Characterization of the Human Lung Response to Coxiella burnetii

贝氏柯克斯体是人类Q热的细胞内细菌因子，Q热是一种使人衰弱的流感样疾病， 也表现为严重的慢性心内膜炎C.贝氏体通过受污染的气溶胶和目标传播 肺泡吞噬细胞在体内，其中病原体积极调节囊泡运输，以建立 吞噬溶酶体样的寄生虫空泡（PV），在其中复制。虽然PV生物成因是 巨噬细胞对感染的先天免疫应答对于感染至关重要，但尚未完全了解。的 目前的建议使用两种新的感染模型，人肺组织和肺泡巨噬细胞， 为了检验C.贝氏菌特异性改变人肺泡巨噬细胞生理学 以防止炎性体活动并避免先天免疫应答。这些模型将 提供使用当前动物模型无法获得的人类特异性信息。目标1将描述 C.伯内特氏菌感染肺细胞，明确证明了人类感染期间靶向的细胞类型。目的2 将定义巨噬细胞炎性小体对无毒力C.贝氏菌鉴定 有毒生物体逃避检测的机制。这些研究将提供 增强了C.贝氏体感染过程和人类先天免疫应答 肺部病原体

Coxiella burnetii is the intracellular bacterial agent of human Q fever, a debilitating flu-like illness that can also present as severe chronic endocarditis. C. burnetii is spread by contaminated aerosols and targets alveolar phagocytes in vivo, where the pathogen actively regulates vesicular trafficking to establish a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. Although PV biogenesis is critical for infection, the macrophage innate immune response to infection is not fully understood. The current proposal uses two novel infection models, human lung tissue and alveolar macrophages, to test the hypothesis that C. burnetii specifically alters human alveolar macrophage physiology to prevent inflammasome activity and avoid the innate immune response. These models will provide human-specific information not obtainable using current animal models. Aim 1 will characterize C. burnetii infection of lung cells, definitively proving the cell type targeted during human infection. Aim 2 will define macrophage inflammasome activation in response to avirulent C. burnetii and identify mechanisms by which virulent organisms avoid detection. Collectively, these studies will provide enhanced modeling of the C. burnetii infectious process and the human innate immune response to pulmonary pathogens.