Molecular Mechanisms of Redox-Regulation in Viral Pathogenesis

The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years.Oxygen radicals such as superoxide(O-D3-(/)2-D3)and hydroxyl radical(·OH)have been implicated as possible pathogenic molecules in viral disease pathogenesis.Much attention has been given to another simple inorganic radical，i.e.，NO in the host‘s defense mechanism and pathogenesis of virus infection。The NO synthesis pathway，in particular the inducible isoform of NO synthase(INOS)，is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-γand interleukin-1β.INOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS，i.e.，neuronal NOS and endothelial NOS.Our present results indicate that overproduction of NO and oxygen radicals should be a common phenomenon in various infections。反应nitrogen oxide species such as peroxynitrite are prod…More uced in biological systems through the reaction of NO with O I D3-(/)2个D 3.Peroxynitrite and its biological actions are of considerable interest in that peroxynitrite causes oxidation and nitration of amino acid residues of proteins and guanine of DNA，lipid peroxidation，and DNA cleavage.In fact，it is revealed in our current study that peroxynitrite is critically involved in the viral pathogenesis through its nonselective injury to the host‘cells and tissues.Thus，understanding of the role of NO and oxygen radical generation in virus infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level.Moreover，among various NO-induced pathological effects，the mutagenic potential of NO in microbial pathogens is also intriguing.For viral mutation，it is of potential interest to investigate a possible association of oxidative stress and virulence of viruses.In this context，our recent study verifies for the first time that oxidative stress induced by high-output NO accelerates RNA virus mutations.Briefly，by using a recombinant RNA virus，Sendai virus(a negative-sense and single-strand RNA virus)，containing a marker gene for genetic mutation and iNOS knockout mice，we obtained solid and direct evidence showing that overproduction of NO in the hosts(wild-type mice)in vivo apparently increases and accelerates viral mutation rates compared with the situation in iNOS-deficient mice.This process of accelerated mutation expands the heterogeneity of variants of the pathogen，leading to rapid evolution under selective pressure。NO and O I D3-(/)2个D3-and hence peroxynitrite generation occurs universally in infected hosts.This finding therefore has great implications for the RNA virus evolution in general，including the rapid generation of drug-resistant and immunologically tolerant and cell tropism-altered mutants of HIV in vivo.Less：Less

The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years. Oxygen radicals such as superoxide (OィイD3-(/)2ィエD3) and hydroxyl radical (・OH) have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical, i.e., NO in the host's defense mechanism and pathogenesis of virus infection. The NO synthesis pathway, in particular the inducible isoform of NO synthase (iNOS), is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-γ and interleukin-1β. iNOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS, i.e., neuronal NOS and endothelial NOS. Our present results indicate that overproduction of NO and oxygen radicals should be a common phenomenon in various infections. Reactive nitrogen oxide species such as peroxynitrite are prod … More uced in biological systems through the reaction of NO with OィイD3-(/)2ィエD3. Peroxynitrite and its biological actions are of considerable interest in that peroxynitrite causes oxidation and nitration of amino acid residues of proteins and guanine of DNA, lipid peroxidation, and DNA cleavage. In fact, it is revealed in our current study that peroxynitrite is critically involved in the viral pathogenesis through its nonselective injury to the host'cells and tissues. Thus, understanding of the role of NO and oxygen radical generation in virus infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level. Moreover, among various NO-induced pathological effects, the mutagenic potential of NO in microbial pathogens is also intriguing. For viral mutation, it is of potential interest to investigate a possible association of oxidative stress and virulence of viruses. In this context, our recent study verifies for the first time that oxidative stress induced by high-output NO accelerates RNA virus mutations. Briefly, by using a recombinant RNA virus, Sendai virus (a negative-sense and single-strand RNA virus), containing a marker gene for genetic mutation and iNOS knockout mice, we obtained solid and direct evidence showing that overproduction of NO in the hosts (wild-type mice) in vivo apparently increases and accelerates viral mutation rates compared with the situation in iNOS-deficient mice. This process of accelerated mutation expands the heterogeneity of variants of the pathogen, leading to rapid evolution under selective pressure. NO and OィイD3-(/)2ィエD3- and hence peroxynitrite generation occurs universally in infected hosts. This finding therefore has great implications for the RNA virus evolution in general, including the rapid generation of drug-resistant and immunologically tolerant and cell tropism-altered mutants of HIV in vivo. Less