key: cord-0003566-sop5vc4q
authors: Rehman, Zaib Ur; Meng, Chunchun; Sun, Yingjie; Safdar, Anum; Pasha, Riaz Hussain; Munir, Muhammad; Ding, Chan
title: Oxidative Stress in Poultry: Lessons from the Viral Infections
date: 2018-12-10
journal: Oxid Med Cell Longev
DOI: 10.1155/2018/5123147
sha: 22b2cb7ff5ea6e57e41098d8cf66aa69a5d04bc4
doc_id: 3566
cord_uid: sop5vc4q

Reactive species (RS), generally known as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are produced during regular metabolism in the host and are required for many cellular processes such as cytokine transcription, immunomodulation, ion transport, and apoptosis. Intriguingly, both RNS and ROS are commonly triggered by the pathogenic viruses and are famous for their dual roles in the clearance of viruses and pathological implications. Uncontrolled production of reactive species results in oxidative stress and causes damage in proteins, lipids, DNA, and cellular structures. In this review, we describe the production of RS, their detoxification by a cellular antioxidant system, and how these RS damage the proteins, lipids, and DNA. Given the widespread importance of RS in avian viral diseases, oxidative stress pathways are of utmost importance for targeted therapeutics. Therefore, a special focus is provided on avian virus-mediated oxidative stresses. Finally, future research perspectives are discussed on the exploitation of these pathways to treat viral diseases of poultry.

The theory of oxidative stress (oxygen-free radicals) existed since the last 60 years. However, extensive research in the last three decades has clarified myriads of misconceptions and explored leading roles of oxidative stress in the pathogenesis of many viral diseases [1, 2] . A wide range of the reactive species (RS) is produced as a result of the metabolic process in the body. These RS can be reactive oxygen species (ROS) or reactive nitrogen species (RNS). Previously, RS were only considered to be toxic compounds: however, recent studies have highlighted their involvements in complex cellular signaling pathways and have improved their importance in several biological systems [3] .

The ROS play vital roles in the signaling pathways, cytokine transcription, immunomodulation, ion transport, and apoptosis [4, 5] . Production of the ROS from activated innate immune cells such as neutrophils and macrophages is involved in the destruction of microbes/viruses and infected cells by oxidative bursts [6] . These ROS guide the development of adoptive immune responses, including the proliferation of T cells and positive mediation of B cell functions [7, 8] .

Importantly, due to the availability of high-tech facilities, commercial poultry is reared in extensive production systems and therefore is under constant threats to pathogens including viruses [9] . These viruses can infect primarily healthy birds and occasionally vaccinated flocks and cause an irreversible damage to different body tissues. Several viral diseases affect the production of the ROS [10] [11] [12] , and overproduction of ROS may cause the damage to DNA, protein, and lipid structures [13] , leading to the disruption of the cell functions. This imbalance in the production and detoxification of the ROS is collectively referred as oxidative stress. This review aims at highlighting the molecular mechanisms of oxidative stresses, deleterious effects on cell functions, and their roles in the pathobiology of avian viral infections.

Owing to the production-dependent oxidative stresses, exploring the molecular mechanisms of ROS production in living organisms is imperative. ROS are primarily produced from the mitochondria, endoplasmic reticulum, plasma membrane, and peroxisomes [14, 15] . Since most of the oxidative processes take place in the mitochondria in an effort to generate energy (about 18 times more energy is produced from oxidative process than from the conventional glycolysis [16] ), more than 90% of total ROS in eukaryotes is produced by the mitochondria [17] . In the living organisms, most of the consumed oxygen is converted to water in the electron-transport chain (ETC) by the cytochrome c oxidase without any contribution to ROS production [18] . These ROS include superoxide anion (O 2 − ), hydroxyl radical (OH), hydrogen peroxide (H 2 O 2 ), hydroperoxyl (HO 2 ), and hypochlorous acid (HOCl). Although all these ROS are important, the OH is of utmost importance due to its high reactivity, high mobility, low-molecular weight, and water solubility ( Figure 1) . A cell produces 50 hydroxyl radicals every second, which are about 4 million hydroxyl radicals in a day [19] . These radicals are generally neutralized and in worse cases could attack the cellular biomolecules leading to many diseases such as neurodegeneration, cardiovascular disease, and cancer [14] . Electrons from the ETC can be transferred to the O 2 resulting in O 2 − (Scheme 1, reaction (1)) by the process of oxidative phosphorylation. Another mode of O 2 − production is through the degradation of purine nucleotides to xanthine and hypoxanthine and subsequently to uric acid via xanthine oxidase (XO) [20, 21] . Hypoxic condition activates the XO by the posttranslational modification of xanthine dehydrogenase (XD). These changes lead to the excessive production of O 2 − and H 2 O 2 . In avian diseases, pathogens are recognised by the innate immune system leading to the production of O 2 − in the phagosome and outside the cells by the process of oxidative or respiratory burst, catalysed by the NADPH oxidase complex (NOX). This process of ROS production is critical to promote cellular responses [7] . The O 2 − , produced by the immune cells, can lead to the formation of other ROS such as HOCl, H 2 O 2 , peroxynitrite (ONOO − ), and OH [20, 22] . The OH radicals are produced from O 2 − by Fenton reaction (Scheme 1: reactions (2)-(4)). Another possible mechanism is the triggering of ROS production by the virus-induced cytokines. Taken together, ROS may be generated from the activation of XO, NADPH oxidase, lipoxygenases, and cyclooxygenase or from the leakage of electrons from ETC [23] .

