Coxiella burnetii Subversion of Host Nrf2 Antioxidant Signaling- Resubmission

贝氏柯克斯体是人类Q热的细胞内细菌因子，Q热是一种急性流感样疾病， 表现为可能致命的慢性心内膜炎C使用的机制。贝氏疟原虫寄生人类 巨噬细胞仍然是个谜。然而，通过使用其他细胞模型，研究 证明了C.贝氏体调节许多宿主过程，包括囊泡运输， 凋亡目前的建议旨在定义C.伯内特避免 人肺泡巨噬细胞的氧化应激反应，这是病原体的 体内靶细胞。我们发现C. Burnetii触发货物受体p62的激活， 潜在地使用这种多功能蛋白质来激活抗氧化转录因子Nrf2。目标1是 旨在定义p62激活Nrf2的机制。目标2将定义下游 Nrf2激活对C. Burnetii预防氧化应激反应和细胞凋亡。 在整个提案中，我们将使用我们的原代人肺泡巨噬细胞感染模型， 识别疾病相关过程。总的来说，本提案的目标将提供 需要深入了解C.贝氏疟原虫寄生于人类巨噬细胞， 这是Q热恶化的先决条件

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.