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

项目总结/摘要 细菌病原体使用III型分泌系统将效应子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性的代偿性先天免疫应答。为 例如，III型分泌可触发宿主细胞中的炎性小体组装，导致细胞因子的释放 IL-1b。致病性病原体可抑制III型分泌物引发的代偿性保护性免疫反应 但如何在体内的细胞和分子水平上实现这一点仍然知之甚少。为了解决这个 知识差距，该项目旨在确定在细胞和分子水平上如何III型分泌 毒性耶尔森氏菌属物种中的效应子抑制体内保护性炎性体途径。耶尔森菌使用两种 效应物YopM和YopJ，以抑制pyrin炎性体。尚不清楚YopM和YopJ是否促进毒力 通过以细胞特异性方式抑制pyrinininflammasome。在淋巴组织侵袭性感染期间 耶尔森氏菌作为细胞外小菌落生长，与组织免疫系统内的中性粒细胞直接接触。 称为脓肉芽肿的结构。脓肉芽肿可以被认为是耶尔森氏菌毒力的战场 因子对抗中性粒细胞中的保护性免疫应答，中性粒细胞充当步兵。缺乏突变型耶尔森氏菌 YopM和YopJ在淋巴组织中具有显著的存活缺陷，这表明这些效应物抑制淋巴细胞的增殖。 嗜中性粒细胞脓肉芽肿中的Pyrin炎性小体。此外，IL-1b对于宿主保护免受 缺乏YopM和YopJ的耶尔森氏菌感染。根据这些已发表的数据和初步结果， 假设YopM和YopJ通过抑制嗜中性粒细胞中Pyrin炎性体来促进耶尔森氏菌毒力 以防止脓肉芽肿中IL-1b的释放。这一假设将在目标1中得到检验。YopM与吡啉结合 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是不确定的。基于 我们假设YopM靶向pyrin结构域以抑制炎性小体， 体内并促进耶尔森氏菌毒力。目标2将检验这一假设。这些目标的实现将使 重要的知识空白，推动耶尔森氏菌致病机理研究向前发展，对该领域产生广泛影响。 中性粒细胞炎性小体和旨在增强保护性中性粒细胞的新治疗策略 炎性小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.