise to reactive nitric oxide species (RNOS) and reacts with O2- to form peroxynitrite (ONOO-). ONOO- and OH• are potent oxidizers that can alter the structure and function of different macromolecules.

JU


replication and be detrimental to the cell due to their mitogenic

Here, we review ROS production and metabolism in the context of viral infections and focus on the effects of ROS on viral pathogens as well as the host. PHYSIOPATHOLOGICAL MECHANISMS OF ROS/RNOS PRODUCTION

O2- is produced by physical ROS inducers, such as UV irradiation, and during metabolic processes via different mechanisms [1]. Mitochondria are important sites of ROS production since the electrons flowing through the respiratory chain can be transferred to O2 via oxidative phosphorylation. O2- can also be produced by the degradation of purine nucleotides, mainly AMP, to xanthine and

PT ED

hypoxanthine and subsequently to uric acid via xanthine oxidase

translational modifications of xanthine dehydrogenase (XD). These modifications include changes in the oxidation state of thiolic

groups, proteolytic cleavage, and the use of O2 instead of NAD as a cofactor and lead to the release of large amounts of O2- and H2O2 by XO. Granulocytes and macrophages can also produce O2- via the

CE

membrane-associated NADPH-dependent respiratory burst oxidase. Pathogen recognition triggers the translocation of respiratory burst oxidase to the plasma membrane of the cell. This complex regulates the release of O2- outside the cell and inside phagosomes, which

AC

form other radicals (e.g., ONOO- and HOCl) that serve as pathogen defence mechanisms. O2- is then converted into the more damaging OH• by reacting with H2O2 via Fenton’s reaction [4]. Fenton’s reaction is catalysed by metals found in ferritin, the Fe-S clusters of

ST

mitochondrial proteins, heme-like protein domains, and lactoferrin. The H2O2 in the reaction is generated several ways; most notably, H2O2 is generated by the direct addition of an electron to hydrogen ions and O2- or by the enzymatic production of various oxidases and

JU


(XO) [1]. XO is activated under hypoxic conditions through post-

superoxide dismutase [4]. During viral infections, ROS production can be triggered by cytokines that are secreted in response to the pathogen or by viral components. Table 1 summarizes the main viruses associated with ROS production. The Th1 cytokine tumor necrosis factor (TNF)-α is

produced by phagocytes in response to HIV or influenza and controls O2- production by inhibiting complex III in the mitochondrial respiratory chain [5]. TNF-α is also produced in hepatic cell lines that are transfected with HBV [6], and changes in detoxification have been observed in HBV and HCV-infected patients [7]. Viruses also trigger other proteins to stimulate ROS

PT ED

production. The core protein of HCV activates Nox4, which initiates NS5A proteins are also known to induce oxidative [10-12]. During liver diseases (such as hepatocellular or cholestatic problems), the

produced ROS are involved in transcriptional activation of a large

number of cytokines and growth factors, and continued production of ROS feed into the vicious cycle that not only causes hepatic

CE

damage but also stimulates the processes to reduce treatment of

damage [13]. Epstein-Barr virus (EBV) induces ROS production in B lymphocytes via NADPH oxidase by upregulating EBNA1 and Nox2 [14,15]. HSV-1 J protein and the matrix protein (MP) of the

AC

vesicular stomatitis virus (VSV) can also induce ROS production [16,17], and the nucleoprotein (N) of the measles and rubella viruses can induce ROS production by increasing the activity of the mitochondria respiratory chain [18,19]. RSV has also been shown to

ST

induce ROS production in different cell types, including respiratory epithelia [20-22]. The HIV gp120 and TAT proteins, which are known to activate iNOS, may also play a role in superoxidemediated HIV-related neurotoxicity [23,24], while the HIV RT

JU


mitochondrial ROS production [8,9]; the E1, E2, NS3/4A, and

protein has been shown to induce ROS production [25]. Moreover, Nef and Vpr proteins have also been described to induce superoxide production in different cell types and tissues in HIV infection [26]. Human T cell leukaemia virus type 1 (HTLV-1) has also been found to affect mitochondrial ROS production via the p13 protein during

glucose deprivation [27], while its Tax protein promotes ROS formation by attenuating ubiquitin-specific protease 10 (USP-10), which regulates ROS in T cells [28]. While ROS and RNOS production is generally part of host defences in phagocytic cells, other cell types (such as fibroblasts, endothelial cells, osteoclasts, and chondrocytes) can also produce ROS, which can participate in

PT ED

cell signalling, apoptosis, and gene expression [29].

of NF-kB and IRF1 to distinct sites in the iNOS promoter. This calcium-independent enzyme produces large amounts of NO•,

around 10 to 100 times that produced by endothelial and neuronal nitric oxide synthase (eNOS and nNOS), which are calcium

dependent. These three enzymes share 50% amino acid homology

CE

and are significantly homologous to cytochrome p450 reductase [30]. iNOS can be indirectly activated by Th1 cells and their subsequent cytokine production. In the majority of human cells,

iNOS can be induced by a cytokine cocktail containing interferon

AC

(IFN)-γ, interleukin (IL)-1β, and TNF-α [30]. Many viruses can directly induce iNOS production. HIV-1, HCV, and RSV are all able to upregulate iNOS expression [31-37]. iNOS is also inhibited by many other factors either directly or indirectly. For example, IL-4

