Research on the role of NO in microbial pathogenesis

NO在微生物发病机制中的作用研究

基本信息

批准号：
12470065
负责人：
MAEDA Hiroshi
金额：
$ 7.94万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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 and hydroxyl radical have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical [nitric oxide (NO)] in me 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-α 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. NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections. Our work on murine salmonellosis in iNOS-deficient mice indicated that NO has significant host defense functions in Salmonella infections not only because of its direct antimicrobial effect but also via cytoprotective actions for infected host cells, possibly through its antiapoptotic effect. Reactive nitrogen oxide species such as peroxynitrite are produced in biological systems through the reaction of NO with superoxide. Among these reactive nitrogen species, 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. Peroxynitrite thus formed in infectious foci may be a dominant nitrogen oxide species during the host's defense reactions. Thus, understanding of the role of NO and oxygen radical generation in infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level.

近年来，人们越来越认识到自由基分子种类在各种病毒性疾病发病机制中的重要性，超氧化物和羟基自由基等氧自由基被认为是病毒性疾病发病机制中可能的致病分子。无机自由基[一氧化氮(NO)]在宿主防御机制和病毒感染发病机制中的作用 NO合成途径，特别是诱导型NO合酶(iNOS)，在不同病毒中表达。与其他 NOS 亚型（即神经元 NOS 和内皮 NOS 生物合成）相比，诱导促炎细胞因子（例如干扰素-α 和白细胞介素-1β）会长期产生过量的 NO。一种诱导型一氧化氮合酶 (iNOS)，发生在多种微生物感染中。我们对 iNOS 缺陷小鼠的沙门氏菌病进行了研究。表明NO在沙门氏菌感染中具有显着的宿主防御功能，不仅因为其直接抗菌作用，还因为其对受感染宿主细胞的细胞保护作用，可能是通过其在生物系统中通过反应产生的反应性氮氧化物（例如过氧亚硝酸盐）的作用。在这些活性氮物质中，过氧亚硝酸盐及其生物作用引起了人们的极大兴趣，因为过氧亚硝酸盐引起蛋白质和鸟嘌呤的氨基酸残基的氧化和硝化。因此，在感染病灶中形成的 DNA、脂质过氧化和 DNA 裂解可能是宿主防御反应期间的主要氮氧化物种类，因此，了解 NO 和氧自由基生成在感染中的作用不仅有助于了解病毒发病机制。还包括分子水平上微生物感染中宿主与病原体的相互作用。