Modulation of Inflammasome Activation by Yersinia

耶尔森菌对炎症小体激活的调节

• 批准号: 8709985
• 负责人: IGOR E BRODSKY
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709985
• 关键词: Address; Affect; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Binding; Biochemical; Biological Assay; Biological Models; Caspase-1; Cell Death; Cell membrane; Cells; Critical Pathways; Cytosol; Data; Defect; Detection; Development; Drug Design; Ectopic Expression; Escherichia coli; Event; Family; Flagellin; Foundations; Future; Genetic; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Homeostasis; Host Defense; Immune; Immune response; Immune system; Immunity; Infection; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-1; Interleukin-18; Ions; Knowledge; Mediating; Membrane; Modeling; Molecular; Mouse Strains; Multi-Drug Resistance; Multiprotein Complexes; Mus; Mutant Strains Mice; Pasteurella pseudotuberculosis; Pathogenesis; Pathway interactions; Pattern recognition receptor; Plague; Play; Process; Production; Proteins; Public Health; Relative (related person); Role; Shapes; Stimulus; Stress; Testing; Therapeutic; Type III Secretion System Pathway; Virulence; Virulence Factors; Yersinia; Yersinia infections; Yersinia pestis; antimicrobial; antimicrobial drug; base; cytokine; in vivo; inhibitor/antagonist; insight; mutant; novel; novel strategies; pathogen; porin; prevent; public health relevance; receptor; response; retinal rods

DESCRIPTION (provided by applicant): The overall goal of this project is to understand molecular mechanisms of how the innate immune system senses and responds to bacterial pathogens and the evasion strategies utilized by bacterial pathogens to avoid immune detection. In particular we use Yersinia pseudotuberculosis, which expresses many of the same virulence factors as its close relative and plague pathogen Yersinia pestis, as a model to understand the host- pathogen interface and discover shared features of host innate immune responses to Gram-negative bacterial pathogens. The rapid expansion of multi-drug resistance among Gram-negative bacteria has increased the importance of developing new approaches to antimicrobial therapeutics, and understanding how the innate immune system initially detects bacterial pathogens and the corresponding pathogen evasion strategies holds promise for identifying novel antimicrobials. The Type III secretion system (T3SS) is a broadly conserved virulence determinant that is essential for virulence of many Gram-negative bacterial pathogens from E. coli to Y. pestis, and injects virulence factors into host cells that disrupt cellular signling pathways. However, T3SS activities can also be sensed by cytosolic pattern recognition receptors of the Nod-like receptor (NLR) family and induce host immune responses. Previous studies demonstrated that the Y. pseudotuberculosis and Y. pestis T3SS induces activation of an NLRP3-dependent inflammasome, resulting in cell death and caspase-1 dependent cytokine secretion. Furthermore, studies demonstrated that the essential Yersinia virulence factor YopK, which modulates the pore-forming activity of the T3SS and limits translocation of other Yop effector proteins, prevents inflammasome activation. Inflammasome activation plays an important role in host defense against Yersinia, as the virulence defect of YopK-deficient bacteria is restored in mice that lack inflammasome components. However, the molecular basis for how cells sense the activity of Yersinia's T3SS and how YopK prevents this sensing is not known. We propose three Specific Aims to address this important gap in our knowledge. First we will test the hypothesis that delivery of translocon components into the host cell cytosol activates the NLRP3 inflammasome through disruption of intracellular compartments. Second we will test the hypothesis that YopK prevents NLRP3 inflammasome activation by binding to the translocon and limiting injection of translocon components into the cell. Third, we will test te hypothesis that inflammasome activation in vivo controls Yersinia infection via production of caspase-1 dependent cytokines that induce activation of specific immune cell subsets that promote bacterial clearance.

描述（由申请人提供）：该项目的总体目标是了解先天免疫系统如何感应并响应细菌病原体以及细菌病原体使用的逃避策略的分子机制，以避免免疫检测。特别是，我们使用耶尔森氏菌菌血症，它表达了许多与其近亲和瘟疫病原体鼠疫耶尔森氏病相同的毒力因子，以了解宿主病原体界面并发现宿主对革兰氏阴性细菌病原体的宿主免疫反应的共同特征。革兰氏阴性细菌中多药耐药性的快速扩展提高了开发新方法的抗菌治疗方法的重要性，并了解先天免疫系统如何最初检测到细菌病原体和相应的病原体逃避策略具有识别新型抗微生物剂的希望。 III型分泌系统（T3SS）是一种广泛保守的毒力决定因素，对于从大肠杆菌到耶和华的许多革兰氏阴性细菌病原体的毒力至关重要，并将毒力转移到破坏细胞签名途径的宿主细胞中。然而，T3SS活性也可以通过NOD样受体（NLR）家族的胞质模式识别受体来感知，并诱导宿主免疫反应。先前的研究表明，Y. pseudotuberculosis和Y. Pestis T3SS诱导NLRP3依赖性炎症体的激活，从而导致细胞死亡和caspase-1依赖性细胞因子分泌。此外，研究表明，调节T3SS的孔形成活性并限制了其他Yop效应蛋白的易位，它可以防止炎症体激活炎症。炎性体激活在宿主防御耶尔森氏菌中起着重要作用，因为缺乏炎症体成分的小鼠恢复了Yopk缺陷型细菌的毒力缺陷。但是，细胞如何感知Yersinia t3ss的活性以及Yopk如何阻止这种传感的分子基础。我们提出了三个特定的目标，以解决我们知识的这一重要差距。首先，我们将检验以下假设：转运成分传递到宿主细胞胞质中，通过破坏细胞内室室的破坏会激活NLRP3炎症体。其次，我们将测试Yopk通过与易位的易位并限制转运成分进入细胞的假设，以防止NLRP3炎症体激活。第三，我们将测试假设，即通过产生caspase-1依赖性细胞因子来控制耶尔森氏菌感染，从而诱导促进细菌清除率的特定免疫细胞亚群激活。