ST

directly inhibits iNOS by inhibiting IRF1 translation [38], while other factors (IL-4, IL-10, IL13, tumor growing factor [TGF-β]) indirectly inhibit iNOS by inducing arginase, which reduces the availability of L-arginine, the substrate of iNOS substrate [39]. Viral

JU


During viral infections, iNOS expression is enhanced by the binding

proteins, such as the E1A protein of adenovirus, can also inhibit

iNOS expression [40]. NO• homeostasis is maintained by NO dioxygenase and oxyhemoglobin, which oxidize NO• [1]. NO• can react with oxygen to produce N2O3, which can irreversibly react with halogen ions to

produce nitrosyl halides and NO2-. NO• can also react with O2- to produce ONOO-; this reaction can occur in the intracellular compartments of immune cells (e.g., macrophages and neutrophils) or when NO• diffuses into O2- producing cells. ONOO- decays via proton- or CO2-mediated lysis to produce nitrate (NO3-), and nitrite (NO2-); NO2•, CO3•-, and OH• are secondary (weaker) products. In

PT ED

vivo, ONOO- exists in a “solvent-caged” form and is surrounded by nitrative stress and is produced by peroxidases (myeloperoxidase and eosinophilic peroxidase in neutrophils and eosinophils,

respectively) that oxidize nitrite. NO• can also play a role in

signalling by binding the heme iron of guanylate cyclase, thereby

activating it and stimulating the production of cyclic guanosine 3’ 5’

CE

monophosphate (cGMP). cGMP participates in many processes, including vasodilation, cytokine regulation, cell migration, and apoptosis.

AC

THE EFFECTS OF ROS AND RNOS ON VIRUSES AND THEIR HOSTS

Table 2 summarizes the main effects of ROS and RNOS on viruses and their hosts. In pathological conditions, ROS typically promotes cell death by stimulating cytochrome c release from the

ST

mitochondria and by damaging macromolecules [1]. Unsaturated fatty acids, particularly polyunsaturated ones (two to four double bonds) are the main lipid target of ROS. Reactions with ROS produce aldehydes (malondialdehyde and 2- or 4-

JU


OH• and nitrogen dioxide (NO2) [41-43]. NO2 can also generate

hydroxynonenaldehyde), which target nucleic acid bases or protein amino groups, as well as hydrocarbons like penthane or hexane. When ROS react with esterified fatty acids, cell membrane function, including receptor signalling, is impaired; membrane permeability is also altered, which can lead to cell damage and lysis [1].

ROS can also react with proteins and modify protein backbones and side chains. This frequently results in amino acid chain fragmentation and aldehyde and ketone production. Oxidative damage diminishes or impairs enzymatic protein activities, decreases protein solubility, and can trigger proteasome degradation [44]. High ROS levels have also been correlated with higher tRNA

PT ED

misacylation, thereby lowering the fidelity of protein translation

immunoproteasome can be presented by major histocompatibility complex class I proteins [46].

Nucleic acids, particularly DNA, are also prone to ROS damage.

ROS can modify the sugar backbone and nucleobases, leading to strand crosslinking, breakages, and base loss. In addition,

CE

malondialdehyde and/or reactive nucleobase derivatives, such as the highly mutagenic 8-oxoguanine, are released [1]. Since OH• is extremely reactive, oxidative DNA damage is generally mediated by H2O2 that diffuses across the nuclear membrane or OH• produced by

AC

Fe2+-catalysed Fenton reactions close to the DNA backbone. Proliferating cells are more sensitive to nuclear DNA damage because they are in an active transcription state where the DNA is dissociated from the histones that can protect it against ROS.

ST

Mitochondrial DNA is also very prone to ROS damage since mitochondria are the major site of OH• production; furthermore, mitochondrial enzymes are sensitive to ROS damage, and mitochondria have ineffective DNA repair mechanisms [47].

JU


[45]. The peptides of oxidized proteins that are degraded by the

Nitrative stress occurs in many diseases with viral origins, such as

viral pneumonia and encephalitis [48-50]. NROS can react with thiols, iron-sulfur centers, proteins, unsaturated membrane lipids, and nucleic acids. NROS reactions with cysteine thiol groups results in S-nitrosylation, which activates several proteins with important

roles in cell signalling in apoptosis; these proteins include matrix metalloproteinases (MMPs), albumin, various transcription factors, and caspases [51]. NO• commonly reacts with the iron-sulfur centre of metalloproteins, which typically inactivates the protein (e.g., haemoglobin, the main NO• sink in humans) [52].

PT ED

Tyrosine nitration is mediated by ONOO- and NO2 and is catalysed 3-nitrotyrosine, a widely used marker of nitrative stress [53]. 3nitrotyrosine can be incorporated in α-tubulin, which alters microtubule structure and causes structural and functional

aberrations in cells. As previously mentioned, ONOO- activates MMPs, which are involved in tissue remodelling; MMP

CE

hyperactivation has pathological consequences following infection. ONOO- also inactivates tissue inhibitors of MMP and plasma inhibitors of α-1 proteinase, thereby amplifying tissue damage during host responses to viral pathogens. ONOO- also promotes

AC

prostaglandin production by triggering cyclooxygenase, enhancing the host inflammatory response. NROS play conflicting roles in apoptosis. ONOO- has pro-apoptotic effects by inducing mitochondrial damage and cytochrome c release. In contrast, NO•