The RNS are different products, derived from nitric oxide (NO), including nitrogen dioxide (NO 2 ), dinitrogen trioxide (N 2 O 3 ), nitroxyl anion (HNO), nitrosonium (NO + ), nitronium (NO 2 + ), ONOO − , nitrousoxide (HNO 2 ), nitrosoperoxycarbonate anion (ONOOCO 2 ), S-nitrosothiols (RSNOs), nitryl chloride (Cl-NO 2 ), and alkyl peroxynitrates (RONOO) [24] . The RNS are produced mainly from the NO, which is produced by the NO synthases (NOS), from L-arginine and oxygen. Direct biological action of NO is limited due to its less movement ability and less biological half-life in vivo. The NO 2 and NO 3 are considered to be the final products of NO and are produced by the oxidation of NOS-derived NO. Similarly, another RNS, ONOO − , is a result of the reaction of NO and O 2 − . This ONOO − reacts with tyrosine residues to result in nitration and reacts with CO 2 leading to the formation of carbonate (CO 3 − ) and NO 2 . Peroxynitrite affects many biological molecules ( Figure 1 ) such as modification of receptors [25] [26] [27] , calcium dysregulation [28, 29] , mitochondrial dysfunction [30, 31] , nitration and peroxidation of lipids [32] , protein damage [33] , and DNA damage ( Figure 1 ) [34] . These NO 2 and CO 3 − have strong ability to nitrate the proteins, lipids, and nucleic acids.

To cope with the oxidative stress, induced by the overproduction of the above-mentioned ROS and RNS, birds have a multilayered and well-defined antioxidant system. It is comprised of an enzymatic antioxidant system made up of catalases (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutaredoxins (GR) and a nonenzymatic system which is composed of glutathione (GSH), vitamin E, vitamin C, carotenoids, flavonoids, anserine, carnosine, homocarnosine, and melatonin. Enzymatic antioxidants are always produced in the body; however, they require cofactors such as zinc, magnesium, copper, manganese, iron, and selenium for their optimal functions whereas nonenzymatic antioxidants are naturally produced in situ or supplied by food/feeding [11] . Therefore, dietary supplementation of antioxidants may be a promising factor to reduce the damage caused by virus-induced oxidative stresses in the poultry [5] .

To prevent the oxidative damage to cells/tissues, O 2 − is converted to H 2 O 2 by the enzymatic action of SOD. There are four different selenium-dependent forms of GSH-Px in birds, which primarily convert the hydroperoxides and H 2 O 2 , to the H 2 O and O 2 by using the GSH [35] , whereas CAT also perform the same function ( Figure 1 ).

Due to continued production, all living organisms are in a constant struggle to minimize the oxidative damage. Excessive production of ROS and RNS has been observed in many viral infections [5, 10, 11, 20, 36] . Oxidative stress conditions contribute to the pathogenesis of viral infection. Even though these ROS and RNS are involved in many signalling pathways in viral diseases, the imbalance of ROS and RNS production and poor detoxification lead to extensive damage to many cellular compounds such as lipids, nucleic acids, and proteins ( Figure 1 ).

3.1. Nucleic Acid Damage. All the organic molecules are susceptible to oxidative stress; however, the most important impact is nucleic acid damage [37] . Oxidative stressinduced DNA damage may result in genomic instability, modification of nitrogenous bases and/or sugars, doublestranded DNA breaks, translocation, increased mutation rates, and apoptosis [34, [38] [39] [40] . Virus-induced oxidative stress directly or indirectly causes the DNA damage by modifying the nucleobases and sugar backbone and results in strand crosslinking, breakages, and base loss. Reactive species such as O 2 − , H 2 O 2 , and HO 2 lack any marked reactivity to nucleobases and 2-deoxyribose, but OH reacts with DNA in different ways. Recently, excellent reviews have been published on the oxidative damage to DNA [16, 40, 41] . Briefly, the production of OH radicals from the O 2 − by Fenton-type reaction reacts with the double bond of the 5,6-pyrimidine and 7,8-purine nucleobases leading to the formation of radical intermediates, which may react as oxidising agents [42] . Another most common method is the abstraction of hydrogen from the thymine and 5methylcytosine by OH radical, resulting in the formation of 5-(uracilyl) and 5-(cytosyl) methyl radicals [43] . These abstractions of hydrogen atoms at C3 and C5 result in the strand breakage; however, the abstraction of hydrogen at C4 results in more complex reactions. Guanine moiety most frequently undergoes oxidation by the RNS and ROS due to its lower reduction rate. Oxidation of adenine may be the initial site; however, it is repaired by the neighbouring guanine leading to the production of highly mutagenic 8- ), and dysfunctioning in the mitochondrial proteins function occurs. These defective mitochondrial proteins result in the leakage of electrons and superoxides from the mitochondria, as well as initiating the cell death pathways by cytochrome c (cyt c) or permeability transition pore (PTP). The NF-κB-induced transcription is initiated by the NF-κB resulting in the production of many cytokines as well as inducible NO synthase (iNOS). This iNOS produces large amounts of nitric oxide (NO). The NO and O 2 − react together to produce peroxynitrite (ONOO) which is a highly reactive compound and can cause the protein nitration, lipid peroxidation, DNA damage, and viral mutations. Similarly, higher production of O 2 − results in the production of H 2 O 2 by the catalytic activity of superoxide dismutase (SOD). Uncontrolled production of H 2 O 2 produces hydroxyl radicals (OH-) via reaction with metal cations, and these H 2 O 2 and OH-cause irreversible damage to cellular macromolecules: proteins, lipids, nucleic acids, etc.

