Bacterial modulation of noncanonical inflammasome

项目摘要/摘要 在宿主-细菌病原体相遇期间，宿主细胞暴露在一系列 微生物成分，包括致病因子，如细菌毒素和病原体- 相关分子模式(PAMP)，如脂多糖(LPS)和鞭毛蛋白。这个 先天免疫系统使用生殖线编码的模式识别受体来检测 为PAMP的存在提供细胞外和细胞内环境并采取适当的防御措施 回应。同时，细菌毒力因子直接诱导和/或重新连接细胞 有利于细菌定植的过程，无论有没有组织损伤。两个人之间的串扰 PAMP诱导的先天免疫反应和毒力因子诱导的细胞反应是 宿主-病原体相互作用命运的重要决定因素。因此，深入了解 这些相互作用对于深入了解细菌疾病的机制至关重要。 然而，在几种细菌感染中，这些相互作用的特征很差。这个项目 将利用一种人类病原体--肠出血性大肠杆菌来解决这一知识差距 出血性结肠炎和溶血性尿毒症综合征(HUS)的病原体。在.期间 EHEC感染时，宿主细胞会遇到细菌因素，包括志贺毒素、III型分泌物 系统组件和内毒素。一种独特的非典型性炎症体通路感测EHEC 内毒素通过外膜小泡进入宿主细胞胞浆；胞内内毒素结合并激活一个 炎症性caspase，caspase-11，然后介导细胞死亡，caspase-1激活，以及 下游IL-1细胞因子的产生。在三个具体目标中提出的研究将 系统地描述EHEC毒力因子如何颠覆非规范的 炎症体介导的宿主反应以及非典型性炎症体如何相互作用 在EHEC感染的临床相关小鼠模型中调节EHEC疾病的发病机制。 因此，这项研究的发现提供了对复合体的关键分子和细胞洞察力 经典细菌PAMP和毒力因子诱导的宿主信号通路之间的相互作用 以及它在临床相关感染中对疾病发病机制的影响。

Project Summary/Abstract During host-bacterial pathogen encounters, the host cells are exposed to an array of microbial components, including virulence factors such as bacterial toxins and pathogen- associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and flagellin. The innate immune system employs germline-encoded pattern recognition receptors to survey the extra- and intra-cellular milieu for the presence of PAMPs and mount appropriate defense responses. Concurrently, bacterial virulence factors directly induce and/or rewire cellular processes that favor bacterial colonization with or without tissue damage. The crosstalk between the PAMP-induced innate immune responses and virulence factor-induced cellular responses are vital determinants of the fate of host-pathogen interactions. Therefore, an in-depth understanding of these interactions is critical for gaining insights into the mechanisms of bacterial diseases. However, these interactions are poorly characterized in several bacterial infections. This project will address this knowledge gap utilizing a human pathogen, Enterohemorrhagic Escherichia coli (EHEC), the causative agent of hemorrhagic colitis and hemolytic uremic syndrome (HUS). During EHEC infection, host cells encounter bacterial factors, including Shiga toxin, type III secretion system components, and LPS. A unique noncanonical inflammasome pathway senses EHEC LPS entering host cell cytosol via outer membrane vesicles; cytosolic LPS binds and activates an inflammatory caspase, caspase-11, which then mediates cell death, caspase-1 activation, and downstream IL-1 cytokine production. The studies proposed in three specific aims will systematically characterize how an EHEC virulence factor subverts the noncanonical inflammasome-mediated host responses and how the noncanonical inflammasome reciprocally regulate EHEC disease pathogenesis in a clinically relevant murine model of EHEC infection. Thus, the findings from this study provides critical molecular and cellular insights into a complex interplay between a classic bacterial PAMP- and virulence factor-induced host signaling pathways and its impact on disease pathogenesis in a clinically relevant infection.