ST

and nitrosothiols formed via S- or transnitrosylation inhibit apoptosis by modifying the caspases involved [54]. Nitrosylating membrane lipids generates peroxide adducts and aldehydes, such as malonyldialdehyde (MDA) and ketones. These

JU


by heavy metals, such as iron and copper. Tyrosine nitration forms

molecules impair cell membrane function, alter membrane permeability, and further diffuse throughout the cell to affect

additional targets [54]. RNOS also form DNA and RNA adducts [53]. ONOO- and NO2 react with guanine nucleobases to form 8-nitroguanosine, 8-

nitrodeoxyguanosine, and 8-oxodeoxyguanine, the major nitrated nucleotide/nucleoside derivatives. 8-nitroguanosine is widely used as a nitrative stress marker; it uncouples NADPH electron transport through the cytochrome-NOS complex, thereby promoting the production of ONOO- [55], which also induces P53 inactivation [56]. Furthermore, 8-nitrodeoxyguanosine (8-nitroguanosine for

PT ED

RNA) can be incorporated into DNA by mispairing with thymine or consequently, cell metabolism dysregulation. RNA viruses are

particularly prone to ROS/RNOS-induced mutations due to their

lack of proofreading activity, integration into the host cell genome, and the relative instability of RNA (when compared to DNA) [57]. Viral mutations caused by ROS and RNOS contribute to the

CE

selection for more virulent strains that can escape the immune

response [58,59]. The immunosuppressive effects of ROS may also favour the selection of more virulent strains [60]. ROS production induced by viral infections are often more detrimental than helpful to

AC

the host. This is due to different factors such as the relative inability of the innate immune system to physically contain viral infections (compared to bacterial infections) [61]. In addition, NO• does not affect some virus families, such as paramyxoviridae, despite having

ST

antimicrobial effects against others, including influenza viruses, Coxsackievirus B3, HSV-1, severe acute respiratory syndrome coronavirus, and hantaviruses [62-70]. Several studies have shown cytokine biases in response to RNOS

JU


adenine. This results in mutations, protein alterations, and

production. These are typically thought to reflect the selective impairment of Th1 responses compared to Th2 as well as the possibility of a higher sensitivity to apoptosis in activated Th1 cells [71-77]. This likely affects the clearance of cytopathic viruses, such as influenza or HSV-1, where Th1 responses play a major role.

Macrophages are also affected by RNOS-induced apoptosis [72,73]. Some recent studies have shown that Th1 is not selectively impaired compared to Th2, however [74,75]. ROS AND RNOS DETOXIFICATION ROS and RNOS tissue concentrations are tightly regulated. ROS and RNOS decomposition is mediated by several detoxifying enzymes.

PT ED

The importance of these enzymes has been clearly demonstrated in play a key role in this process; these enzymes catalyse the

conversion of O2- to H2O2 and O2, thereby inhibiting ROS

production at an early step. There are three major SODs: cytosolic SOD1 (a homodimeric enzyme that uses Cu/Zn ions as cofactors),

mitochondrial SOD2 (a homotetrameric Mn-requiring enzyme), and

CE

extracellular SOD3 (which is Cu/Zn dependent) [78,79]. Catalase, a tetrameric hemoprotein, eliminates low concentrations of H2O2 and produces H2O and O2. High concentrations of H2O2 are eliminated by glutathione peroxidase (GPX) enzymes, particularly GPX1,

AC

which use selenium as cofactor; GPX enzymes convert H2O2 to H2O by oxidating monomeric glutathione (GSH) to glutathione disulfide (GS-SG) [79]. In addition, GPX4 transforms lipid peroxides to their corresponding alcohols. Glutathione homeostasis is maintained by

ST

glutathione reductase, which uses nicotinammide adenine dinucleotide phosphate (NADP)(H) and H+ to convert glutathione disulfide into its monomeric form. NADP(H) is produced via the pentose phosphate pathway.

JU


knockout mouse models [78,79]. Superoxide dismutases (SODs)

OH• is detoxified via non-enzymatic systems, such as dietary antioxidants (vitamins A, C, and E). Antioxidants interact with OH• and are converted into harmless secondary molecules, thereby limiting the damaging effects of OH• [80,81]. Other OH• scavenging

molecules are alpha-lipoic acid, glutathione, and homocysteine [80,81]. Peroxiredoxins (Prx) are an additional family of detoxifying enzymes with cytosolic (PrxI and II), mitochondrial (PrxIII), and extracellular (PrxIV) locations. Although the main function of Prx enzymes are to detoxify H2O2, Prx enzymes, particularly PrxV and

PT ED

PrxII, have also been shown to have peroxynitrite-clearing activity Most genes that encode for antioxidant proteins are controlled by

antioxidant response elements (ARE). These elements are located in the promoter region upstream of the genes and their expression and activity significantly decrease in response to RSV infection [84,85]. Moreover, ARE are bound by nuclear factor E2-related factor 2

CE

(Nrf2), the main transcription factor for the oxidant response [86]. Nrf2 is bound in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which promotes its degradation by the

proteasome. Oxidative stress causes Nrf2 to dissociate from Keap1.

