Characterization of the Human Lung Response to Coxiella burnetii

伯氏柯克斯体是人类Q热的细胞内细菌病原体，Q热是一种类似流感的衰弱疾病，可以 也表现为严重的慢性心内膜炎。伯氏梭菌通过受污染的气雾剂和目标传播 肺泡吞噬细胞在体内，其中病原体积极调节泡的运输，以建立一个 吞噬酶体样的寄生空泡(PV)，在其中复制。尽管光伏生物发生是 巨噬细胞对感染的先天免疫反应是感染的关键，但目前尚不完全清楚。这个 目前的提议使用了两种新的感染模型，人肺组织和肺泡巨噬细胞， 为了验证伯氏梭菌特异性改变人肺泡巨噬细胞生理学的假设 防止炎症小体活动，避免先天免疫反应。这些型号将 提供使用当前动物模型无法获得的人类特有信息。目标1将描述 伯氏梭菌感染肺部细胞，明确证明了人类感染期间的目标细胞类型。目标2 将定义巨噬细胞炎症体激活对伯氏无毒梭菌的反应，并识别 有毒生物体躲避检测的机制。总的来说，这些研究将提供 伯氏梭菌感染过程和人类先天免疫反应的增强模型 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.