Inflammation Research

, Volume 64, Issue 11, pp 845–852 | Cite as

Role of nitric oxide in immune responses against viruses: beyond microbicidal activity

  • Elaine Uchima Uehara
  • Beatriz de Stefano Shida
  • Cyro Alves de Brito



Nitric oxide (NO) is a free radical produced during l-arginine metabolism. In addition to its physiological activities in vascular and neuronal functions, its role in the immune system as a microbicide and tumor-killing mediator has been well described, as well as its release by activated macrophages. Furthermore, NO is produced by a variety of immune and non-immune cells and is involved in the regulation of several immune functions, such as T-cell polarization and suppression.


Viral infections generally promote NO production; however, according to its concentration, NO can trigger different effector mechanisms in immune responses. NO can activate the second messenger cyclic guanosine monophosphate (cGMP), can increase the cytoplasmic p53 tumor suppressor molecule, and can modify host and viral molecules by nitrosylation. Because of its microbicide function, NO has frequently been considered a protective mediator in viral infections; however, in some cases NO could be deleterious, potentiating inflammation or contributing to virus latency.


Thus, advances in the knowledge of the role of NO in immunomodulation and in the pathogenesis of viral diseases could contribute not only to the development of vaccines and therapeutic strategies but also to the use of its metabolites (nitrate/nitrite) and the enzyme responsible for its production (iNOS) as prognostic markers of some of these viral infections.


Nitric oxide Immunomodulation Virus Immune response 



Danger-associated molecular pattern


N G-methyl-d-arginine


Inducible nitric oxide synthase


Interferon regulatory factor 1


N G-Methyl-l-arginine


N G-Monomethyl-l-arginine


Pathogen-associated molecular pattern



We would like to thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—2013/03563-6) for funding support.


