Inflammasome activation by Salmonella typhimurium biofilms

鼠伤寒沙门氏菌生物膜激活炎症小体

• 批准号: 9167723
• 负责人: Cagla Tukel
• 金额: $ 23.4万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167723
• 关键词: Acute; Amyloid; Amyloid Proteins; Amyloid fibers; Apoptosis; Bacteria; Bacterial Infections; CASP1 gene; Caspase; Cecum; Cell Death; Cells; Data; Development; Disease; Enzymes; Epithelial; Epithelial Cells; Extracellular Matrix; Fiber; Flagellin; Generations; Goals; Human; Immune response; Immune system; Immunologic Surveillance; Infection; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-17; Interleukin-18; Intestines; Knowledge; Microbe; Microbial Biofilms; Morbidity - disease rate; Multiprotein Complexes; Mus; Pathogenesis; Pattern recognition receptor; Play; Production; Proteins; Role; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Serum amyloid A protein; Signal Transduction; Structure; Systemic infection; TLR2 gene; Testing; United States; beta pleated sheet; cytokine; foodborne; innovation; islet amyloid polypeptide; killings; macrophage; mortality; mutant; novel; novel therapeutic intervention; protein structure; public health relevance; receptor; response

Summary Activation of cytosolic activation of Nod like receptors (NLRs) induces the assembly of inflammasomes, which are cytosolic multiprotein complexes that activate inflammatory caspases (caspase-1 and -11). These caspases promote the cleavage of pro-IL-1 and pro- IL-18 to active IL-1 and IL-18, triggering also pyroptosis, an inflammatory cell death that kills the infected cell. IL-1 is a key cytokine that has been implicated in the pathogenesis of several inflammatory diseases as well as bacterial infections including Salmonella enterica serovar Typhimurium (S. Typhimurium) infection. NLRP3 is the best-characterized inflammasome, which can be activated with a wide range of danger signals and uses apoptosis-associated speck-like protein containing a CARD (ASC) as an adaptor molecule. Nonetheless, the molecule that trigger NLRP3 assembly during S. Typhimurium infection is not known. Amyloid proteins, produced both by bacteria and humans, are characterized by their conserved cross--sheet quaternary structure. Amyloid fibers are an important extracellular matrix component of biofilms formed by diverse groups of bacteria. Intriguingly, human amyloid-, islet amyloid polypeptide and serum amyloid A (SAA) have all been demonstrated to activate the NLRP3 inflammasome resulting in the production of IL-1 . Our long-range goal is to elucidate the role of bacterial amyloids in microbe-host interactions. Amyloid fibers produced in the biofilms of S. Typhimurium are termed curli and have been shown to be expressed during infection. The objective of this application is to determine whether bacterial amyloid curli would trigger IL-1 and IL-18 production through NLRP3 activation during S. Typhimurium infection.

总结 Nod样受体（NLR）的胞质激活的激活诱导Nod样受体（NLR）的组装。 炎性小体，其是激活炎性半胱天冬酶的细胞溶质多蛋白复合物 （半胱天冬酶-1和-11）。这些半胱天冬酶促进IL-18原和IL-18原的切割，以激活IL-18的表达。 IL-1 β和IL-18，也会引发焦亡，一种杀死受感染细胞的炎性细胞死亡。 IL-1 β是一种关键的细胞因子，参与了多种炎症性疾病的发病机制。 疾病以及细菌感染，包括肠道沙门氏菌鼠伤寒血清型（S. 鼠伤寒）感染。NLRP 3是最具特征的炎性体，其可以被激活， 具有广泛的危险信号，并使用与糖尿病相关的斑点样蛋白， CARD（ASC）作为衔接分子。尽管如此，触发NLRP 3组装的分子 在S.鼠伤寒感染未知。 由细菌和人类产生的淀粉样蛋白，其特征在于它们的 保守的交叉折叠四级结构。淀粉样纤维是重要的细胞外基质 由不同细菌群形成的生物膜的组成部分。有趣的是，人类淀粉样蛋白，胰岛 淀粉样蛋白多肽和血清淀粉样蛋白A（SAA）都已被证明激活 NLRP 3炎性体导致IL-1 β的产生。 我们的长期目标是阐明细菌淀粉样蛋白在微生物宿主中的作用， 交互.淀粉样纤维产生于S.鼠伤寒被称为卷曲， 在感染过程中表达。本申请的目的是确定 细菌淀粉样蛋白卷曲是否会通过NLRP 3激活触发IL-1 β和IL-18的产生 在S.鼠伤寒感染。