Regulation of host innate and adaptive immunity by bacterial type III effectors

项目摘要/摘要 细菌病原体使用III型分泌系统将效应物转移到宿主细胞中，以促进毒力。 III型分泌物还可以激活具有宿主保护作用的代偿性先天免疫反应。为 例如，III型分泌物可以触发宿主细胞中的炎症体组装，导致细胞因子的释放 IL-1b。强毒病原体可抑制III型分泌物触发的代偿性保护性免疫反应 但这是如何在体内的细胞和分子水平上实现的，仍然知之甚少。要解决这个问题 知识鸿沟，这个项目试图在细胞和分子水平上确定III型分泌物是如何 耶尔森氏菌强毒物种中的效应物在体内抑制保护性炎症小体途径。耶尔西尼亚使用两个 效应剂，YopM和YopJ，以抑制吡咯炎症体。目前尚不清楚YopM和YopJ是否促进了毒力 通过以细胞特异性的方式抑制吡咯炎症体。在淋巴组织侵袭性感染期间 耶尔森氏菌以细胞外微克隆的形式生长，与组织免疫中的中性粒细胞直接接触 被称为化脓性肉芽肿的结构。脓性肉芽肿可以被认为是耶尔森氏菌毒力的战场 在充当步兵的中性粒细胞中，各种因子对抗保护性免疫反应。耶尔森氏菌突变体缺失 YopM和YopJ在淋巴组织中存在明显的存活缺陷，表明这些效应物抑制了 化脓性肉芽肿中性粒细胞中的比林炎性小体。此外，IL-1b对于宿主保护也很重要。 耶尔森氏菌感染缺乏YopM和YopJ。根据这些公布的数据和初步结果，我们 YopM和YopJ通过抑制中性粒细胞中的吡咯炎性小体促进耶尔森氏菌毒力的假设 目的：预防化脓性肉芽肿中IL-1b的释放。这一假设将在Aim 1中得到验证。 感染的宿主细胞和纯化的形式，但这种相互作用的分子基础尚不清楚。基于 已发表的初步假设YopM靶向吡咯域抑制炎症小体。 活体和促进耶尔森氏菌的毒力。这一假设将在目标2中得到验证。完成这些目标将满足 重要的知识空白，推动了耶尔森氏菌致病机理的研究，对该领域产生了广泛的影响 中性粒细胞炎性小体和提供旨在增强保护性中性粒细胞的新治疗策略 炎症体对细菌病原体的反应。

Project Summary/Abstract Bacterial pathogens use type III secretion systems to translocate effectors into host cells to promote virulence. Type III secretion can also activate compensatory innate immune responses that are host protective. For example, type III secretion can trigger inflammasome assembly in host cells, resulting in release of the cytokine IL-1b. Virulent pathogens can inhibit compensatory protective immune responses triggered by type III secretion but how this is achieved at the cellular and molecular levels in vivo remains poorly understood. To address this knowledge gap, this project seeks to determine at the cellular and molecular levels how type III secretion effectors in virulent Yersinia species inhibit a protective inflammasome pathway in vivo. Yersinia uses two effectors, YopM and YopJ, to inhibit the pyrin inflammasome. It is not known if YopM and YopJ promote virulence by inhibiting the pyrin inflammasome in a cell specific manner. During invasive infections of lymphoid tissues Yersinia grow as extracellular microcolonies in direct contact with neutrophils within an organize immune structure known as a pyogranuloma. Pyogranulomas can be considered battlefields where Yersinia virulence factors combat protective immune responses in neutrophils acting as foot soldiers. Yersinia mutants lacking YopM and YopJ have a significant survival defect in lymphoid tissues suggesting that these effectors inhibit the pyrin inflammasome in pyogranuloma neutrophils. Additionally, IL-1b is important for host protection against infection by Yersinia lacking YopM and YopJ. Based on these published data and preliminary results we hypothesize that YopM and YopJ promote Yersinia virulence by inhibiting the pyrin inflammasome in neutrophils to prevent release of IL-1b in pyogranulomas. This hypothesis will be tested in Aim 1. YopM binds to pyrin in infected host cells and in purified form, but the molecular basis of this interaction is undefined. Based on published and preliminary we hypothesize that YopM targets the pyrin domain to inhibit the inflammasome in vivo and promote Yersinia virulence. This hypothesis will be tested in Aim 2. Completion of these aims will fill important knowledge gaps, move Yersinia pathogenesis research forward, have a broad impact on the field of neutrophil inflammasomes and inform new therapeutic strategies aimed at augmenting protective neutrophil inflammasome responses to bacterial pathogens.