Bacterial modulation of noncanonical inflammasome

非典型炎症小体的细菌调节

基本信息

批准号：
10893667
负责人：
Sivapriya Kailasan Vanaja
金额：
$ 48.4万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10893667
关键词：
Address Affect Antibiotics Bacterial Infections Bacterial Toxins Bacterial exotoxin Binding Biochemical CASP1 gene CASP3 gene Caspase Cell Communication Cell Death Cell physiology Cells Child Citrobacter rodentium Clinical Management Colitis Complex Cytosol Data Disease Endothelial Cells Epithelial Cells Escherichia coli EHEC Escherichia coli Infections Exotoxins Exposure to Flagellin Hemolytic-Uremic Syndrome Hemorrhagic colitis Hospitalization Human IL18 gene Immune response Immunologic Surveillance Infection Inflammasome Inflammatory Innate Immune Response Innate Immune System Interleukin-1 Intestinal Diseases Kidney Diseases Kidney Failure Knowledge Length Life Lipopolysaccharides Macrophage Mediating Membrane Molecular Mus Myeloid Cells N-terminal Outcome Pathogenesis Pathogenicity Pathway interactions Pattern Pattern recognition receptor Persons Process Production Role Severity of illness Shapes Shiga Toxin Signal Pathway Signal Transduction Surveys Testing Tissues Toxin Type III Secretion System Pathway VDAC1 gene Vesicle Virulence Factors Work cell type clinically relevant cytokine defense response design enteric pathogen extracellular human pathogen immune activation in vivo innate immune pathways insight intestinal epithelium microbial monocyte mouse model neutrophil novel therapeutic intervention novel therapeutics pathogen pathogenic bacteria response treatment strategy

项目摘要

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.

项目摘要/摘要在宿主 - 细菌病原体相遇期间，宿主细胞暴露于微生物成分，包括毒力因子，例如细菌毒素和病原体 - 相关的分子模式（PAMP），例如脂多糖（LPS）和鞭毛蛋白。这先天免疫系统采用种系编码的模式识别受体来调查用于弹丸和安装适当防御的细胞内和细胞内环境回答。同时，细菌毒力因子直接诱导和/或重新线细胞有利于或没有组织损伤的细菌定植的过程。之间的串扰 PAMP引起的先天免疫反应和毒力因子诱导的细胞反应是宿主 - 病原体相互作用的命运的重要决定因素。因此，深入的理解这些相互作用对于获得细菌疾病机制的见解至关重要。但是，这些相互作用在几种细菌感染中的特征很差。这个项目将利用人类病原体，肠haporhagic大肠杆菌来解决这种知识差距（EHEC），出血性结肠炎和溶血性尿毒症综合征（HUS）的病因。期间 EHEC感染，宿主细胞会遇到细菌因子，包括志贺毒素，III型分泌系统组件和LP。独特的非规范炎性体途径感应EHEC LPS通过外膜囊泡进入宿主细胞胞质溶液；胞质LPS结合并激活炎症caspase，caspase-11，然后介导细胞死亡，caspase-1激活和下游IL-1细胞因子产生。提出的三个特定目标的研究将系统地表征了EHEC毒力因子如何颠覆非规范炎性介导的宿主反应以及非规范炎症体如何相互互动在EHEC感染的临床相关鼠模型中调节EHEC疾病发病机理。因此，这项研究的发现为复合物提供了关键的分子和细胞见解经典细菌弹药和毒力因子诱导的宿主信号通路之间的相互作用及其对临床相关感染中疾病发病机理的影响。