AC

Consequently, Nrf2 is phosphorylated phosphorylation by multiple kinases and translocated to the nucleus where it heterodimerization with other transcription factors [86]. Phosphorylating Nrf2 at additional sites translocates it back to the cytosol where it is then

ST

degraded. Caveolin-1 has recently been reported to inhibit Nrf2 in both the cytoplasm and nucleus. Nrf2 has been shown to regulate influenza virus entry and replication in airway epithelial cells, possibly by upregulating antiviral genes such as IFN-beta [87]. In

JU


[82,83].

addition, Nrf2 is affected by HIV transgenes and modulates the expression of adhesion molecules in rat pulmonary epithelia cells; this may explain why HIV-infected patients often experience pulmonary dysfunction [88]. RSV infection has been shown to downregulate Nrf2 expression in both cell models and in children

with RSV-induced bronchiolitis [20-22]; in addition, RSV promotes ROS production and downregulates key antioxidant enzymes such as SOD1, SOD3, catalase, and glutathione peroxidase. It has been shown that antioxidant treatment significantly improves RSV-induced oxidative stress, clinical disease and pulmonary inflammation in a mouse model of infection, thus suggesting a

PT ED

casual relationship between increased ROS production and lung antioxidant capacity can have a significant impact on viral-

associated oxidative cell damage, and may be a new therapeutic

approach to modulating virus-induced lung disease. However, as

most of the data are in vitro data and regard only RSV and not other important respiratory viruses, human studies are required before any

CE

attempt is made to use antioxidising drugs to treat viral infections.

ANTIOXIDANTS AS TREATMENTS FOR VIRAL DISEASES The literature reviewed here indicates that ROS and RNOS production is strongly associated with pathogenesis of viral diseases.

AC

Therefore, the use of antioxidant molecules to ameliorate the symptoms and prognosis of viral infections is an active area of research. Current findings have been primarily confined to cell and animal models but remain promising. Reviews of specific pathogens

ST

and pathogen-related complications can be found elsewhere [89-92]. Vitamin and micronutrient supplementation have been shown to improve outcomes in HIV-infected patients either alone or with antiretroviral treatment [93,94]; vitamins and micronutrients work as

JU


disease [84,85]. These results highlight that increasing cellular

cofactors for enzymatic detoxification systems or by directly quenching ROS. However, optimal dosing must be taken into account since high doses have been shown to increase mortality and

toxicity [95]. Natural (epigallocatechin 3-gallate) and synthetic (dimethyl fumarate) antioxidants have also been shown to affect

gene transcription, act in pathways linked to host responses to viral pathogens, and have direct antiviral effects. This makes it difficult to isolate effects only associated with their antioxidant activity. A pilot study in human subjects showed that fermented papaya extract upregulated the expression of metabolism phase II enzymes and of SOD, which is promising for its use as a dietary supplement [96].

PT ED

Recent studies have also suggested that the use of NOS inhibitors and tissue damage [63,64]. CONCLUSION

ROS and RNOS production is common during viral infections and often results in pathological consequences. Many molecules that

regulate the cellular redox balance have proven promising in cell and

CE

animal models of infection. This encourages their use for clinical practice either alone or with existing therapies. However, well-

designed clinical trials are needed since the redox balance also has important roles in the host defence against pathogens. These trials

AC

are needed to assess the therapeutic benefits and secondary effects of these molecules and to analyse whether these effects vary for different viral infections. REFERENCES

ST

1. Burdon RH. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radical Biol Med 1995;18:775-94.

2. Castro SM, Guerrero-Plata A, Suarez-Real G, Adegboyega

JU


(i.e., during influenza infection) may attenuate lung inflammation

PA, Colasurdo GN, Khan AM, et al. Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation. Am J Respir Crit Care Med 2006;174:1361-9.

3. Garofalo RP, Kolli D, Casola A. Respiratory syncytial virus infection: mechanisms of redox control and novel therapeutic opportunities. Antioxid Redox Signal 2013;18:186-217. 4. Halliwell B, Gutteridge JM. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 1984;219:1-14. 5. Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert

PT ED

R, Jacob WA, Fiers W. Cytotoxic activity of tumor necrosis functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992;267:5317-23.

6. González-Amaro R, García-Monzón C, García-Buey L,

Moreno-Otero R, Alonso JL, Yagüe E et al. Induction of

tumor necrosis factor alpha production by human hepatocytes

CE

in chronic viral hepatitis. J Exp Med 1994;179:841-8. 7. Chrobot AM, Szaflarska-Szczepanik A, Drewa G.

Antioxidant defense in children with chronic viral hepatitis B and C. Med Sci Monit 2000;6:713-8.

AC

8. Boudreau HE, Emerson SU, Korzeniowska A, Jendrysik MA, Leto TL. Hepatitis C virus (HCV) proteins induce NADPH oxidase 4 expression in a transforming growth factor betadependent manner: a new contributor to HCV-induced

ST

oxidative stress. J Virol 2009;83:12934-46.

9. Li Y, Boehning DF, Qian T, Popov VL, Weinman SA. Hepatitis C virus core protein increases mitochondrial ROS

production by stimulation of Ca2+ uniporter activity. FASEB

JU


factor is mediated by early damage of mitochondrial

J 2007;21:2474-85.

10. Ming-Ju H, Yih-Shou H, Tzy-Yen C, Hui-Ling C. Hepatitis C virus E2 protein induce reactive oxygen species (ROS)related fibrogenesis in the HSC-T6 hepatic stellate cell line. J Cell Biochem 2011;112:233-43.

