Analysis of interacellular host defenses in Salmonella pathogenesis

沙门氏菌发病机制中细胞间宿主防御的分析

• 批准号: 7616056
• 负责人: Andres Vazquez-Torres
• 金额: $ 25.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616056
• 关键词: Alleles; Animals; Bacteria; Binding; Biochemical; Biochemical Genetics; Biology; CD4 Positive T Lymphocytes; Clinical; Data; Dimerization; Genetic; Genetic Transcription; Goals; Health; Host Defense; Host Defense Mechanism; Human; Integration Host Factors; Investigation; Knowledge; Laboratories; Ligands; Light; Mediating; Metabolism; Modeling; Modification; Molecular; Molecular Weight; Mononuclear; Nitric Oxide Synthase; Oxidation-Reduction; Oxygen; Parasites; Pathogenesis; Pathogenicity Island; Phagocytes; Reactive Nitrogen Species; Repression; Research; Resistance; SKIL gene; Salmonella; Salmonella enterica; Salmonella infections; Signal Transduction; Source; Sulfhydryl Compounds; Suppressor Mutations; System; Systemic disease; Testing; Time; Type III Secretion System Pathway; Variant; Virulence; Virulence Factors; Virus; Work; antimicrobial; base; cell type; dimer; fungus; human disease; innovation; macrophage; nitrosative stress; pathogen; prevent; public health relevance; response; sensor

DESCRIPTION (provided by applicant): Salmonella enterica represents a considerable burden to human and animal health worldwide. A significant effort has been made to understand the pathogenesis of this intracellular pathogen and the host factors that mediate host defense. Clinical and experimental evidence have unequivocally demonstrated that CD4+ T cells and IFN3 are critical for preventing systemic disease by non-typhoidal Salmonella. IFN3 likely exerts diverse functions in resistance to this intracellular bacterium, including the activation of the antimicrobial arsenal of macrophages. Recent studies have indicated that IFN3 synergizes with Salmonella ligands to enhance the transcription of iNOS. The resultant high NO synthesis mediates most of the profound and long-lasting anti-Salmonella activity of IFN3-primed macrophages. The molecular mechanism(s) by which IFN3- activated NO synthesis enhances the anti-Salmonella activity of macrophages remains, however, largely unknown. We have generated biochemical and genetic evidence in support of a model in which C203 of the SsrB response regulator that mediates global Salmonella pathogenicity island 2 (SPI2) transcription is an important target of reactive nitrogen species (RNS). The goal of this application is to identify the molecular mechanisms underlying the RNS-mediated repression of SPI2 transcription. It is hypothesized that NO congeners repress SPI2 transcription by S-nitrosylating (-SNO) C203 of the dimerization domain of the SsrB response regulator. Specifically, we propose to 1) determine the RNS-mediated modifications that inactivate SsrB regulatory functions; 2) examine SPI2 function in the context of Salmonella antinitrosative defenses; 3) select for ssrB variant alleles that render SsrB signaling insensitive to RNS; and 4) characterize SsrB residues critical for dimerization. PUBLIC HEALTH RELEVANCE Salmonella enterica represents a considerable burden to human and animal health worldwide. The mechanisms underlying the pathogenesis of salmonellosis are incompletely understood. The proposed research will shed light on the host pathogen interactions that modulate the expression of a virulence factors key to the ability of Salmonella to cause human disease.

描述（由申请方提供）：肠道沙门氏菌对全球人类和动物健康造成相当大的负担。一个显着的努力已经了解这种细胞内病原体的发病机制和宿主因子介导的宿主防御。临床和实验证据已经明确表明，CD 4 + T细胞和IFN 3对于预防非伤寒沙门氏菌引起的全身性疾病至关重要。IFN 3可能在抵抗这种细胞内细菌方面发挥多种功能，包括激活巨噬细胞的抗菌武器库。最近的研究表明，IFN 3与沙门氏菌配体协同作用，以增强iNOS的转录。由此产生的高NO合成介导了IFN 3引发的巨噬细胞的大部分深刻和持久的抗沙门氏菌活性。然而，IFN 3激活的NO合成增强巨噬细胞抗沙门氏菌活性的分子机制在很大程度上仍然未知。我们已经产生了生化和遗传证据支持的模型中，C203的SSRB反应调节剂，介导全球沙门氏菌致病岛2（SPI 2）转录是一个重要的目标活性氮物质（RNS）。本申请的目的是鉴定RNS介导的SPI 2转录抑制的分子机制。据推测，NO同源物通过SsrB反应调节剂的二聚化结构域的S-亚硝基化（-SNO）C203来抑制SPI 2转录。具体来说，我们建议1）确定RNS介导的修饰，使SsrB的调节功能; 2）检查SPI 2功能的背景下，沙门氏菌的反硝化防御; 3）选择的ssrB变异等位基因，使SsrB信号不敏感RNS;和4）表征SsrB残基的二聚体的关键。肠道沙门氏菌对全世界人类和动物健康造成相当大的负担。沙门氏菌病的发病机制还不完全清楚。拟议的研究将揭示宿主病原体的相互作用，调节沙门氏菌引起人类疾病的能力的关键毒力因子的表达。