Innate immune sensing of ER stress during bacterial infection

摘要 致病性和非致病性细菌都产生病原体相关分子模式（PAMP）， 通过模式识别受体如Toll样受体刺激真核宿主的先天免疫应答 受体。病原体的毒力因子提供额外的信号，使先天免疫系统 区分无害的细菌和病原体。这些信号包括毒力因子，如 III型和IV型分泌系统，其将效应蛋白易位到宿主细胞中。总的来说，这些 免疫系统将这些过程检测为“发病模式”， 途径。流产布鲁氏菌是一种隐蔽的病原体，表达经修饰的PAMP，不再作为激动剂 用于模式识别受体。因此，在B.流产感染完全是 依赖于检测其T4 SS的功能，作为病原体诱导的过程。在这里，我们建议使用这个 询问连接内质网扰动的新型先天免疫信号传导途径的生物体 炎症的功能。本申请的目的是确定IRE 1 α通路的激活 宿主细胞的未折叠蛋白质反应通过以下方式影响细胞内细菌感染的结果： 引发炎症反应并提供驱动受感染细胞存活或死亡的输入。的 一项拟议的研究将检验这样一种假设，即在巨噬细胞中，含有NOD 1/NOD 2的信号复合物 检测B期间ER功能的扰动。流产感染诱导炎症反应，并促进 感染巨噬细胞的存活，而在分泌细胞型感染诱导的ER应激触发免疫原性 细胞死亡，导致胎盘炎和流产。这项工作的成功完成将推动该领域向前发展， 确定细胞如何检测病原体诱导的ER功能扰动以及由此产生的反应如何 驱动不同细胞类型中的细胞存活与细胞死亡结果。这一概念具有重要的影响， 不仅用于细菌致病，而且用于理解宿主-病毒相互作用、先天免疫和 与ER应激相关的炎性疾病的发病机制，如1型糖尿病、炎症性肠病、 疾病和神经炎性疾病。

ABSTRACT Both pathogenic and non-pathogenic bacteria produce pathogen-associated molecular patterns (PAMPs) that stimulate innate immune responses in their eukaryotic hosts via pattern-recognition receptors such as toll-like receptors. Virulence factors of pathogens provide additional signals that allow the innate immune system to differentiate between harmless commensals and pathogens. These signals include virulence factors, such as Type III and Type IV secretion systems that translocate effector proteins into the host cell. Collectively, these processes are detected by the immune system as “patterns of pathogenesis” and can activate cytosolic signaling pathways. Brucella abortus is a stealthy pathogen expressing modified PAMPs that no longer serve as agonists for pattern recognition receptors. As a result, host responses generated during B. abortus infection are entirely dependent on detecting the function of its T4SS, as a pathogen-induced process. Here we propose to use this organism to interrogate novel innate immune signaling pathways linking perturbation of endoplasmic reticulum function to inflammation. The objectives of this application are to determine how activation of the IRE1α pathway of the host cell’s unfolded protein response influences the outcome of infection with intracellular bacteria, by eliciting inflammatory responses and providing inputs that drive survival or death of the infected cell. The proposed research will test the hypothesis is that in macrophages, a NOD1/NOD2-containing signaling complex detects perturbation of ER function during B. abortus infection to induce inflammatory responses and promote survival of infected macrophages, while in a secretory cell type infection-induced ER stress triggers immunogenic cell death, resulting in placentitis and abortion. Successful completion of this work will move the field forward by determining how cells detects pathogen-induced perturbation of ER function and how the resulting response drives cell survival vs cell death outcomes in different cell types. This concept has important ramifications not only for bacterial pathogenesis, but also for understanding host-virus interactions, innate immunity and the pathogenesis of inflammatory disorders associated with ER stress, such as type 1 diabetes, inflammatory bowel disease and neuroinflammatory disease.