11. Dionisio N, Garcia-Mediavilla MV, Sanchez-Campos S, Majano PL, Benedicto I, Rosado JA, et al. Hepatitis C virus NS5A and core proteins induce oxidative stress-mediated calcium signalling alterations in hepatocytes. J Hepatol 2009;50:872-82. 12. Machida K, Cheng KT, Lai CK, Jeng KS, Sung VM, Lai

PT ED

MM. Hepatitis C virus triggers mitochondrial permeability to DNA damage and STAT3 activation. J Virol 2006;80:7199-207.

13. Paracha UZ, Fatima K, Alqahtani M, Chaudhary A,

Abuzenadah A, Damanhouri G, et al. Oxidative stress and hepatitis C virus. Virol J 2013;10:251.

CE

14. Lassoued S, Ben Ameur R, Ayadi W, Gargouri B, Ben

Mansour R, Attia H. Epstein-Barr virus induces an oxidative stress during the early stages of infection in B lymphocytes, epithelial, and lymphoblastoid cell lines. Mol Cell Biochem

AC

2008;313:179-86.

15. Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG. The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of

ST

reactive oxygen species. Proc Natl Acad Sci U.S.A. 2009;106:2313-8.

16. Aubert M, Chen Z, Lang R, Dang CH, Fowler C, Sloan DD, et al. The antiapoptotic herpes simplex virus glycoprotein J

JU


transition with production of reactive oxygen species, leading

localizes to multiple cellular organelles and induces reactive oxygen species formation. J Virol 2008;82:617-29.

17. Zeng D, Zhang T, Zhou S, Hu H, Li J, Huang K, et al. Proteomic analyses of gastric cancer cells treated with

vesicular stomatitis virus matrix protein. Protein J 2011;30:308-17. 18. Bhaskar A, Bala J, Varshney A, Yadava P. Expression of measles virus nucleoprotein induces apoptosis and modulates diverse functional proteins in cultured mammalian cells. PLoS One 2011;6:e18765.

PT ED

19. Claus C, Schönefeld K, Hübner D, Chey S, Reibetanz U,

by rubella virus with marginal induction of oxidative stress. J Virol 2013;87:8481-92.

20. Hosakote YM, Komaravelli N, Mautemps N, Liu T, Garofalo RP, Casola A. Antioxidant mimetics modulate oxidative

stress and cellular signaling in airway epithelial cells infected

CE

with respiratory syncytial virus. Am J Physiol Lung Cell Mol Physiol 2012;303:L991-1000.

21. Hosakote YM, Liu T, Castro SM, Garofalo RP, Casola A. Respiratory syncytial virus induces oxidative stress by

AC

modulating antioxidant enzymes. Am J Respir Cell Mol Biol 2009;41:348-57.

22. Hosakote YM, Jantzi PD, Esham DL, Spratt H, Kurosky A, Casola A, et al. Viral-mediated inhibition of antioxidant

ST

enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 2011;183:1550-60.

23. Agrawal L, Louboutin JP, Marusich E, Reyes BA, Van

JU


Liebert UG. Activity increase in respiratory chain complexes

Bockstaele EJ, Strayer DS. Dopaminergic neurotoxicity of HIV-1 gp120: reactive oxygen species as signaling intermediates. Brain Res 2010;1306:116-30.

24. Agrawal L, Louboutin JP, Strayer DS. Preventing HIV-1 Tatinduced neuronal apoptosis using antioxidant enzymes:

mechanistic and therapeutic implications. Virology 2007;363:462-72. 25. Isaguliants M, Smirnova O, Ivanov AV, Kilpelainen A, Kuzmenko Y, Petkov S, et al. Oxidative stress induced by HIV-1 reverse transcriptase modulates the enzyme's performance in gene immunization. Hum Vaccin

PT ED

Immunother 2013;9:2111-9.

vascular complications. Free Radic Biol Med 2012;53:14359.

27. Silic-Benussi M, Cavallari I, Vajente N, Vidali S, ChiecoBianchi L, Di Lisa F, et al. Redox regulation of T-cell

turnover by the p13 protein of human T-cell leukemia virus

CE

type 1: distinct effects in primary versus transformed cells. Blood. 2010;116:54-62.

28. Takahashi M, Higuchi M, Makokha GN, Matsuki H, Yoshita M, Tanaka Y, et al. HTLV-1 Tax oncoprotein stimulates

AC

ROS production and apoptosis in T cells by interacting with USP10. Blood 2013;122:715-25. 29. Hancock JT, Desikan R, Neill SJ . Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans

ST

2001;29(Pt 2):345-50.

30. Geller DA, Billiar TR. Molecular biology of nitric oxide synthases. Cancer and Metastasis Rev 1998;17:7-23.

31. Adamson DC, Kopnisky KL, Dawson TM, Dawson VL.

JU


26. Porter KM, Sutliff RL. HIV-1, reactive oxygen species, and

Mechanisms and structural determinants of HIV-1 coat protein, gp41-induced neurotoxicity. J Neurosci 1999;19:6471.

32. Yu QR, Zhang ZP, Zhang H, Lin HT, Li XM, Bai L, et al. Inducible nitric oxide synthase is involved in the oxidation

stress induced by HIV-1 gp120 in human retina pigment epithelial cells. Chin Med J (Engl) 2008;121:2578-83. 33. Polazzi E, Levi G, Minghetti L. Human immunodeficiency virus type 1 Tat protein stimulates inducible nitric oxide synthase expression and nitric oxide production in microglial cultures. J Neuropathol Exp Neurol 1999;58:825-31.

