Identification ofNitric Oxide Synthase 2as an Innate Resistance Locus against Ectromelia Virus Infection

Abstract

To assess whether nitric oxide synthase 2 (NOS2) fulfills the criteria of an innate resistance locus against an acute viral infection, we inoculated genetically deficient NOS2؊/؊ mice with virulent ectromelia virus (EV), the causative agent of mousepox. NOS2؊/؊ mice proved highly susceptible to EV yet showed no diminution in other well-characterized anti-EV immune responses, i.e., gamma interferon secretion and NK cell and EVspecific cytotoxic T lymphocyte activities. Thus, the NOS2 locus can be considered a critical monogenic determinant of EV resistance that contributes to host survival.

Role of epithelial nitric oxide in airway viral infection

“…NOS II is sufficient for antiviral defense in human airway epithelial cells [16,34,35,[57][58][59][60][61]. Replication of a wide range of DNA and RNA viruses are inhibited in vitro by the addition of chemical donors of NO, or by the overexpression or induction of NOS II.…”

“…Replication of a wide range of DNA and RNA viruses are inhibited in vitro by the addition of chemical donors of NO, or by the overexpression or induction of NOS II. NO inhibits both virus replication and latency of viruses, including coxsackievirus, influenza A and B, rhinovirus, cytomegalovirus, vaccinia virus, ectromelia virus, human herpesvirus-1, and HPIV3 [18,34,[57][58][59][61][62][63][64][65]. Likewise, loss of NO synthesis leads to increase of virus titers with infection, and significantly more severe clinical outcomes [34,35,60,66,67].…”

“…Chemical donors of NO or induction of NOS II inhibit virus replication in vitro [16,34,35,[57][58][59][60][61][62][63][64]. Since loss of NO synthesis is a primary pathophysiologic event in the susceptibility of CF patients to virus and other microbial pathogens [16,87], overexpression of NOS II or NO donors is rational strategy to protect from viral infection.…”

The role of IL-12, IL-23 and IFN-γ in immunity to viruses

“…References for each of the experimental infection are indicated. Genetic backgrounds were: IFN-␥KO mice: Balb/C [112,125,127,128,141,149]; C57BL/6 [114,116,117,123,127,128,145,147]; IFN-␥R1KO mice: 129/SV/E [112,115,122,126,[136][137][138][139][140]; Balb/C [147]; anti-IFN␥ antibody-treated mice: Balb/C [113,132,142]; C57BL/6 [112,119,135,143,144]; 129/SV/E [113]; CBA/Ht [140]; IL-12p40KO mice: C57BL/6 [118,121,145]; anti-IL-12-antibody treated mice: Balb/C [143]. and anti-IFN-␥ Ab-treated [119,130,131] mice become more susceptible or succumb to LCMV infection.…”

“…GKO and anti-IFN-␥ Ab-treated mice succumbed to infection with mousepox virus, and ecromelia virus (EV) [135,136]. Inhibition of EV replication is due to the ability of IFN-␥ to induce nitric oxide synthases [137,138]. By contrast, infection with lactate dehydrogenase (LDV)-elevating virus had no effect in either GKO or anti-IFN-␥ treated mice [139,140].…”