(1)

Scheme 1: Production of ROS and Fenton reaction.

nitrodeoxyguanosine may be incorporated into the DNA by thymine or adenine, resulting in mutation and protein alteration. Proliferating cells are highly prone to nucleic acid damage by ROS and RNS, because those cells have dissociated histone from DNA which cannot protect them from the oxidative damage [20] . These reactive species also increase the mutation rate in viruses, particularly RNA viruses [46] . One of the most common damages by virusinduced oxidative stresses occurs to mitochondrial DNA (mDNA) due to ineffective repair mechanisms. ROS and RNS react with mDNA leading to mitochondrial dysfunction and activation of different cell death pathways ( Figure 1 ).

Extensive research has been conducted on the oxidative modification of proteins. These are the main targets of oxidants within the cell (about 69%) compared to lipids and nucleic acids (about 18% and 15%, respectively) [47, 48] . ROS and RNS react with proteins, resulting in the fragmentation of peptide chain, decreased protein solubility, aldehyde and ketone production, crosslinking of proteins, and oxidation of specific amino acid [20, 39, 49, 50] . Oxidative stresses can affect the proteins in a variety of ways both directly or indirectly. Direct oxidation is performed by different ROS, and indirect modification is mediated by oxidized forms of lipids and carbohydrates. Examples of direct modification include carbonylation, nitrosylation, glutathionylation, and disulphide bond formation of proteins. The second way of protein modification is through the oxidative products of lipids, proteins/amino acids, carbohydrates, and glutathione [51, 52] ; i.e., lipid peroxidation products from the hydroxynonenal, malondialdehyde, and acrolein react with proteins to induce protein oxidation [53, 54] . Different amino acids in the polypeptide chain differ in their susceptibility to oxidative stress. Sulphur-containing amino acids and thiol groups are more susceptible to oxidative stress [51] . ROS removes the hydrogen atom from the cysteine residue leading to the formation of thiyl radical, which reacts with the second thiyl radical to form disulphide bond and sulfenic, sulfinic, and sulfonic acids. Another way of oxidative damage is the addition of oxygen to methionine residue resulting in the formation of methionine sulphoxide derivative [55] . Tyrosine oxidation and nitration are mediated by O 2 − , ONOO − , and NO 2 to form bityrosine and 3-nitrotyrosine (markers of nitrative stress) [56] [57] [58] . These oxidised proteins undergo proteolytic digestion and proteasomal degradation. The 3-nitrotyrosine severely affects the microtubule structure leading to the functional impairments in the cell. 

Lipids are comparatively reduced molecules and an important cellular component [64] . Lipids undergo oxidation in the presence of ROS and/or RNS [65] and have been associated with the pathophysiology of many diseases. Oxidation of lipids is a complex process which is influenced by different factors including the degree of unsaturated fatty acids, position of fatty acids in the triacylglycerol molecules, lipid class, and presence of antioxidants in lipids [66] . Oxidation and nitrosylation of lipids generate highly reactive electrophilic aldehyde, peroxide adducts, and ketones. These molecules disrupt the lipid bilayer, cause inactivation of enzymes and other cellular proteins and membrane-bound receptors, and increase tissue permeability and diffusion [39, 67, 68] . The oxidation process of lipids is catalysed by different enzymes like lipoxygenases, cyclooxygenases, and cytochrome P450 [69] . Polyunsaturated fatty acids and low-density lipoprotein are the major targets of oxidation leading to cellular and tissue damages. For example, oxidation of lipids with ROS produces aldehydes, which react with proteins, nucleic acids, and other hydrocarbons. Lipid peroxidation is a three-step process, consisting of initiation, propagation, and termination [14, 69] . Initiation of oxidation can be mediated by different stimuli including gamma irradiation, transition metals, enzymes, hydroxyl radicals, and pathogen stress. These initiators like OH react with unsaturated lipids (LH) and extract the allylic hydrogen from lipids to produce alkyl radical (L * ) of unsaturated fatty acid (Scheme 2: equation (1)). In the propagation step, O 2 reacts with L * to form lipid peroxy radical (LOO * ) (Scheme 2: equation (2)). Then, LOO * reacts with another unsaturated lipid (LH) to form hydroperoxides and lipid radical (L * ) (Scheme 2: equation (3)). In the last stage of lipid peroxidation, two LOO * react with each other to form a nonradical product. Many antioxidants, like vitamin E, can dismiss the propagation step of lipid peroxidation. Vitamin E works as a chain-breaking antioxidant, reacts with LOO * to donate hydrogen ion, and converts to vitamin E radical and lipid hydroperoxide (LOOH) (Scheme 2: equation (5)). 

