Early Events in the Pathogenesis of Pneumonic Plague

描述(由申请人提供)：肺鼠疫是由鼠疫耶尔森氏菌引起的最致命的疾病形式，也是该细菌被归类为A类选择剂的基础。大多数关于鼠疫发病机制的研究都集中在腺体感染途径上，而对病原体的研究大多是利用耶尔森氏菌的减毒、无毒或相关物种进行的。从小鼠感染模型的发展中出现了更完整的肺鼠疫图景，表明由完全毒力的鼠疫杆菌引起的肺部疾病经历了两个不同的阶段：延长的炎症前期阶段，随后是导致严重支气管肺炎和死亡的强烈的促炎阶段。 这项建议的最终目标是更全面地了解肺炎鼠疫炎症前期阶段鼠疫杆菌与呼吸道免疫细胞的相互作用、激活和耗尽。我们将使用细菌和宿主突变来进一步表征这些早期细菌-宿主细胞相互作用在发病机制上的影响。 具体目标1.鉴定鼠疫杆菌与肺部宿主细胞之间的早期相互作用。我们的假设是，鼠疫杆菌以肺部特定的免疫细胞群为靶标，实现对先天免疫的定向和局部抑制。这一目标的研究将表征体内III型分泌系统靶向的肺细胞，并评估炎症前阶段发生的宿主细胞群的变化。 特定目的2.鉴定鼠疫杆菌介导的炎性小体激活及其在疾病进展/病理中的作用。初步数据表明，在体外和体内，完全毒力的鼠疫杆菌在接种后不久就会激活炎症体。这是惊人的，因为在感染的早期阶段看不到炎症或病理的迹象。这一目的的研究旨在确定这一反应的细菌和宿主贡献者，以及评估这种早期细胞因子激活对后来的免疫发病机制的重要性。

DESCRIPTION (provided by applicant): Pneumonic plague is the deadliest form of disease caused by Yersinia pestis and the basis for this bacterium's classification as a Category A Select Agent. Most studies of plague pathogenesis have focused on the bubonic route of infection, and most research on the pathogen has been performed with attenuated, avirulent or related species of Yersinia. A more complete picture of pneumonic plague has emerged from the development of a mouse model of infection showing that pulmonary disease caused by fully virulent Y. pestis progresses in two distinct stages: an extended pre-inflammatory phase followed by a robust pro-inflammatory phase that leads to severe bronchopneumonia and mortality. The ultimate goal of this proposal is to obtain a more complete understanding of respiratory immune cell interactions, activation and depletion by Y. pestis during the pre-inflammatory phase of pneumonic plague. We will use both bacterial and host mutants to further characterize the effects of these early bacterial - host cell interactions on pathogenesis. Specific Aim 1. Characterize early interactions between Y. pestis and host cells in the lung. Our hypothesis is that Y. pestis targets specific immune cell populations in the lung to achieve directed and localized suppression of innate immunity. The studies in this Aim will characterize the lung cells targeted by the type III secretion system in vivo and evaluate host cell population changes that occur during the preinflammatory phase. Specific Aim 2. Characterize Y. pestis-mediated inflammasome activation and its contribution to disease progression/pathology. Preliminary data demonstrates that fully virulent Y. pestis activates the inflammasome soon after inoculation both in vitro and in vivo. This is striking, as no signs of inflammation or pathology are visible at this early stage of infection. The studies in this Aim are designed to identify both the bacterial and host contributor to this response, as well as evaluate the importance of this early cytokine activation to later immunopathogenesis.