Characterization of the Human Lung Response to Coxiella burnetii

人肺对伯内氏柯克斯体反应的特征

• 批准号: 9386624
• 负责人: Daniel E Voth
• 金额: $ 21.99万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-25 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386624
• 关键词: Acute Disease; Address; Aerosols; Alveolar; Alveolar Macrophages; Animal Model; Bacteria; Biogenesis; Cell Death; Cell model; Cells; Cellular Morphology; Chronic; Coxiella burnetii; Data; Detection; Development; Disease; Endocarditis; Environment; Eukaryotic Cell; Goals; Growth; Human; Human Cell Line; Immune response; Individual; Infection; Inflammasome; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1 beta; Interleukin-6; Lipopolysaccharides; Lung; Mediating; Modeling; Mus; Nature; Organism; Phagocytes; Phagolysosome; Physiology; Prevention; Process; Production; Q Fever; Research; Structure of parenchyma of lung; System; TNF gene; Testing; Vacuole; Virulence; Virulent; cell type; cellular targeting; cytokine; design; flu; in vivo; macrophage; novel; pathogen; prevent; response; trafficking

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.

Coxiella burnetii是人类Q发烧的细胞内细菌剂，这是一种令人衰弱的流感样疾病，可以 也表现为严重的慢性心内膜炎。 C. burnetii通过被污染的气溶胶和目标传播 体内肺泡吞噬细胞，病原体主动调节水泡贩运以建立一个 吞噬溶血体样的寄生虫液泡（PV），可以在其中复制。尽管PV生物发生是 对于感染至关重要，巨噬细胞对感染的先天免疫反应尚不完全了解。这 当前建议使用两个新型感染模型，即人类肺组织和肺泡巨噬细胞， 为了检验c。burnetii特异性改变人肺泡巨噬细胞生理的假设 为了防止炎症体活动并避免先天免疫反应。这些模型将 提供无法使用当前动物模型获得的人类特异性信息。 AIM 1将表征 C. C. burnetii感染肺细胞，明确证明了人类感染过程中针对的细胞类型。目标2 将针对无抗菌C. burnetii定义巨噬细胞炎症体激活 有毒生物避免检测的机制。这些研究共同提供 增强了C. burnetii感染过程的建模和人类先天免疫反应 肺病原体。