(3)

(1)

Scheme 2: Lipid peroxidation mechanism.

Vitamin E radical can be converted to nonradical vitamin E in the subsequent reaction by the ascorbic acid (vitamin C) or glutathione. The LOOH can decompose to generate different lipid peroxidation products; however, among those, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), hexanal, and propanal are the most studied [14, [70] [71] [72] [73] [74] . Comprehensive reviews and book chapters with chemistry detail of every step are available [66, 69, 75] . NO is not a strong oxidant and cannot directly abstract the bis-allylic hydrogen from fatty acids to initiate the lipid peroxidation [76] , but its products such as NO 2 and ONOO − initiate lipid oxidation [77] . In fact, NO is an inhibitor of lipid oxidation by facile scavenging of lipid peroxyl radicals [76, 78] .

Innate immune cells are activated in all the viral infections, causing the production of ROS and prooxidant cytokines and enhancing the iron uptake of a mononuclear phagocytic system (reticuloendothelial system) [79] . Viruses enhance the production of oxidants such as superoxide and NO and prevent the synthesis of CAT, SOD, and GPx resulting in the disruption of the redox balance. Less production and activity of these enzymes lead to a weak immune response, as these are required in high quantities for immune cells compared to other cells [11] . During viral infections, production of ROS is increased from the granulocytes and macrophages and exerts antimicrobial action against many pathogens [6] . Failure to ROS production leads to many opportunistic pathogens including Salmonella, Staphylococcus aureus, Serratia marcescens, and Aspergillus spp. [80] [81] [82] [83] . The direct antimicrobial action includes oxidation of DNA, protein, and lipid peroxidation [84] . Upon viral infection, ROS triggers a different pathway to kill or spread viral infections, including autophagy [85] , apoptosis [86] , and inhibition of mammalian target of rapamycin [87] . Moreover, ROS also interfere with the antigen presentation by innate immune cells, T cell polarization, and adaptive immune responses [84] . At the same time, research also supports the immunosuppressive effects of ROS which may also facilitate the viral infection and evolution [88] .

In the following sections, a disease/virus-wise cellular senescence in poultry is discussed.

Virus. Avian avulavirus 1, also known as Newcastle disease virus (NDV), is one of the most important pathogens affecting the poultry industry worldwide [89] . The first evidence of virus-induced oxidative stress came from the paramyxovirus, where it was highlighted that Sendai virus induces the oxidative stress by increasing the production of RS [90] .

Mesogenic and velogenic NDV cause the oxidative stress and increase the level of MDA and decrease the GSH and activities of SOD, CAT, GPx, GR, and GST in the brain and liver of chickens [91, 92] . Similarly, increased concentrations of the NO and MDA were noted in NDV-infected chickens [93] . NDV also increases the XO, uric acid (UA), superoxides, intracellular protein carbonyls (PCO), and nitrates in the brain and liver of infected birds [92, 94] . These adverse oxidative effects created by the NDV can be mitigated by the supplementation of vitamin E (Table 1) [92, 94] . It has been reported that haemagglutinin-neuraminidase (HN) increases the oxidative stress in chicken embryo fibroblast [95] . Further studies are needed to determine the role of other viral proteins and patterns of the oxidative stress in different tissues, which are mainly affected in Newcastle disease. Many studies have demonstrated the increased level or expression of NO in NDV-infected birds or cell lines [93, [96] [97] [98] [99] [100] [101] . These increased concentrations of RS are associated with the tissue damage in the brain and intestine of chickens [91] . Recently, saponins have shown the immune stimulatory for NDV [102, 103] and antioxidant properties for cyclophosphamide-induced oxidative stress in chicken [104] .

Avian influenza is the most serious zoonotic disease, caused by avian influenza virus (AIV), affecting the poultry industry worldwide. Extensive efforts to explore the pathology of AIV have revealed that RS plays an important role in mammals. But studies related to the role of oxidative stress induced by AIV are less in birds. AIV infection induces a strong influx of inflammatory cells, leading to the increased production of ROS by activating NADPH oxidase activity. Ye et al. [105] have performed a comprehensive study to elucidate the role of oxidative stress in the pathogenicity of H5N1, H7N9, H5N3, and H1N1 in different cells like adenocarcinomic human alveolar basal epithelial cells (A549), Madin-Darby canine kidney (MDCK) cells, chicken HD-11 macrophage, and DF-1 embryo fibroblast. Results indicate that inhibition of a Nox2 by apocynin inhibits the production of cytokines and reactive oxygen species (Table 1 ). Apocynin has also increased the virusinduced mRNA and protein expression of SOCS1 and SOCS3, which enhance the negative regulation of cytokines. In another study, Qi et al. [36] have found that NS1 protein of the H9N2 AIV is responsible for the ROS production and oxidative stress in primary chicken oviduct epithelial cells (COECs) ( Table 1 ). This disturbance of cellular redox homeostatic causes the apoptosis of COECs via a mitochondria-dependent pathway. NO is involved in the pathogenesis of influenza, and results of the previous studies indicate that inhibition of NO production increases the survival rate in influenza [106, 107] . Increased concentration of NO and/or iNOS expression was observed in influenza-infected chickens and ducks [108] [109] [110] . A number of studies suggest that RS increases the mortality, lung injury, and inflammation in influenza infection [111, 112] . Administration of antioxidants including vitamin E, vitamin C, N-acetyl-L-cysteine, pyrrolidine dithiocarbamate, glutathione, resveratrol, ambroxol, isoquercetin, and quercetin decreases the pathological effects caused by the influenza virus [113] [114] [115] [116] .

