Innate Immune Recognition of Intracellular Salmonella

细胞内沙门氏菌的先天免疫识别

• 批准号: 8504897
• 负责人: Denise M Monack
• 金额: $ 37.67万
• 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/8504897
• 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.

描述（由申请人提供）：我们使用S。鼠伤寒沙门氏菌（Stm）小鼠模型来研究沙门氏菌-宿主相互作用，并且已经显示哺乳动物炎性体（一种介导促炎宿主应答的先天免疫保护性复合物）对于控制Stm感染是重要的。这项研究应用的长期目标是了解宿主如何识别细胞内的Stm，以及这种病原体如何进化以破坏先天免疫防御。我们已经证明，多种宿主胞质受体参与识别细胞内Stm和激活炎性小体。在Aim 1中，我们将使用遗传方法来识别有助于促炎细胞因子释放和caspase-1激活的新细菌因子。在目标2中，我们将采取生物化学和遗传学方法来鉴定参与caspase-1和细胞因子成熟和释放的宿主分子和途径。在目标3中，我们将描述目标2中确定的宿主胞质受体的作用，这些受体对小鼠感染Stm期间的caspase-1依赖性细胞因子释放或巨噬细胞死亡很重要。这些研究旨在更好地了解细胞内识别的分子机制，这将导致合理设计有益于公众健康的治疗方法。