PT ED

34. García-Mediavilla MV, Sánchez-Campos S, González-Pérez Differential contribution of hepatitis C virus NS5A and core proteins to the induction of oxidative and nitrosative stress in human hepatocyte-derived cells. J Hepatol 2005;43:606-13. 35. Machida K, Cheng KT, Sung VM, Lee KJ, Levine AM, Lai MM. Hepatitis C virus infection activates the immunologic

CE

(type II) isoform of nitric oxide synthase and thereby

enhances DNA damage and mutations of cellular genes. J Virol 2004;78:8835-43.

36. Pindado J, Balsinde J, Balboa MA. TLR3-dependent

AC

induction of nitric oxide synthase in RAW 264.7 macrophage-like cells via a cytosolic phospholipase A2/cyclooxygenase-2 pathway. J Immunol 2007;179:4821-8. 37. Mgbemena V, Segovia J, Chang TH, Bose S. KLF6 and

ST

iNOS regulates apoptosis during respiratory syncytial virus infection. Cell Immunol 2013;283:1-7.

38. Morris KR, Lutz RD, Bai X, McGibney MT, Cook D, Ordway D, et al. Suppression of IFNgamma+mycobacterial

JU


P, Gómez-Gonzalo M, Majano PL, López-Cabrera M, et al.

lipoarabinomannan-induced NO by IL-4 is due to decreased IRF-1 expression. Tuberculosis (Edinb) 2009;89:294-303.

39. Stempin CC, Dulgerian LR, Garrido VV, Cerban FM. Arginase in parasitic infections: macrophage activation,

immunosuppression, and intracellular signals. J Biomed Biotechnol 2010;2010:683485. 40. Higashimoto Y, Ohata M, Yamagata Y, Iwata T, Masuda M, Ishiguchi T, et al. Effect of the adenovirus E1A gene on nitric oxide production in alveolar epithelial cells. Clin Microbiol Infect 2005;11:644-50.

PT ED

41. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and 1996;271(5 Pt 1):C1424-37.

42. van der Vliet A, Eiserich JP, Shigenaga MK, Cross CE. Reactive nitrogen species and tyrosine nitration in the respiratory tract: epiphenomena or a pathobiologic 1999;160:1-9.

CE

mechanism of disease? Am J Respir Crit Care Med

43. van Dalen CJ, Winterbourn CC, Kettle AJ. Mechanism of nitrite oxidation by eosinophil peroxidase: implications for oxidant production and nitration by eosinophils. Biochem J

AC

2006;394(Pt 3):707-13.

44. Mehlhase J, Grune T. Proteolytic response to oxidative stress in mammalian cells. Biol Chem 2002;383:559-67. 45. Netzer N, Goodenbour JM, David A, Dittmar KA, Jones RB,

ST

Schneider JR, et al. Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 2009;462:522-6.

46. Teoh CY, Davies KJ. Potential roles of protein oxidation and

JU


peroxynitrite: the good, the bad, and ugly. Am J Physiol

the immunoproteasome in MHC class I antigen presentation: the 'PrOxI' hypothesis. Arch Biochem Biophys 2004;423:8896.

47. Graziewicz MA, Day BJ, Copeland WC. The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res 2002;30:2817-24. 48. Akaike T, Okamoto S, Sawa T, Yoshitake J, Tamura F, Ichimori K, et al. 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis. Proc Natl

PT ED

Acad Sci USA 2003;100:685-90.

N, Koga Y. Nitric oxide mediates murine cytomegalovirusassociated pneumonitis in lungs that are free of the virus. J Clin Invest 1997;100:1822-30.

50. Mori I, Liu B, Hossain MJ, Takakuwa H, Daikoku T,

Nishiyama Y, et al. Successful protection by amantadine

CE

hydrochloride against lethal encephalitis caused by a highly neurovirulent recombinant influenza A virus in mice. Virology 2002;303:287-96.

51. Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS.

AC

Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 2005;6:150-66. 52. Toledo JC Jr, Augusto O. Connecting the chemical and biological properties of nitric oxide. Chem Res Toxicol

ST

2012;25:975-89.

53. Aslan M, Ryan TM, Townes TM, Coward L, Kirk MC, Barnes S, et al. Nitric oxide-dependent generation of reactive species in sickle cell disease. Actin tyrosine induces defective

JU


49. Tanaka K, Nakazawa H, Okada K, Umezawa K, Fukuyama

cytoskeletal polymerization.J Biol Chem 2003;278:4194-204.

54. Brown GC, Borutaite V. Nitric oxide, cytochrome c and mitochondria. Biochem Soc Symp 1999;66:17-25.

55. Li Z, Wu J, Deleo CJ. RNA damage and surveillance under oxidative stress. IUBMB Life 2006;58:581-8.

56. Calmels S, Hainaut P, Ohshima H. Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. Cancer Res 1997;57:3365-9. 57. Domingo E, Menéndez-Arias L, Holland JJ. RNA virus fitness. Rev Med Virol 1997;7:87-96. 58. Beck MA, Shi Q, Morris VG, Levander OA. Rapid genomic

PT ED

evolution of a non-virulent coxsackievirus B3 in seleniumisolates. Nat Med 1995;1:433-6.

59. Beck MA, Kolbeck PC, Rohr LH, Shi Q, Morris VC, Levander OA. Vitamin E deficiency intensifies the

myocardial injury of coxsackievirus B3 infection of mice. J Nutr 1994;124:345-8.