Avian reoviruses (ARV) are the members of Orthoreovirus genus which belongs to the Reoviridae family. ARV is a pathogenic agent for chicken, turkeys, [127] Antioxidant effects of vitamin E on the liver, brain, and heart of Newcastle disease virus-(NDV-) infected chickens

Chicken NDV infection increases in MDA levels and decreases activities of SOD, CAT, GPx, GR, GST, and levels of GSH in the brain and liver vitamin E lessens these effects NDV induces histological changes in the brain, liver, and heart [92] Investigate the role of NDV-induced oxidative stress in pathogenesis and protective effects of vitamin E Mesogenic NDV Chicken NDV infection increases XOD activity, UA, and superoxide radical level as well as intracellular protein carbonyls and nitrates in the brain and liver. Vitamin E mitigates NDVinduced oxidative damage NDV increases the apoptosis in the brain [94] Effect of NDV-induced pathological changes in the brain and protective effects of vitamin E [129] To examine the proteome profiles of tracheal and kidney tissues from chicken infected with highly virulent and attenuated IBV Highly virulent and attenuated IBV Chicken Virulent virus increasing the MnSOD protein than attenuating Some proteins involved in cytoskeleton organization and stress showed changes according to virus strain [130] To determine the antioxidant effects of Sargassum polysaccharide in IBDV induces oxidative stress

Sargassum polysaccharide prevents the lymphocytes from oxidative stress [134] To examine oxidative stress and DNA damage caused by MDV MDV Chicken Increase MDA and PCO and NO metabolites and decrease in antioxidant activity and GSH Positive correlation exists between DNA damage, MDA, PCO, and NOx in MDV-infected birds [145] Effect of inhibition of ROS production by apocynin on host cytokine homeostasis H1N1, H5N3, H5N1, H7N9

A549, MDCK, HD-11, and DF-1 cells Apocynin inhibited the ROS production from infected cells Apocynin increased the expression of SOCS1 and SOCS3 and inhibited the influenza-induced cytokines [105] To elucidate the role of H9N2 NS1 protein in the pathogenicity in the COECs H9N2 NS1 protein COECs H9N2 NS1 protein increases the ROS production and decreases SOD activity

Pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC) significantly inhibited NS1-induced apoptosis [36] ducks, geese, and many other species of birds and causes viral arthritis/tenosynovitis, stunting syndrome, respiratory and enteric disease, immunosuppression, and malabsorption syndrome [117, 118] . The ARV and its σC protein have been shown to increase the lipid peroxidation and generation of ROS (Table 1) . Furthermore, ARV and σC also induce DNA damage which was confirmed by comet assay and expression patterns of DNA-damage-responsive gene DDIT-3 and H2AX phosphorylation [119] . This DNA damage response might be associated with the ROS because DDIT-3 has been shown to be induced by ROS [120] . Overexpression of DDIT-3 may be the reason for ARV-induced apoptosis because it has been confirmed in many other viral infections [121, 122] .

is an acute, contagious, and lethal disease of young ducklings, characterized by rapid transmission and severe hepatitis, which was first described on Long Island, NY, USA, in 1949 [123] [124] [125] . There are three different serotypes (1, 2, and 3) of DHAV; from these, serotype 1 (DHAV 1) is commonly distributed and the most virulent compared to others [126] . DHAV leads to persistent infection and causes oxidative stress in ducks. Culturing of LMH chicken hepatoma cells in the presence of different concentrations of the hydrogen peroxide increases the integration of the duck hepatitis virus (DHV) genome into the host genome in a dose-dependent way [127] . DHAV 1infected ducklings show higher plasma levels of iNOS and MDA and decreased level of the GPx and CAT (Table 1) , which leads to necrosis as well as apoptosis of hepatocytes [128] . Supplementation of icariin, phosphorylated icariin, and baicalin-linarin-icariin-notoginsenoside R1 (BLIN) decreases the hepatocyte damage caused by DHAV by attenuating the oxidative stress [123, 128] . Another study confirmed that Taraxacum mongolicum extract protects the duck embryo hepatocytes from the infection of duck hepatitis B virus by alleviating the oxidative stress [129] . Furthermore, these studies confirm that DHAV causes damage to hepatocytes by oxidative stress, and prevention of oxidative stress lessens the tissue damage, necrosis, and mortality of duckling, clearly indicating the role of oxidative stress in the pathogenesis of DHV ( Figure 2 ).

in all poultry-producing regions of the world. The IBV virulence affects the oxidative status by differentially modulating MnSOD. Highly virulent strain significantly increases the level of MnSOD than an attenuated virus. Increased level of MnSOD may direct the more significant immune response to eradicate the virus [130] . The same group of researchers also demonstrated that IBV infection increases the abundance of glutathione S-transferase 2, a protein of the sulfotransferase family, and L-lactate dehydrogenase [131] .

