Early Events in the Pathogenesis of Pneumonic Plague

肺鼠疫发病机制的早期事件

• 批准号: 8443017
• 负责人: WILLIAM E GOLDMAN
• 金额: $ 19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443017
• 关键词: Acute; Aerosols; Antibiotics; Attenuated; Bacteria; Bioterrorism; Bronchopneumonia; Bubonic Plague; Categories; Cell Communication; Cells; Cessation of life; Classification; Cytokine Activation; Data; Development; Disease; Disease Progression; Employee Strikes; Environment; Event; Exposure to; Foundations; Future; Goals; Hour; Immune; Immune System Diseases; Immune response; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Laboratories; Lung; Lung diseases; Mediating; Modeling; Monitor; Mus; Natural Immunity; Nature; Pathogenesis; Pathology; Peptide Hydrolases; Phase; Plague; Plasminogen; Pneumonic Plague; Population; Production; Publishing; Research; Route; Septicemic plague; Solid; Staging; Symptoms; Syndrome; Therapeutic; Time; Tissues; Type III Secretion System Pathway; Virulent; Work; Yersinia; Yersinia pestis; base; cell type; chemokine; cytokine; design; in vivo; mortality; mouse model; mutant; neutrophil; novel therapeutics; pathogen; pathogenic bacteria; prevent; prophylactic; public health relevance; research study; respiratory; response

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.

描述（由申请人提供）：鼠疫是由鼠疫耶尔森氏菌引起的最致命的疾病形式，也是该细菌被分类为A类选择性病原体的基础。大多数鼠疫致病机制的研究都集中在淋巴腺感染途径，大多数研究的病原体已与减毒，无毒或相关的耶尔森氏菌物种。肺鼠疫的一个更完整的图像已经出现在一个小鼠感染模型的发展中，该模型表明由完全强毒的Y。鼠疫以两个不同的阶段发展：延长的炎症前期，随后是导致严重支气管肺炎和死亡的强烈促炎期。 本提案的最终目标是获得更完整的理解呼吸道免疫细胞的相互作用，激活和消耗的Y。在肺炎鼠疫的炎症前期，我们将使用细菌和宿主突变体来进一步表征这些早期细菌-宿主细胞相互作用对发病机制的影响。 具体目标1。描述Y之间的早期相互作用。鼠疫菌和宿主细胞我们的假设是Y.鼠疫以肺中的特定免疫细胞群为目标，以实现对先天免疫的定向和局部抑制。本目标中的研究将表征体内III型分泌系统靶向的肺细胞，并评价炎症前阶段发生的宿主细胞群变化。 具体目标2。描述Y. pestis介导的炎性小体活化及其对疾病进展/病理学的贡献。初步数据表明，完全毒力的Y。鼠疫菌在体外和体内接种后很快激活炎性小体。这是惊人的，因为在感染的早期阶段没有炎症或病理学的迹象。本目标中的研究旨在鉴定这种应答的细菌和宿主贡献者，以及评价这种早期细胞因子激活对后期免疫发病机制的重要性。