Bacterial modulation of noncanonical inflammasome

项目总结/摘要 在宿主-细菌病原体遭遇期间，宿主细胞暴露于一系列的 微生物成分，包括细菌毒素和病原体等毒力因子， 相关分子模式（PAMP），如脂多糖（LPS）和鞭毛蛋白。的 先天性免疫系统利用生殖细胞编码的模式识别受体来调查 PAMP存在的细胞外和细胞内环境，并进行适当的防御 应答同时，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，有或没有组织损伤。之间的串扰 PAMP诱导的先天免疫应答和毒力因子诱导的细胞应答是 宿主-病原体相互作用的命运的重要决定因素。因此，深入了解 研究这些相互作用对于深入了解细菌性疾病的机制至关重要。 然而，这些相互作用在几种细菌感染中的特征很差。这个项目 我将利用人类病原体肠出血性大肠杆菌来填补这一知识空白 肠出血性大肠杆菌（EHEC）是出血性结肠炎和溶血性尿毒综合征（HUS）的病原体。期间 肠出血性大肠杆菌感染后，宿主细胞遇到细菌因子，包括滋贺毒素、III型分泌物 系统组件和LPS。一种独特的非经典炎性体途径感知EHEC LPS通过外膜囊泡进入宿主细胞胞质溶胶;胞质溶胶LPS结合并激活细胞膜。 炎症性半胱天冬酶，半胱天冬酶-11，然后介导细胞死亡，半胱天冬酶-1活化， 下游IL-1细胞因子产生。在三个具体目标中提出的研究将 系统地描述了肠出血性大肠杆菌毒力因子如何颠覆非经典的 炎性小体介导的宿主反应以及非典型炎性小体如何介导宿主反应 在临床相关的EHEC感染鼠模型中调节EHEC疾病发病机制。 因此，这项研究的发现为复杂的细胞和分子生物学提供了重要的见解。 经典细菌PAMP-和毒力因子诱导宿主信号传导途径之间的相互作用 及其对临床相关感染中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.