4.6. Infectious Bursal Disease Virus. Infectious bursal disease (IBD) or Gumboro is caused by the infectious bursal disease virus (IBDV), which is one of the most devastating diseases of poultry, worldwide [132] . In intensive poultry production, IBD causes heavy economic loses by causing 80-100% mortality and prolonged immunosuppression [133] . Figure 2 : The scheme summarizes the effect of common avian viruses on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). After viral insult, cells recognise them by different pattern recognition receptors and enhance the production of ROS/RNS species, which are involved in the cell migration, cell signalling, macrophage polarization, requirement of immune cells, and importantly clearance to host from invading pathogens. But in chronic or overproduction of viruses, hijack the production of ROS/RNS by disturbing different cellular pathways/organelles like mitochondrial metabolism, leading to a decrease the activity/level of cellular enzymatic and nonenzymatic antioxidants. It leads to increased pathological damage in poultry. It leads to increased pathological damage in poultry.

impairment of the antibody response [132] . Infectious bursal disease virus (IBDV) infection of bursal lymphocytes increases intracellular ROS levels, decreases the GSH content and activities of GPx and SOD [134] , and increases serum levels of lipid peroxidation (Table 1 ) [135] . The increased level of ROS may be involved in the shutoff cellular protein synthesis [136] , because ROS are involved in the activation of the protein kinase R pathway [137] , leading to cell death [136, 138] . Although the precise pathway of IBDV-induced apoptosis is not known, it has been shown that overexpression of oral cancer overexpressed 1 (ORAOV1) protein decreased the release of IBDV from infected cells. Stable overexpression of ORAOV1 is involved in the resistance to oxidative stress [139] which may decrease the IBDVinduced apoptosis [140] . These IBDV-induced oxidative stress and mortality can be reduced by Sargassum polysaccharide, Ginsenoside Rg1, and vitamin E supplementation (Table 1 ) [134, 135, 141, 142] .

Marek's Disease Virus.

Marek's disease (MD), caused by the MD virus (MDV) also known as Gallid herpesvirus 2, is an important neoplastic disease of poultry. MD has been shown to cause the aberrations in the oxidative status of birds (Table 1) . Hao et al. [143] have found that MDV infection of chickens leads to increased lipid peroxidation and decreased activity of Se-GSH-PX in the spleen, thymus, bursa, heart, liver, kidneys, and gonads. Similarly, Kishore [144] found the decreased activities of SOD, CAT, GST, and GPX and level of GSH in the liver of MDV-infected chickens. Keles et al. [145] have demonstrated that MD induces DNA damage and increases concentration of MDA and PCO and plasma concentration of NO. Furthermore, it also decreases the total antioxidant activities as well as GSH in MDVinfected birds. The MDV-infected chicken shows a significant positive correlation between DNA damage, MDA, PCO, and NOx. Results of Bencherit et al. [146] suggest that MDV infection increases the production of ROS and RNS and induces DNA damage. This DNA damage may be the result of ROS and RNS. MDV infection only causes the DNA breaks in lytically infected cells and not in latently infected cells. DNA damage in MDV-infected cells is caused by the viral protein 22 and might be involved in the oncogenicity of MDV [146] .

Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus, belongs to genus Alpharetrovirus of the subfamily Orthoretrovirinae of family Retroviridae, and causes immunosuppressive and oncogenic disease in poultry, leading to heavy economic losses [147] [148] [149] .

The ALV-J induces the production of NO from monocyte-derived macrophages at 12, 24, and 36 hours postinfection [150] , but this production was not too much. However, the results of Landman et al. [151] demonstrate the nonsignificant effect of ALV-J on NO of spleen-derived macrophages. Birds infected with avian erythroblastosis virus show suppressed splenic T cell mitogen responses [152] . These immune dysfunctions can be ameliorated by the supplementation of vitamin E, Trolox, butylated hydroxyanisole, and butylated hydroxytoluene [153] . These protective effects of antioxidants indicate the involvement of oxidative stress in retrovirus infection in chicken. Another indirect evidence indicates the involvement of oxidative stress in avian sarcoma and leukosis virus infection, as it increases the cellular DNA damage response in infected cells [154] .

