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）：伯内特柯克斯体是人类 Q 热的细胞内细菌病原体，Q 热是一种使人衰弱的流感样疾病，也可表现为严重的慢性心内膜炎。伯氏念珠菌通过受污染的气溶胶传播，并以体内的肺泡巨噬细胞为目标，其中病原体调节囊泡运输以建立吞噬溶酶体样寄生液泡（PV）并在其中进行复制。真核激酶信号传导与吞噬体成熟和宿主对细菌病原体的反应密切相关；然而，它们与伯内特念珠菌感染的关系尚未完全确定。目前的提议旨在测试伯内特念珠菌操纵宿主 cAMP/PKA 信号传导以产生 PV 并防止宿主细胞死亡的假设。目标 1 将阐明 PKA 在 PV 形成中的作用。该目的的实验将探索 PKA 和肌动蛋白相关蛋白运输至 PV 的需求。目标 2 将确定 PKA 在 C. burnetii 抗凋亡活性中的作用。这些实验将评估 PKA 依赖性促凋亡 Bad 失活以及该事件预防细胞凋亡的必要性。目标 3 将探讨 cAMP 产生在 PV 形成、细菌复制、细胞凋亡抑制和转录调节中的总体作用。总的来说，当前提案的目标是探索 cAMP/PKA 信号在 C. burnetii 巨噬细胞寄生中的多功能作用。