Coxiella burnetii Subversion of Host Nrf2 Antioxidant Signaling- Resubmission

伯氏柯克斯体颠覆宿主 Nrf2 抗氧化信号 - 重新提交

基本信息

批准号：
10247813
负责人：
Daniel E Voth
金额：
$ 18.6万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247813
关键词：
Acute Acute Disease Alveolar Macrophages Anti-Bacterial Agents Antioxidants Apoptosis Area Autophagosome Binding Proteins Biochemical Biological Assay Cell Death Cell Nucleus Cell Survival Cell model Cells Cellular Stress Cellular Stress Response Chronic Coxiella burnetii Cytoplasmic Protein Cytosol Disease Disease Progression Endocarditis Eukaryotic Cell Event Gene Expression Growth Human Infection Investigation Lysosomes Mediating Modeling Oxidative Stress Parasites Pathway interactions Phosphorylation Prevention Process Proteins Publishing Q Fever Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Small Interfering RNA Testing Type IV Secretion System Pathway Vacuole Virulent biological adaptation to stress design flu in vivo inhibitor/antagonist insight macrophage novel pathogen pathogenic bacteria prevent receptor recruit response trafficking transcription factor

项目摘要

Coxiella burnetii is the intracellular bacterial agent of human Q fever, an acute flu-like illness that can present as potentially fatal chronic endocarditis. Mechanisms used by C. burnetii to parasitize human macrophages remain a mystery. However, through the use of other cell models, studies have demonstrated that C. burnetii regulates numerous host processes, including vesicular trafficking and apoptosis. The current proposal is designed to define mechanisms used by C. burnetii to avoid the oxidative stress response of human alveolar macrophages, which are the pathogen’s target cell in vivo. We found that C. burnetii triggers activation of the cargo receptor p62 and potentially uses this versatile protein to activate the antioxidant transcription factor Nrf2. Aim 1 is designed to define the mechanism by which p62 activates Nrf2. Aim 2 will define the downstream impact of Nrf2 activation on C. burnetii prevention of the oxidative stress response and apoptosis. Throughout the proposal, we will use our primary human alveolar macrophage model of infection to identify disease relevant processes. Collectively, the aims in the current proposal will provide needed insight into the mechanisms used by C. burnetii to parasitize human macrophages, which is a prerequisite for progression of Q fever.

coxiala burnetii是人类Q发烧的细胞内双骨性双歧杆菌，这是一种急性流感样疾病，可以表现为潜在的致命慢性心内膜炎。巨噬细胞仍然是一个谜。证明C. burnetii规则会定期许多宿主过程，含有囊泡的贩运和凋亡目前的建议旨在定义C. burnetii使用的机制人肺泡巨噬细胞的氧化应激重酮，这是病原体的靶细胞在体内。电位使用此时间蛋白来激活抗氧化剂转录因子NRF2 旨在定义p62激活NRF2的机制。 NRF2激活对预防氧化应激反应和腹膜抗体的影响。在整个提案中，我们将使用我们的主要人类肺泡巨噬细胞模型。确定疾病相关的过程。需要深入了解C. burnetii用于使人类巨噬细胞寄生的机制，这是Q发烧进展的先决条件。