Production of RS by the innate immune cells is a typical process in viral diseases to counteract their replication. Nonetheless, many viruses employ different strategies to manipulate this phenomenon and it became overwhelming for the endogenous antioxidants leading to the oxidation of lipids, proteins, nucleic acids, cell membranes, and other organelles. Scavenging of oxidative stress is an important tool to prevent tissue damage and severe complications associated with the viral diseases in the poultry. Many antioxidants have been proven to prevent the oxidative stresses, enhance the immune responses, and inhibit the virus replication, which can be used to decrease the tissue damage and complications associated with viral diseases in poultry. It would be of great interest to supplement the antioxidants such as vitamin E, vitamin C, N-acetyl-L-cysteine, pyrrolidine dithiocarbamate, glutathione, resveratrol, ambroxol, isoquercetin, and quercetin to decrease the pathological effects triggered by avian viral diseases. However, clinical trials are required to demonstrate the therapeutic roles of these antioxidants in avian viral diseases.

None of the authors of this study has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the article.

The authors declare that they have no competing interests.

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Glutathione peroxidases in poultry biology: part 1. Classification and mechanisms of action

The NS1 protein of avian influenza virus H9N2 induces oxidative-stressmediated chicken oviduct epithelial cells apoptosis

The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium

Nitrative DNA damage in inflammation and its possible role in carcinogenesis

Oxidative stress and antioxidant defense

Formation and repair of oxidatively generated damage in cellular DNA

DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation

Oxidatively generated base damage to cellular DNA by hydroxyl radical and one-electron oxidants: similarities and differences

Oxidatively generated base damage to cellular DNA

Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurination

8-nitroguanosine formation in viral pneumonia and its implication for pathogenesis

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates

Redox regulation of protein kinases

Protein quality control under oxidative stress conditions

Protein oxidation at the airlung interface

Oxidative modification of proteins: age-related changes

Protein oxidation: basic principles and implications for meat quality

Malondialdehydealtered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits

A novel mechanism for oxidative cleavage of prolyl peptides induced by the hydroxyl radical

Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein

Effects of dietary protein content and 2-hydroxy-4-methylthiobutanoic acid or DL-methionine supplementation on performance and oxidative status of broiler chickens

Protein damage and degradation by oxygen radicals. I. General aspects

Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions

Connecting the chemical and biological properties of nitric oxide

Peroxynitrite: biochemistry, pathophysiology and development of therapeutics

Hydrogen peroxide inactivates the Escherichia coli Isc iron-sulphur assembly system, and OxyR induces the Suf system to compensate

Inhibitory effects of theophylline on the peroxynitrite-augmented release of matrix metalloproteinases by lung fibroblasts

Role of ROS and RNS sources in physiological and pathological conditions

Oxidative stress, mitochondrial damage and neurodegenerative diseases

An introduction to redox balance and lipid oxidation

Lipid peroxidation and neurodegenerative disease

Lipid oxidation and improving the oxidative stability

Mitochondria and reactive oxygen species. Which role in physiology and pathology?

Mitochondria and nitric oxide: chemistry and pathophysiology

Free radical lipid peroxidation: mechanisms and analysis

4-Hydroxy-2-nonenal, a reactive product of lipid peroxidation, and neurodegenerative diseases: a toxic combination illuminated by redox proteomics studies

Lipid peroxidation and its toxicological implications

Studies on the mechanism of formation of 4-hydroxynonenal during microsomal lipid peroxidation

Detection of 4-hydroxynonenal as a product of lipid peroxidation in native Ehrlich ascites tumor cells

Detection of malonaldehyde by high-performance liquid chromatography

Lipid peroxidation: chemical mechanism, biological implications and analytical determination

Nitric oxide and lipid peroxidation

Peroxynitrite rapidly permeates phospholipid membranes

Nitric oxide reaction with lipid peroxyl radicals spares α-tocopherol during lipid peroxidation. Greater oxidant protection from the pair nitric oxide/α-tocopherol than α-tocopherol/ascorbate

Oxidative stress during viral infection: a review

Chronic granulomatous disease and other disorders of phagocyte function

Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production

Chronic granulomatous disease: the European experience

Report on a national registry of 368 patients

Are reactive oxygen species always detrimental to pathogens?

Autophagy signaling through reactive oxygen species

Possible role of reactive oxygen species in antiviral defense

Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling

Rapid evolution of viral RNA genomes

Potential of genotype VII Newcastle disease viruses to cause differential infections in chickens and ducks

Sendai virus stimulates chemiluminescence in mouse spleen cells

Vitamin E supplementation ameliorates Newcastle disease virus-induced oxidative stress and alleviates tissue damage in the brains of chickens

Perturbations in the antioxidant metabolism during Newcastle disease virus (NDV) infection in chicken: protective role of vitamin E

The effects of different velogenic NDV infections on the chicken bursa of Fabricius

Newcastle disease virus (NDV) induces protein oxidation and nitration in brain and liver of chicken: ameliorative effect of vitamin E

HN protein of Newcastle disease virus causes apoptosis in chicken embryo fibroblast cells

In vitro responses of chicken macrophage-like monocytes following exposure to pathogenic and non-pathogenic E. coli ghosts loaded with a rational design of conserved genetic materials of influenza and Newcastle disease viruses

Virulent Newcastle disease virus elicits a strong innate immune response in chickens

