Innate immune sensing of ER stress during bacterial infection

摘要 病原菌和非病原菌都会产生病原体相关的分子模式(PAMP)， 通过Toll样受体等模式识别受体刺激真核宿主的先天免疫反应 感受器。病原体的毒力因子提供了额外的信号，允许先天免疫系统 区分无害的共生体和病原体。这些信号包括毒力因子，例如 III型和IV型分泌系统将效应蛋白转移到宿主细胞中。总而言之，这些 免疫系统检测到的过程是“致病模式”，可以激活胞浆信号。 小路。流产布鲁氏菌是一种隐形病原体，表达不再作为激动剂的修饰的PAMP 用于模式识别受体。因此，在感染流产杆菌期间产生的宿主反应完全是 依赖于检测其T4SS的功能，作为病原体诱导的过程。在这里，我们建议使用这个 生物体将询问与内质网扰动相关的新的先天性免疫信号通路 抗炎作用。本应用的目的是确定IRE1α途径的激活方式 宿主细胞的未折叠蛋白反应通过以下方式影响细胞内细菌感染的结局 引发炎症反应，并提供推动受感染细胞生存或死亡的输入。这个 拟议中的研究将检验这一假设，即在巨噬细胞中，含有NOD1/NOD2的信号复合体 检测流产杆菌感染过程中ER功能的扰动，以诱导炎症反应并促进 感染的巨噬细胞存活，而在分泌细胞型感染诱导的内质网应激触发免疫原性 细胞死亡，导致胎盘炎和流产。这项工作的成功完成将使该领域向前推进 确定细胞如何检测病原体诱导的内质网功能扰动以及由此产生的反应 在不同的细胞类型中驱动细胞存活和细胞死亡结果。这个概念有重要的影响，而不是 不仅用于细菌的致病机理，而且还用于了解宿主与病毒的相互作用、先天免疫和 内质网应激相关炎性疾病的发病机制，如1型糖尿病、炎症性肠病 疾病和神经炎症性疾病。

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.