Nitric oxide and viral infection: NO antiviral activity against a flavivirus in vitro, and evidence for contribution to pathogenesis in experimental infection in vivo.
Upon stimulation murine macrophages produce high levels of nitric oxide (NO), a potent microbicidal and tumoricidal agent recently also implicated as a mediator of antiviral defense. As dysregulated production of NO may lead to extensive tissue damage, the production of this powerful mediator is tightly regulated. Viral infection, however, may alter the regulation of certain macrophage functions, and recent work from our group demonstrated that viral infection--via induction of interferon-alpha beta synthesis -- may either prime for or down-modulate NO production. In light of antiviral activities of NO, down-modulation of NO production in viral infection would seem contradictory to antiviral defense. As others, however, have provided evidence that NO production may contribute to pathogenesis of infection with several neurotropic viruses, the role of NO production was investigated in vitro and in vivo in murine macrophages and in BALB/c mice infected with tick-borne encephalitis virus (TBE-V), a flavivirus. Macrophages from TBE-V-infected mice, but not from control mice, spontaneously produced NO upon culture in vitro. In contrast to the inhibitory effect of NO on replication of several poxviruses and herpes simplex virus, high levels of NO production did not display an inhibitory influence on TBE-V replication in vitro. And finally, in vivo administration of a competitive inhibitor of NO production, aminoguanidine, to TBE-V-infected mice significantly increased their mean survival time. Our results thus demonstrate that the antiviral activity of NO in vitro may be confined to certain viruses, whereas others remain unaffected. Furthermore, we provide evidence that NO production may even contribute to pathogenesis of viral infection in vivo.
Kreil
T R
TR
Department of Infectious and Pediatric Immunology, University of Vienna, Austria.
Eibl
M M
MM
D000818:Animals; D002478:Cells, Cultured; D004669:Encephalitis Viruses, Tick-Borne / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D004675:Encephalitis, Tick-Borne / Q000097:blood / Q000276:immunology* / Q000821:virology; D006146:Guanidines / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000276:immunology*
D006146:Guanidines; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D009569:Nitric Oxide; C004479:pimagedine