  1. 1.
    Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Hibbs JB, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for l-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987;235:473–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Stuehr DJ, Gross SS, Sakuma I, Levi R, Nathan CF. Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J Exp Med. 1989;169:1011–20.CrossRefPubMedGoogle Scholar
  4. 4.
    Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994;298(Pt 2):249–58.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol. 1997;15:323–50.CrossRefPubMedGoogle Scholar
  6. 6.
    Kleinert H, Pautz A, Linker K, Schwarz PM. Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol. 2004;500:255–66.CrossRefPubMedGoogle Scholar
  7. 7.
    Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–37.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Niedbala W, Wei XQ, Campbell C, Thomson D, Komai-Koma M, Liew FY. Nitric oxide preferentially induces type 1 T cell differentiation by selectively up-regulating IL-12 receptor beta 2 expression via cGMP. Proc Natl Acad Sci USA. 2002;99:16186–91.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Niedbala W, Wei XQ, Piedrafita D, Xu D, Liew FY. Effects of nitric oxide on the induction and differentiation of Th1 cells. Eur J Immunol. 1999;29:2498–505.CrossRefPubMedGoogle Scholar
  10. 10.
    Yang Jianjun, Zhang R, Lu G, Shen Y, Peng L, Zhu C, et al. T cell–derived inducible nitric oxide synthase switches off Th17 cell differentiation. J Exp Med. 2013;210:1447–62.PubMedCentralCrossRefGoogle Scholar
  11. 11.
    Niedbala W, Cai B, Liu H, Pitman N, Chang L, Liew FY. Nitric oxide induces CD4+ CD25+ Foxp3 regulatory T cells from CD4+ CD25 T cells via p53, IL-2, and OX40. Proc Natl Acad Sci USA. 2007;104:15478–83.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Niedbala W, Besnard AG, Jiang HR, Alves-Filho JC, Fukada SY, Nascimento D, et al. Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function. J Immunol. 2013;191:164–70.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, et al. Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J Exp Med. 2013;210:1433–45.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Giordano D, Draves KE, Li C, Hohl TM, Clark EA. Nitric oxide regulates BAFF expression and T cell-independent antibody responses. J Immunol. 2014;193:1110–20.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Saini AS, Shenoy GN, Rath S, Bal V, George A. Inducible nitric oxide synthase is a major intermediate in signaling pathways for the survival of plasma cells. Nat Immunol. 2014;15:275–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Akaike T, Maeda H. Nitric oxide and virus infection. Immunology. 2000;101:300–8.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Schmutzhard E. Viral infections of the CNS with special emphasis on herpes simplex infections. J Neurol. 2001;248:469–77.CrossRefPubMedGoogle Scholar
  18. 18.
    Zolini GP, Lima GK, Lucinda N, Silva MA, Dias MF, Pessoa NL, et al. Defense against HSV-1 in a murine model is mediated by iNOS and orchestrated by the activation of TLR2 and TLR9 in trigeminal ganglia. J Neuroinflammation. 2014;11:20.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Phipps S, Lam CE, Mahalingam S, Newhouse M, Ramirez R, Rosenberg HF, et al. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood. 2007;110:1578–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Su YC, Townsend D, Herrero LJ, Zaid A, Rolph MS, Gahan ME, et al. Dual pro-inflammatory and antiviral properties of pulmonary eosinophils in respiratory syncytial virus (RSV) vaccine-enhanced disease. J Virol. 2014.Google Scholar
  21. 21.
    Tripp RA, Jones L, Anderson LJ, Brown MP. CD40 ligand (CD154) enhances the Th1 and antibody responses to respiratory syncytial virus in the BALB/c mouse. J Immunol. 2000;164:5913–21.CrossRefPubMedGoogle Scholar
  22. 22.
    Bingaman AW, Pearson TC, Larsen CP. The role of CD40L in T cell-dependent nitric oxide production by murine macrophages. Transpl Immunol. 2000;8:195–202.CrossRefPubMedGoogle Scholar
  23. 23.
    Costa E, Vasconcelos J, Santos E, Laranjeira A, Castro e Melo J, Barbot J. Neutrophil dysfunction in a case of glucose-6-phosphate dehydrogenase deficiency. J Pediatr Hematol Oncol. 2002;24:164–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Al-Alimi AA, Ali SA, Al-Hassan FM, Idris FM, Teow SY, Mohd Yusoff N. Dengue virus type 2 (DENV2)-induced oxidative responses in monocytes from glucose-6-phosphate dehydrogenase (G6PD)-deficient and G6PD normal subjects. PLoS Negl Trop Dis. 2014;8:e2711.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity. 2003;19:59–70.CrossRefPubMedGoogle Scholar
  26. 26.
    Aldridge JR, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci USA. 2009;106:5306–11.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Ghafourifar P, Cadenas E. Mitochondrial nitric oxide synthase. Trends Pharmacol Sci. 2005;26:190–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Piccoli C, Scrima R, Quarato G, D’Aprile A, Ripoli M, Lecce L, et al. Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress. Hepatology. 2007;46:58–65.CrossRefPubMedGoogle Scholar
  29. 29.
    Akaike T, Noguchi Y, Ijiri S, Setoguchi K, Suga M, Zheng YM, et al. Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci USA. 1996;93:2448–53.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Perrone LA, Belser JA, Wadford DA, Katz JM, Tumpey TM. Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice. J Infect Dis. 2013;207:1576–84.CrossRefPubMedGoogle Scholar
  31. 31.
    Torre D, Pugliese A, Speranza F. Role of nitric oxide in HIV-1 infection: friend or foe? Lancet Infect Dis. 2002;2:273–80.CrossRefPubMedGoogle Scholar
  32. 32.
    Jiménez JL, González-Nicolás J, Alvarez S, Fresno M, Muñoz-Fernández MA. Regulation of human immunodeficiency virus type 1 replication in human T lymphocytes by nitric oxide. J Virol. 2001;75:4655–63.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Bukrinsky MI, Nottet HS, Schmidtmayerova H, Dubrovsky L, Flanagan CR, Mullins ME, et al. Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. J Exp Med. 1995;181:735–45.CrossRefPubMedGoogle Scholar
  34. 34.
