Inflammasome Response to Bacterial Infection

炎症小体对细菌感染的反应

• 批准号: 8652644
• 负责人: Edward A Miao
• 金额: $ 2.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652644
• 关键词: Adoptive Transfer; Africa South of the Sahara; Agonist; Amino Acids; Anatomy; Anti-Bacterial Agents; Attenuated Live Virus Vaccine; Bacteremia; Bacteria; Bacterial Infections; Bacterial Typing; Biological Models; Caspase-1; Cell physiology; Cleaved cell; Communicable Diseases; Communities; Complex; Cytosol; Detection; Developed Countries; Developing Countries; Disease; Event; Family; Flagellin; Food; Gastroenteritis; Hour; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Interferons; Interleukin-1; Interleukin-18; Lead; Location; Mediating; Medicine; Microbe; Modeling; Molecular; Monitor; Mus; Natural Killer Cells; Pathologic; Pattern recognition receptor; Peptide Hydrolases; Phagosomes; Process; Production; Property; Proteins; Proteolytic Processing; Public Health; Recruitment Activity; Regulation; Relative (related person); Residual state; Role; Salmonella; Salmonella typhi; Salmonella typhimurium; Signal Transduction; Structure of aggregated lymphoid follicle of small intestine; System; Techniques; Testing; Time; Tissues; Toxin; Type III Secretion System Pathway; Typhoid Fever; Vaccine Adjuvant; Virulence Factors; cell type; combat; cytokine; design; in vivo; insight; macrophage; novel vaccines; pathogen; pathogenic bacteria; prevent; protein complex; receptor; receptor coupling; response; retinal rods; sensor

Salmonellae are a significant public health threat in both developing and developed countries, causing Typhoid fever or gastroenteritis, and recently have been observed as emerging pathogens causing community acquired bacteremia in sub-Saharan Africa. Salmonellae use virulence factors, including type III secretion systems, to manipulate host cell physiology. The innate immune system detects perturbations in the cytosol during infection. An important family of cytosolic pattern recognition receptors that mediate this detection is the Nod- like receptors (NLR). Some NLRs, including NLRP3 and NLRC4, form inflammasomes that recruit and activate Caspase-1, a protease that subsequently cleaves the inflammatory cytokines IL-1 and IL-18 to their mature, secreted forms. NLRP3 and NLRC4 detect Salmonella typhimurium infection, and the resulting Caspase-1 activation reduces bacterial burden in vivo primarily through the activities of IL-18. In this application, we will analyze the molecular determinants of detection by NLRC4 (Aim 1) and NLRP3 (Aim 2), and the IL-18 response (Aim 3) during S. typhimurium infection. NLRC4 responds to flagellin and rod protein secreted into the macrophage cytosol. We will dissect the molecular determinants of this detection and examine the relative importance of flagellin and rod protein detection in vivo. NLRP3 responds to a variety of cellular perturbations, and we will investigate the hypothesis that NLRP3 detects the prolonged presence of undigested bacteria within the phagosome. We will compare the anatomic localization of NLRP3 and NLRC4 detection, testing the hypothesis that NLRC4 has a discrete window of time to detect S. typhimurium that have recently emigrated from the gut lumen, while NLRP3 detects bacteria after dissemination. Finally, we will define the role of NK cells in the IL-18 response. These studies will provide insight into the complex interplay of innate immune detection through two inflammasomes that respond to different cytosolic perturbations triggered by S. typhimurium. Our results will be instructive for designing live attenuated vaccines as well as vaccine adjuvants. The general mechanisms revealed by these studies will also facilitate the understanding of inflammatory disease.

在发展中国家和发达国家，鲑鱼是一个重大的公共卫生威胁，导致伤寒或胃​​肠炎，最近被认为是新兴的病原体，导致撒哈拉以南非洲的社区获得的菌血症。沙门氏菌使用包括III型分泌系统在内的毒力因素来操纵宿主细胞生理。先天免疫系统检测到感染过程中细胞质的扰动。介导该检测的胞质模式识别受体的重要家族是点头像受体（NLR）。一些NLR，包括NLRP3和NLRC4，会形成炎症，这些炎症体募集和激活caspase-1，这种蛋白酶随后将炎性细胞因子IL-1和IL-18切割成成熟的分泌形式。 NLRP3和NLRC4检测鼠伤寒沙门氏菌感染，所得的caspase-1激活主要通过IL-18的活性来减轻体内细菌负担。在此应用中，我们将分析NLRC4（AIM 1）和NLRP3（AIM 2）的分子决定因素，以及在伤寒链霉菌感染期间的IL-18反应（AIM 3）。 NLRC4对分泌到巨噬细胞细胞质中的鞭毛蛋白和棒蛋白反应。我们将剖析该检测的分子决定因素，并检查体内鞭毛蛋白和杆蛋白检测的相对重要性。 NLRP3对各种细胞扰动做出了反应，我们将研究NLRP3检测吞噬体内未消化的细菌的假设。我们将比较NLRP3和NLRC4检测的解剖学定位，以检验NLRC4具有离散的时间窗口的假设，用于检测鼠伤寒沙门氏菌最近从肠腔移民，而NLRP3在发出后检测细菌。最后，我们将定义NK细胞在IL-18反应中的作用。这些研究将通过两种对鼠伤寒沙门氏菌触发的不同胞质扰动的反应，对先天免疫检测的复杂相互作用提供深入的了解。我们的结果将具有启发性设计活疫苗和疫苗佐剂的启发性。这些研究揭示的一般机制也将促进对炎症疾病的理解。