CE

60. Domingo E. Rapid evolution of viral RNA genomes. J Nutr 1997;127(5 Suppl):958S-961S.

61. Zumla A, James DG. Granulomatous infections: etiology and classification. Clin Infect Dis 1996;23:146-58.

AC

62. Croen KD. Evidence for antiviral effect of nnitric oxide. Inhibition of herpes simplex virus type 1 replication. J Clin Invest 1993;91:2446-52.

63. Saura M, Zaragoza C, McMillan A, Quick RA, Hohenadi C,

ST

Lowenstein JM. An antiviral mechanism of nitric oxide: inhibition of viral protease. Immunity 1999;10:21-8.

64. Akerström S, Gunalan V, Keng CT, Tan YJ, Mirazimi A. Dual effect of nitric oxide on SARS-CoV replication: viral

JU


deficient mice results in selection of identical virulent

RNA production and palmitoylation of the S protein are affected. Virology 2009;395:1-9.

65. Akerström S, Mousavi-Jazi M, Klingström J, Leijon M, Lundkvist A, Mirazimi A. Nitric oxide inhibits the

replication cycle of severe acute respiratory syndrome coronavirus. J Virol 2005;79:1966-9. 66. Charnsilpa W, Takhampunya R, Endy TP, Mammen MP, Libraty DH, Ubol S. Nitric oxide radical suppresses replication of wild-type dengue 2 viruses in vitro. J Med Virol 2005;77:89-95.

PT ED

67. Rimmelzwaan GF, Baars MM, de Lijster P, Fouchier RA, nitric oxide. J Virol 1999;73:8880-3.

68. Hobson L, Everard ML. Persistent of respiratory syncytial

virus in human dendritic cells and influence of nitric oxide. Clin Exp Immunol 2008;151:359-66.

69. Klingström J, Akerström S, Hardestam J, Stoltz M, Simon M,

CE

Falk KI, et al. Nitric oxide and peroxynitrite have different antiviral effects against hantavirus replication and free mature virions. Eur J Immunol 2006;36:2649-57. 70. Zheng S, De BP, Choudhary S, Comhair SA, Goggans T,

AC

Slee R, et al. Impaired innate host defense causes susceptibility to respiratory virus infections in cystic fibrosis. Immunity 2003;18:619-30.

71. Zhang X, Brunner T , Carter L, Dutton RW, Rogers P,

ST

Bradley L, et al. Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 1997;185:1837-49.

72. Chang RH, Feng MH, Liu WH, Lai MZ. Nitric oxide

JU


Osterhaus AD. Inhibition of influenza virus replication by

increased interleukin-4 expression in T lymphocytes. Immunology 1997;90:364-9.

73. Kallmann BA, Malzkorn R, Kolb H. Exogenous nitric oxide modulates cytokine production in human leukocytes. Life Sci 1999;65:1787-94.

74. Bauer H, Jung T, Tsikas D, Stichtenoth DO, Frölich JC, Neumann C. Nitric oxide inhibits the secretion of T-helper 1and T-helper 2-associated cytokines in activated human T cells. Immunology 1997;90:205-11. 75. Macphail SE, Gibney CA, Brooks BM, Booth CG, Flanagan BF, Coleman JW. Nitric oxide regulation of human

PT ED

peripheral blood mononuclear cells: critical time dependence Immunol 2003;171:4809-15.

76. Albina JE, Cui S, Mateo RB, Riecher JS. Nitric oxide-

mediated apoptosis in murine peritoneal macrophages. J Immunol 1993;150:5080-5.

77. Mebmer UK, Ankarcrona M, Nicotera P, Brune B. p53 1994;355:23-6.

CE

expression in nitric oxide-induced apoptosis. FEBS Lett

78. Melov S, Coskun P, Patel M, Tuinstra R, Cottrell B, Jun AS, et al. Mitochondrial disease in superoxide dismutase 2 mutant

AC

mice. Proc Natl Acad Sci U.S.A. 1999;96:846-51. 79. Esposito LA, Kokoszka JE, Waymire KG, Cottrell B, MacGregor GR, Wallace DC. Mitochondrial oxidative stress in mice lacking the glutathione peroxidase-1 gene. Free

ST

Radic Biol Med 2000;28:754-66.

80. Matsugo S, Yan LJ, Han D, Trischler HJ, Packer L. Elucidation of antioxidant activity of alpha-lipoic acid toward hydroxyl radical. Biochem Biophys Res Commun

JU


and selectivity for cytokine versus chemokine expression. J

1995;208:161-7.

81. Galano A, Alvarez-Idaboy JR. Glutathione: mechanism and kinetics of its non-enzymatic defense action against free radicals. RSC Adv 2011;1:1763-71.

82. Knoops B, Goemaere J, Van der Eecken V, Declercq JP. Peroxiredoxin 5: structure, mechanism, and function of the mammalian atypical 2-Cys peroxiredoxin. Antioxid Redox Signal 2011;15:817-29. 83. Manta B, Hugo M, Ortiz C, Ferrer-Sueta G, Trujillo M, Denicola A. The peroxidase and peroxynitrite reductase

PT ED

activity of human erythrocyte peroxiredoxin 2. Arch

84. Hosakote YM, Komaravelli N, Mautemps N, Liu T, Garofalo RP, Casola A. Antioxidant mimetics modulate oxidative

stress and cellular signaling in airway epithelial cells infected with respiratory syncytial virus. Am J Physiol Lung Cell Mol Physiol 2012;303:L991-1000.