    Torre D, Ferrario G. Immunological aspects of nitric oxide in HIV-1 infection. Med Hypotheses. 1996;47:405–7.CrossRefPubMedGoogle Scholar
  35. 35.
    de Souza KP, Silva EG, de Oliveira Rocha ES, Figueiredo LB, de Almeida-Leite CM, Arantes RM, et al. Nitric oxide synthase expression correlates with death in an experimental mouse model of dengue with CNS involvement. Virol J. 2013;10:267.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Lin CF, Lei HY, Shiau AL, Liu HS, Yeh TM, Chen SH, et al. Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol. 2002;169:657–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Chen CL, Lin CF, Wan SW, Wei LS, Chen MC, Yeh TM, et al. Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation. J Immunol. 2013;191:1744–52.CrossRefPubMedGoogle Scholar
  38. 38.
    Lin CF, Lei HY, Shiau AL, Liu CC, Liu HS, Yeh TM, et al. Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol. 2003;69:82–90.CrossRefPubMedGoogle Scholar
  39. 39.
    Ronaldson PT, Bendayan R. HIV-1 viral envelope glycoprotein gp120 produces oxidative stress and regulates the functional expression of multidrug resistance protein-1 (Mrp1) in glial cells. J Neurochem. 2008;106:1298–313.CrossRefPubMedGoogle Scholar
  40. 40.
    Walsh KA, Megyesi JF, Wilson JX, Crukley J, Laubach VE, Hammond RR. Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity. J Neuroinflammation. 2004;1:8.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature. 1993;364:626–32.CrossRefPubMedGoogle Scholar
  42. 42.
    Tache DE, Stănciulescu CE, BaniŢă IM, Purcaru SO, Andrei AM, Comănescu V, et al. Inducible nitric oxide synthase expression (iNOS) in chronic viral hepatitis and its correlation with liver fibrosis. Rom J Morphol Embryol. 2014;55:539–43.PubMedGoogle Scholar
  43. 43.
    Hazam RK, Deka M, Kar P. Role of nitric oxide synthase genes in hepatitis E virus infection. J Viral Hepat. 2014;21:671–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD, et al. Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. J Virol. 2004;78:10370–7.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Hensley LE, Young HA, Jahrling PB, Geisbert TW. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunol Lett. 2002;80:169–79.CrossRefPubMedGoogle Scholar
  46. 46.
    Geisbert TW, Young HA, Jahrling PB, Davis KJ, Larsen T, Kagan E, et al. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Am J Pathol. 2003;163:2371–82.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol. 2003;163:2347–70.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Akaike T, Fujii S, Kato A, Yoshitake J, Miyamoto Y, Sawa T, et al. Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J. 2000;14:1447–54.CrossRefPubMedGoogle Scholar
  49. 49.
    Beck MA, Shi Q, Morris VC, Levander OA. Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nat Med. 1995;1:433–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Colasanti M, Persichini T, Venturini G, Ascenzi P. S-nitrosylation of viral proteins: molecular bases for antiviral effect of nitric oxide. IUBMB Life. 1999;48:25–31.CrossRefPubMedGoogle Scholar
  51. 51.
    Hernansanz-Agustín P, Izquierdo-Álvarez A, García-Ortiz A, Ibiza S, Serrador JM, Martínez-Ruiz A. Nitrosothiols in the immune system: signaling and protection. Antioxid Redox Signal. 2013;18:288–308.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Saura M, Zaragoza C, McMillan A, Quick RA, Hohenadl C, Lowenstein JM, et al. An antiviral mechanism of nitric oxide: inhibition of a viral protease. Immunity. 1999;10:21–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Persichini T, Colasanti M, Fraziano M, Colizzi V, Medana C, Polticelli F, et al. Nitric oxide inhibits the HIV-1 reverse transcriptase activity. Biochem Biophys Res Commun. 1999;258:624–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Atochina-Vasserman EN. S-nitrosylation of surfactant protein D as a modulator of pulmonary inflammation. Biochim Biophys Acta. 2012;1820:763–9.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Niedbala W, Besnard AG, Nascimento DC, Donate PB, Sonego F, Yip E, et al. Nitric oxide enhances Th9 cell differentiation and airway inflammation. Nat Commun. 2014;5:4575.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Mian AI, Laham FR, Cruz AT, Garg H, Macias CG, Caviness AC, et al. Nitric oxide metabolites as biomarkers for influenza-like acute respiratory infections presenting to the emergency room. Open Respir Med J. 2012;6:127–34.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Chiappini E, Galli L, Azzari C, de Martino M. Nitric oxide in HIV-1 perinatally infected children treated with highly active antiretroviral therapy. Lancet Infect Dis. 2003;3:128–9 (author reply 129–30).CrossRefPubMedGoogle Scholar
  58. 58.
    Al-Nimer MS, Mahmood MM, Khazaal SS. Nitrostative stress status during seasonal and pdmH1N1 infection in Iraq. J Infect Dev Ctries. 2011;5:863–7.CrossRefPubMedGoogle Scholar
  59. 59.
    de Oliveira LR, Peresi E, MeA Golim, Gatto M, Araújo Junior JP, da Costa EA, et al. Analysis of Toll-like receptors, iNOS and cytokine profiles in patients with pulmonary tuberculosis during anti-tuberculosis treatment. PLoS One. 2014;9:e88572.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Torre D, Ferrario G, Speranza F, Orani A, Fiori GP, Zeroli C. Serum concentrations of nitrite in patients with HIV-1 infection. J Clin Pathol. 1996;49:574–6.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Valero N, Mosquera J, Añez G, Levy A, Marcucci R, de Mon MA. Differential oxidative stress induced by dengue virus in monocytes from human neonates, adult and elderly individuals. PLoS One. 2013;8:e73221.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Honold J, Pusser NL, Nathan L, Chaudhuri G, Ignarro LJ, Sherman MP. Production and excretion of nitrate by human newborn infants: neonates are not little adults. Nitric Oxide. 2000;4:35–46.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  1. 1.Immunology CenterAdolfo Lutz InstituteSão PauloBrazil
  2. 2.Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil
  3. 3.Laboratory of Dermatology and Immunodeficiencies (LIM-56)Medical School of the University of São PauloSão PauloBrazil

Personalised recommendations