Nitric oxide and virus infection

Abstract

Nitric oxide (NO) has complex and diverse functions in physiological and pathophysiological phenomena. The mechanisms of many events induced by NO are now well defined, so that a fundamental understanding of NO biology is almost established. Accumulated evidence suggests that NO and oxygen radicals such as superoxide are key molecules in the pathogenesis of various infectious diseases. NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections. Although antimicrobial activity of NO is appreciated for bacteria and protozoa, NO has opposing effects in virus infections such as influenza virus pneumonia and certain other neurotropic virus infections. iNOS produces an excessive amount of NO for long periods, which allows generation of a highly reactive nitrogen oxide species, peroxynitrite, via a radical coupling reaction of NO with superoxide. Thus, peroxynitrite causes oxidative tissue injury through potent oxidation and nitration reactions of various biomolecules. NO also appears to affect a host's immune response, with immunopathological consequences. For example, overproduction of NO in virus infections in mice is reported to suppress type 1 helper T-cell-dependent immune responses, leading to type 2 helper T-cell-biased immunological host responses. Thus, NO may be a host response modulator rather than a simple antiviral agent. The unique biological properties of NO are further illustrated by our recent data suggesting that viral mutation and evolution may be accelerated by NO-induced oxidative stress. Here, we discuss these multiple roles of NO in pathogenesis of virus infections as related to both non-specific inflammatory responses and immunological host reactions modulated by NO during infections in vivo.

Figure 1

(a) Mechanisms of iNOS induction in viral diseases. In many virus infections, iNOS expression appears to be regulated indirectly via interferon-γ (IFN-γ) induction. Direct iNOS induction may occur in some cases, such as with respiratory syncytial virus and HIV-1 (gp41). (b) NO generation detected by ESR spectroscopy with N-dithiocarboxy(sarcosine) (DTCS)-iron complexes in influenza virus-infected lung (7 days after virus infection). Wild-type mice (C57BL/6, B6), iNOS heterozygotes (iNOS^+/–), and mice deficient in iNOS (iNOS^–/–) were inoculated with 2 × LD₅₀ of influenza virus, and ESR was performed as described previously.

Figure 2

Mechanisms of formation of various reactive nitrogen intermediates from NO and their biological effects. The opposing effects of NO (both toxic and protective) seem to be produced by interactions of NO with molecular oxygen (O₂), active oxygen and oxygen radicals such as O₂^– and H₂O₂, sulfhydryl-containing substances, and heavy metals (particularly iron and copper). Ceruloplasmin (CP) and copper ion catalyse the formation of nitrosothiols (RS-NO) in the presence of sulfhydryl-containing compounds (RSH) and O₂. MPO, myeloperoxidase from neutrophils; Tyr, l-tyrosine; diTyr, dityrosine; GSH, reduced glutathione; GS-NO, S-nitrosoglutathine; RS-NO₂, nitrothiols; GS-NO₂, S-nitroglutathione.

Figure 3

NO-dependent Sendai virus mutation as revealed by genetic mutation of GFP in Sendai virus during Sendai virus-induced pneumonia in mice. (a) The mutation frequency of the virus isolated from the lung of wild-type B6 and iNOS^–/– mice was quantified by use of the GFP-based mutation assay. (b) Virus yield in the lung of wild-type B6 and iNOS^–/– mice. Data are the mean ± SEM (n = 4). *P < 0·05, †P < 0·01, between wild-type B6 and iNOS^–/– mice (t-test). Adapted from Akaike et al. (FASEB J 2000; 14:1447).

Figure 4

Schematic drawing of the possible involvement of NO-induced oxidative stress and mutagenesis in viral mutation and evolution. NO-derived reactive nitrogen intermediates, via their potent mutagenic activities, may contribute to the molecular evolution of viruses. Alternatively, NO may affect viral evolution by inhibiting a host's antiviral immune responses, which may impair clearance of viral mutants.