CE

85. Dey N, Liu T, Garofalo RP, Casola A. TAK1 regulates NFΚB and AP-1 activation in airway epithelial cells following RSV infection. Virology 2011;418:93-101. 86. Li W, Liu H, Zhou JS, Cao JF, Zhou XB, Choi AM, et al.

AC

Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45related factor-2 (Nrf2). J Biol Chem 2012;287:20922-30. 87. Kesic MJ, Simmons SO, Bauer R, Jaspers I. Nrf2 expression

ST

modifies influenza A entry and replication in nasal epithelial cells. Free Radic Biol Med 2011;51:444–53.

88. Fan X, Staitieh BS, Jensen JS, Mould KJ, Greenberg JA, Joshi PC, et al. Activating the Nrf2-mediated antioxidant

JU


Biochem Biophys 2009;484:146-54.

response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats. Am J Physiol Lung Cell Mol Physiol 2013;305:L267-77.

89. Porter KM, Sutliff RL. HIV-1, reactive oxygen species, and vascular complications. Free Radic Biol Med 2012;53:14359. 90. Uchide N, Toyoda H. Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules 2011;16:2032-52.

PT ED

91. Ha HL, Shin HJ, Feitelson MA, Yu DY. Oxidative stress and 2010;16:6035-43.

92. Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach? Viruses 2012;4:2197-217.

93. Irlam JH, Visser MM, Rollins NN, Siegfried N.

CE

Micronutrient supplementation in children and adults with HIV infection. Cochrane Database Syst Rev 2010;12:CD003650.

94. Isanaka S, Mugusi F, Hawkins C, Spiegelman D, Okuma J,

AC

Aboud S, et al. Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial. JAMA 2012;308:1535-44.

ST

95. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2012;3:CD007176.

JU


antioxidants in hepatic pathogenesis. World J Gastroenterol

96. Marotta F, Naito Y, Jain S, Lorenzetti A, Soresi V, Kumari A et al. Is there a potential application of a fermented nutraceutical in acute respiratory illnesses? An in-vivo placebo-controlled, cross-over clinical study in different age

ST

JU PT ED

CE

AC


groups of healthy subjects. J Biol Regul Homeost Agents

2012;26:285-94.

Table Legends Table 1. Main viruses associated with reactive oxygen species (ROS) production. Virus Human immunodeficiency virus (HIV) Epstein-Barr virus (EBV)

PT ED

Hepatitis B virus (HBV) and hepatitis C virus (HCV)

(VSV)

Respiratory syncytial virus (RSV) Influenza viruses

ST

AC

CE

Human T cell leukaemia virus type 1 (HTLV-1)

JU


Herpes simplex type 1 (HSV-1) and vescicular stomatitis virus

Table 2. Main effects of reactive oxygen species (ROS) and reactive nitric oxide species (RNOS) on viruses and their hosts. Effect Cell damage, lysis and death Impairment in enzymatic protein activities Damage in nucleic acids (mainly DNA)

Mutations, protein alterations and cell metabolism dysregulation Immunosuppressive effects

ST

AC

CE

Impairment of Th1 responses

JU


of tissue damage

PT ED

Enhancement in the host inflammatory response with amplification

Manipulation of environmental oxygen modifies reactive oxygen and nitrogen species generation during myogenesis.

Reactive oxygen and nitrogen species: impact on endothelial dysfunction.

nitrogen species and contractile function in skeletal muscle during fatigue and recovery.

AMPK signaling in skeletal muscle during exercise: Role of reactive oxygen and nitrogen species.

reoxygenation in cardiomyoblasts; the roles of reactive oxygen and nitrogen species.

Role of Reactive Oxygen Species during Cell Expansion in Leaves.

Antagonizing reactive oxygen species during ex vivo lung perfusion.

Potential molecular mechanisms underlying muscle fatigue mediated by reactive oxygen and nitrogen species.

Oxidative Stress in the Developing Rat Brain due to Production of Reactive Oxygen and Nitrogen Species.

Biological Activities of Reactive Oxygen and Nitrogen Species: Oxidative Stress versus Signal Transduction.

Targeting cancer cells with reactive oxygen and nitrogen species generated by atmospheric-pressure air plasma.

Reactive oxygen and nitrogen species disturb Ca(2+) oscillations in insulin-secreting MIN6 β-cells.

In vivo imaging of reactive oxygen and nitrogen species in murine colitis.

Neuroprotection by genipin against reactive oxygen and reactive nitrogen species-mediated injury in organotypic hippocampal slice cultures.

Reactive oxygen species and airway inflammation.

Mitochondrial reactive oxygen species and cancer.

Cardiac mitochondria and reactive oxygen species generation.

Reactive oxygen species and redox compartmentalization.

Reactive Oxygen Species, Granulocytes, and NETosis.

Mitochondrial reactive oxygen species production and elimination.

Reactive oxygen species and human spermatozoa.

Oxygen radicals and reactive oxygen species in reproduction.

Gelidium elegans, an edible red seaweed, and hesperidin inhibit lipid accumulation and production of reactive oxygen species and reactive nitrogen species in 3T3-L1 and RAW264.7 cells.

Downregulation of Reactive Oxygen Species in Apoptosis.