The cytotoxic anti-tumor effect of MTH-68/H, a live attenuated Newcastle disease virus is mediated by the induction of nitric oxide synthesis in rat peritoneal macrophages in vitro

Newcastle disease virus-induced functional impairments and biochemical changes in chicken heterophils

A eukaryotic expression plasmid carrying chicken interleukin-18 enhances the response to Newcastle disease virus vaccine

Genetically engineered Newcastle disease virus expressing human interferon-λ1 induces apoptosis in gastric adenocarcinoma cells and modulates the Th1/Th2 immune response

Enhancement of humoral immune responses to inactivated Newcastle disease and avian influenza vaccines by oral administration of ginseng stem-and-leaf saponins in chickens

Effect of oral administration of ginseng stem-and-leaf saponins (GSLS) on the immune responses to Newcastle disease vaccine in chickens

Oral administration of tea saponins to relive oxidative stress and immune suppression in chickens

Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3

Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice

Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals

Increased inducible nitric oxide synthase expression in organs is associated with a higher severity of H5N1 influenza virus infection

A single substitution in amino acid 184 of the NP protein alters the replication and pathogenicity of H5N1 avian influenza viruses in chickens

NP, PB1, and PB2 viral genes contribute to altered replication of H5N1 avian influenza viruses in chickens

NADPH oxidases as novel pharmacologic targets against influenza A virus infection

Intracellular redox state as target for anti-influenza therapy: are antioxidants always effective?

Antioxidant therapy as a potential approach to severe influenza-associated complications

Effect of vitamin E and vitamin C combination on experimental influenza virus infection

Vitamin E supplementation decreases lung virus titers in mice infected with influenza

Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus

Reovirus infections

Avian reovirus: structure and biology

Avian reovirus S1133-induced DNA damage signaling and subsequent apoptosis in cultured cells and in chickens

Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect

ROS mediates baicalininduced apoptosis in human promyelocytic leukemia HL-60 cells through the expression of the Gadd153 and mitochondrial-dependent pathway

Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response

Treatment effect of a flavonoid prescription on duck virus hepatitis by its hepatoprotective and antioxidative ability

Molecular detection and typing of duck hepatitis A virus directly from clinical specimens

A hitherto-undescribed virus disease of ducks in North America

Characterization of monoclonal antibodies against duck hepatitis type 1 virus VP1 protein

Increase in the frequency of hepadnavirus DNA integrations by oxidative DNA damage and inhibition of DNA repair

Roles of the antioxidant properties of icariin and its phosphorylated derivative in the protection against duck virus hepatitis

Taraxacum mongolicum extract exhibits a protective effect on hepatocytes and an antiviral effect against hepatitis B virus in animal and human cells

Proteomics analysis of differentially expressed proteins in chicken trachea and kidney after infection with the highly virulent and attenuated coronavirus infectious bronchitis virus in vivo

Proteomic analysis of chicken embryonic trachea and kidney tissues after infection in ovo by avian infectious bronchitis coronavirus

Interaction of infectious bursal disease virus with the immune system of poultry

Comparison of the Pathogenesis of Infectious Bursal Disease Virus in Genetically Different Chickens after Infection with Virus Strains of Different Virulence

Inhibitory effect of Sargassum polysaccharide on oxidative stress induced by infectious bursa disease virus in chicken bursal lymphocytes

The effects of vitamin E supplementation on serum lipid peroxidation level and feed intake in birds infected with infectious bursal disease of chickens

Infectious bursal disease virus-host interactions: multifunctional viral proteins that perform multiple and differing jobs

Oxidative stress induces PKR-dependent apoptosis via IFN-γ activation signaling in Jurkat T cells

NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production

VP2 of infectious bursal disease virus induces apoptosis via triggering oral cancer overexpressed 1 (ORAOV1) protein degradation

Ginsenoside Rg1 enhanced immune responses to infectious bursal disease vaccine in chickens with oxidative stress induced by cyclophosphamide

Effect of a vitamin E-selenium combination on chickens infected with infectious bursal disease virus

Changes of activity of Se-GSH-PX and the content of LPO in chickens infected with vMDV

Oxidative stress in liver tissues of Marek's disease affected layer chicken

Increased DNA damage and oxidative stress in chickens with natural Marek's disease

Induction of DNA damages upon Marek's disease virus infection: implication in viral replication and pathogenesis

The long view: 40 years of avian leukosis research

Avian leukosis virus subgroup J: a rapidly evolving group of oncogenic retroviruses

Molecular characteristics of avian leukosis viruses isolated from indigenous chicken breeds in China

ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages

Effect of an in ovo infection with a Dutch avian leukosis virus subgroup J isolate on the growth and immunological performance of SPF broiler chickens

Immune abnormalities in avian erythroblastosis virus-infected chickens

RRR-α-tocopheryl succinate enhances T cell mitogen-induced proliferation and reduces suppressor activity in spleen cells derived from AEVinfected chickens

Avian sarcoma and leukosis virus cytopathic effect in the absence of TVB death domain signaling

Newcastle disease virus-induced cytopathic effect in infected cells is caused by apoptosis