Molecular Mechanisms of Redox-Regulation in Viral Pathogenesis

“自由基分子物种在过去几年中对各种病毒疾病病理学的重要性”。Oxygen radicals such as superoxide （OイイD3-（\）2イエD3） and hydroxyl radical （·OH） have been implicated as possible pathogenic molecules in viral disease pathogenesis。许多关注已经被赋予了另一个简单的非有机自由基，我.....。在宿主的防御机制和病毒感染的病理学中没有。在NO合成的途径中，在NO合成酶（iNOS）的诱导性同位素中，通过诱导的原性细胞因子（如干扰素-γ和介素-1 β）表达了不同的病毒性疾病。iNOS在很长一段时间内生产了一个额外的NO数量，与NOS的其他稳定异构体相比较，i. e神经性NOS和内皮性NOS。我们目前的结果表明，NO和氧基分子的过度生产应该是各种感染中常见的现象。反应性氮氧化物物种，如过氧化物酶是产品 ... More uced in biological systems through the reaction of NO with OイイD3-（/）2イエD3.过氧化物酶及其生物行为在过氧化物酶引起蛋白质和guanine的氨基酸溶液的氧化和硝酸化中具有一定的利益，其中过氧化物酶引起了DNA、脂质过氧化物和DNA清除。在事实上，它在我们目前的研究中被揭示出来，即过氧化物酶被严重地卷入病毒性病理学中，通过其非选择性的伤害对宿主细胞和组织。因此，根据病毒感染中NO和氧化物激进化的作用，不仅提供了病毒病理学，而且还提供了分子水平上微感染中宿主病理学相互作用的洞察力。Moreover，在各种非诱导性病理学效应中，微病理学中NO的突变潜力也是一种启发。由于病毒突变，它的潜在利益是研究氧化物压力和病毒病毒的可能关联。在这种情况下，我们最近的研究证实，这是第一次被高输出不加速RNA病毒突变诱导的氧化性压力。简要地，通过使用重组RNA病毒、Sendai病毒（一种负意义和单链RNA病毒），含有遗传变异和iNOS knockout老鼠的标记基因，我们发现了可靠和直接证据，显示宿主中NO过度生产（野生型老鼠）在体内明显增加和加速病毒变异率与iNOS-deficient老鼠的情况相比较。这一加速突变的过程扩展了病原体变异的异质性，导致了在选择性压力下快速进化。NO and O-D3-（/）2-D3-and hence peroxynit？generation occurs universally in infected hosts。因此，这一发现对RNA病毒在一般情况下的演变有很大的影响，包括抗药物和免疫抑制剂的快速生成和细胞热带质改变的艾滋病毒突变体。Less（低）

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