Innate Immune Recognition of Intracellular Salmonella

细胞内沙门氏菌的先天免疫识别

• 批准号: 8048942
• 负责人: Denise M Monack
• 金额: $ 39.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048942
• 关键词: Bacteria; Biochemical; Biochemical Genetics; Biochemistry; Caspase-1; Cell Death; Cells; Cessation of life; Complex; Cytosol; Data; Disease; Fiber; Flagellin; Genetic; Genetic Screening; Goals; Host Defense; Human; Immune; Immune response; Infection; Inflammation; Inflammatory; Interferons; Lead; Mediating; Molecular; Monitor; Mus; Oral; Pathogenicity Island; Pathway interactions; Phase; Public Health; Research; Role; Route; Salmonella; Salmonella infections; Salmonella typhimurium; Signal Transduction; Signaling Molecule; Sorting - Cell Movement; System; Techniques; Testing; Therapeutic; Time; Tissues; Vacuole; Work; base; beta-Lactamase; cytokine; cytosolic receptor; design; gastrointestinal; improved; insight; intraperitoneal; killings; macrophage; mouse model; mutant; novel; pathogen; receptor; therapeutic vaccine

DESCRIPTION (provided by applicant): We use a S. typhimurium (Stm) mouse model to study Salmonella-host interactions and have shown that the mammalian inflammasome, an innate immune protective complex that mediates a pro- inflammatory host response, is important for controlling Stm infection. The long-term goal of this research application is to understand how the host recognizes intracellular Stm and how this pathogen has evolved to subvert innate immune defenses. We have demonstrated that multiple host cytosolic receptors are involved in recognizing intracellular Stm and activating the inflammasome. In Aim1, we will use genetic approaches to identify new bacterial factors that contribute to pro-inflammatory cytokine release and caspase-1 activation. In Aim 2, we will take biochemical and genetic approaches to identify host molecules and pathways involved in caspase-1 and cytokine maturation and release. In Aim 3, we will characterize the role of the host cytosolic receptors identified in Aim 2 that are important for caspase-1-dependent cytokine release or macrophage death during murine infection with Stm. These studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular recognition, which will lead to the rational design of therapeutics that will benefit public health. PUBLIC HEALTH RELEVANCE: Salmonellosis constitutes a major public health burden with millions of human cases every year and the disease results in thousands of deaths. Our proposed studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular bacterial pathogen recognition and inflammation and may lead to improved therapeutics and vaccines.

描述（由申请人提供）：我们使用鼠伤寒链球菌（STM）小鼠模型研究沙门氏菌 - 宿主相互作用，并表明哺乳动物炎症体是一种介导促炎性宿主反应的先天免疫保护络合物，对于控制STM感染很重要。该研究应用程序的长期目标是了解宿主如何识别细胞内STM以及该病原体如何发展以颠覆先天的免疫防御措施。我们已经证明，多种宿主胞质受体参与识别细胞内STM并激活炎症体。在AIM1中，我们将使用遗传方法来识别有助于促炎性细胞因子释放和caspase-1激活的新细菌因子。在AIM 2中，我们将采用生化和遗传学方法来鉴定与caspase-1和细胞因子成熟和释放有关的宿主分子和途径。在AIM 3中，我们将表征AIM 2中鉴定出的宿主胞质受体的作用，这些受体对于依赖于caspase-1依赖性细胞因子释放或巨噬细胞死亡至关重要。这些研究旨在更好地了解细胞内识别的分子机制，这将导致将有益于公共卫生的治疗剂的合理设计。 公共卫生相关性：沙门氏菌病构成了每年数百万人类病例的重大公共卫生负担，疾病会导致数千人死亡。我们提出的研究旨在更好地了解细胞内细菌病原体识别和炎症的分子机制，并可能导致治疗疗法和疫苗的改善。