Research on microbial mutation and evolution involving oxidative stress

氧自由基和一氧化氮（NO）在各种微生物感染中过量产生。自由基生物学中的新兴概念正在阐明各种疾病的发病机制。自由基诱导的病毒感染致病性是非常重要的，因为证据表明NO和氧自由基如超氧化物是各种感染性疾病发病机制中的关键分子。虽然氧自由基和NO对细菌和原生动物具有抗菌作用，但它们在病毒感染如流感病毒肺炎和其他几种嗜神经病毒感染中具有相反的作用。在各种病毒感染中，诱导型NO合酶的高NO输出通过与氧自由基和活性氧中间体的相互作用产生高活性的氮氧化物物质，如过氧亚硝酸盐。这些不同的活性物质的产生赋予NO不同的生物学功能。活性氮物质通过氧化和硝化各种生物分子如鸟苷引起氧化性组织损伤和诱变。最近的证据表明，NO诱导的氧化应激加速了病毒突变，进一步说明了自由基的独特生物学特性。NO似乎影响宿主的免疫应答，具有免疫病理学后果。例如，据报道，NO在感染期间抑制1型辅助T细胞依赖性免疫应答，导致2型辅助T细胞偏向的免疫宿主应答。因此，NO诱导的免疫抑制可能有助于病毒感染的发病机制，并有助于扩大病毒病原体的数量。在本研究中，我们确实成功地阐明了NO在病毒性疾病的发病机制和与NO修饰核酸相关的病毒突变中的关键作用，即，鸟苷硝化形成8-硝基鸟苷。

Oxygen radicals and nitric oxide (NO) are generated in excess in a diverse array of microbial infections. Emerging concepts in free radical biology are now shedding light on the pathogenesis of various diseases. Free-radical induced pathogenicity in virus infections is of great importance, because evidence suggests that NO and oxygen radicals such as superoxide are key molecules in the pathogenesis of various infectious diseases. Although oxygen radicals and NO have an antimicrobial effect on bacteria and protozoa, they have opposing effects in virus infections such as influenza virus pneumonia and several other neurotropic virus infections. A high output of NO from inducible NO synthase, occurring in a variety of virus infections, produces highly reactive nitrogen oxide species, such as peroxynitrite, via interaction with oxygen radicals and reactive oxygen intermediates. The production of these various reactive species confers the diverse biological functions of NO. The reactive nitrogen species cause oxidative tissue injury and mutagenesis through oxidation and nitration of various biomolecules such as guanosine. The unique biological properties of free radicals are further illustrated by recent evidence showing accelerated viral mutation by NO-induced oxidative stress. NO appears to affect a host's immune response, with immunopathological consequences. For example, NO is reported to suppress type 1 helper T cell-dependent immune responses during infections, leading to type 2 helper T cell-biased immunological host responses. NO-induced immunosuppression may thus contribute to pathogenesis of virus infections and help expansion of quacispeies population of viral pathogens. In the present study, we indeed successfully elucidated the critical roles of NO in the pathogenesis of viral diseases and in viral mutation as related to nucleic acid modifications by NO, i.e., nitration of guanosine to form 8-nitroguanosine.