Coxiella burnetii Subversion of Host Nrf2 Antioxidant Signaling- Resubmission

伯氏柯克斯体是人类Q热的细胞内细菌病原体，Q热是一种急性流感样疾病，可以 可能是致命的慢性心内膜炎。伯氏隐孢子虫寄生人类的机制 巨噬细胞仍然是一个谜。然而，通过使用其他细胞模型，研究已经 证明了伯氏梭菌调节许多寄主过程，包括囊泡运输和 细胞凋亡。目前的提案旨在定义C.burnetii使用的机制，以避免 人肺泡巨噬细胞的氧化应激反应 体内靶细胞。我们发现伯氏梭菌能激活Cargo受体p62，并且 潜在地使用这种多功能蛋白质来激活抗氧化剂转录因子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激活对伯氏梭菌预防氧化应激反应和细胞凋亡的影响。 在整个提案中，我们将使用我们的原始人类肺泡巨噬细胞感染模型来 确定与疾病相关的流程。总体而言，当前提案中的目标将提供 需要深入了解伯氏隐孢子虫寄生人类巨噬细胞的机制， 这是Q热进展的先决条件。

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.