Coxiella burnetii Regulation of Macrophage cAMP/PKA Signaling

伯纳特柯克斯体对巨噬细胞 cAMP/PKA 信号传导的调节

• 批准号: 8660636
• 负责人: Daniel E Voth
• 金额: $ 17.74万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-10 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660636
• 关键词: Actins; Acute Disease; Address; Aerosols; Alveolar Macrophages; Apoptosis; Apoptotic; Biogenesis; Biological Assay; Cell Communication; Cell Death; Cell physiology; Cells; Chronic; Coxiella burnetii; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Data; Disease; Endocarditis; Ensure; Event; Exploratory/Developmental Grant; Fluorescent Probes; Generations; Goals; Human; Immune; Immune response; Infection; Inhibition of Apoptosis; Integration Host Factors; Lysosomes; Maintenance; Membrane; Monitor; Nature; Parasites; Phagolysosome; Phagosomes; Phosphotransferases; Prevention; Production; Protein Kinase; Protein Kinase C; Proteins; Q Fever; Regulation; Research; Role; Second Messenger Systems; Signal Transduction; Small Interfering RNA; Staging; Stimulus; Testing; Therapeutic; Transcriptional Regulation; Vacuole; Virulence; Virulent; base; combat; design; flu; in vivo; insight; macrophage; parasitism; pathogen; polymerization; prevent; programs; protein transport; public health relevance; research study; response; second messenger; therapeutic target; trafficking

DESCRIPTION (provided by applicant): 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 macrophages in vivo, where the pathogen regulates vesicular trafficking to establish a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. Eukaryotic kinase signaling is heavily involved in phagosome maturation and host responses to bacterial pathogens; however, their involvement in C. burnetii infection has not been fully defined. The current proposal is designed to test the hypothesis that C. burnetii manipulates host cAMP/PKA signaling to generate the PV and prevent host cell death. Aim 1 will elucidate the role of PKA in PV formation. The experiments in this aim will explore the requirement for PKA and actin-related protein trafficking to the PV. Aim 2 will determine the role of PKA in C. burnetii anti-apoptotic activity. These experiments will assess PKA-dependent inactivation of pro-apoptotic Bad and the requirement of this event for prevention of apoptosis. Aim 3 will probe the overall role of cAMP production in PV formation, bacterial replication, apoptosis inhibition, and transcriptional regulation. Collectively, the aims in the current proposal will explore a multi-functional role for cAMP/PKA signaling in C. burnetii parasitism of macrophages.

描述（由申请人提供）：Coxiella burnetii是人类Q Fever的细胞内细菌剂，这是一种使人衰弱的流感样疾病，也可以作为严重的慢性心内膜炎。 C. burnetii通过污染的气溶胶和靶向肺泡巨噬细胞在体内扩散，在该病原体中调节囊泡运输以建立一个吞噬体样的寄生虫液泡（PV），在其中复制。真核激酶信号与吞噬体成熟和宿主对细菌病原体的反应很大。但是，它们参与C. burnetii感染尚未完全定义。当前的建议旨在检验以下假设：C。burnetii操纵宿主营地/PKA信号以产生PV并防止宿主细胞死亡。 AIM 1将阐明PKA在PV形成中的作用。此目标中的实验将探讨PKA和与肌动蛋白相关的蛋白质运输的需求。 AIM 2将确定PKA在C. burnetii抗凋亡活性中的作用。这些实验将评估促凋亡坏的PKA依赖性失活，并评估该事件预防凋亡的要求。 AIM 3将探测cAMP生产在PV形成，细菌复制，凋亡抑制和转录调控中的总体作用。总体而言，当前提案中的目的将探讨巨噬细胞孢子虫寄生虫中CAMP/PKA信号的多功能作用。