sRNAs in EHEC virulence

EHEC毒力中的sRNA

基本信息

批准号：
10286819
负责人：
Melissa Kendall
金额：
$ 23.75万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286819
关键词：
5&apos Untranslated Regions Affect Affinity Chromatography Alternative Therapies Bacteria Bacterial Adhesins Base Pairing Base Sequence Binding Binding Sites Biochemical Code Colon Coupled Cues Data Development Disease Dose Enterocytes Environment Epithelial Cells Escherichia coli Escherichia coli EHEC Escherichia coli O157:H7 Ethanolamines Gastrointestinal tract structure Gene Expression Gene Expression Regulation Genetic Genetic Transcription Genomic Islands Growth Hemolytic-Uremic Syndrome Hemorrhagic colitis Human Infection Lead Lesion Ligation Light Maps Messenger RNA Metabolism Molecular Morbidity - disease rate Nutrient Outcome Pathogenesis Play Publishing RNA Regulation Regulon Ribosomes Role Shiga Toxin Small RNA System Transcript Translation Initiation Translations Virulence Virulence Factors base biological adaptation to stress design enteric pathogen functional outcomes gastrointestinal improved in vivo microbiota mortality negative affect pathogen pathogenic bacteria premature response spatiotemporal transcription termination transcriptome sequencing

项目摘要

PROJECT SUMMARY The ability of bacteria to rapidly sense and respond to changes in the environment is fundamental to colonization and survival. This is especially relevant for gastrointestinal pathogens that must effectively compete for nutrients with the microbiota as well as precisely coordinate gene expression to establish infection. Small RNAs (sRNAs) are emerging as important factors that enable efficient spatiotemporal expression of genes in response to the availability of a specific metabolite and/or environmental cues, and thus play a central role in pathogenesis. The bacterial pathogen enterohemorrhagic Escherichia coli O157:H7 (EHEC) colonizes the human colon and causes hemorrhagic colitis and hemolytic uremic syndrome (HUS), which can be fatal. EHEC encodes several important virulence factors, including the potent Shiga toxin that causes HUS and a type three secretion system (T3SS) and effectors necessary for attaching and effacing (AE) lesion formation on enterocytes. EHEC has a very low infectious dose, suggesting that EHEC has evolved mechanisms to exploit nutrients in the host and precisely control virulence gene expression to occur within appropriate host niches. Our studies underscore the importance of sRNAs in bacterial virulence by demonstrating that two sRNAs, DicF and MavR, play important roles in modulating EHEC virulence. DicF influences expression of the T3SS and is required for AE lesion formation. DicF also modulates expression of genes encoding Shiga toxin, transcriptional regulators, and adhesins. MavR regulates EHEC metabolism as well as stress responses and is essential for robust colonization of the mammalian gastrointestinal tract. Moreover, our data indicate that these sRNAs regulate target gene expression via unusual mechanisms. In this application, we will investigate the molecular mechanisms of DicF- and MavR-dependent gene regulation and comprehensively identify direct targets of DicF and MavR. The proposed studies will shed light not only on EHEC virulence but also on sRNA- dependent regulatory mechanisms that may be important for gene regulation in diverse bacterial pathogens.

项目概要细菌快速感知和响应环境变化的能力至关重要殖民和生存。这对于胃肠道病原体尤其重要，这些病原体必须与微生物群有效竞争营养物质并精确协调基因表达建立感染。小RNA (sRNA) 正在成为实现高效的重要因素响应特定代谢物和/或的可用性的基因时空表达环境因素，因此在发病机制中发挥核心作用。细菌病原体肠出血性大肠杆菌 O157:H7 (EHEC) 定植于人类结肠并导致出血性结肠炎和溶血性尿毒症综合征（HUS），这可能是致命的。肠出血性大肠杆菌编码几个重要的毒力因子，包括导致 HUS 的强效志贺毒素和三型毒素分泌系统（T3SS）和效应器是附着和消除（AE）病变形成所必需的肠细胞。肠出血性大肠杆菌的感染剂量非常低，这表明肠出血性大肠杆菌已经进化出机制利用宿主体内的营养物质并精确控制毒力基因的表达适当的宿主生态位。我们的研究强调了 sRNA 在细菌毒力中的重要性证明两种 sRNA，DicF 和 MavR，在调节 EHEC 毒力中发挥重要作用。 DicF 影响 T3SS 的表达，并且是 AE 病变形成所必需的。 DicF 还具有调节作用编码志贺毒素、转录调节因子和粘附素的基因的表达。 MavR 调节 EHEC 代谢以及应激反应对于 EHEC 的稳健定植至关重要哺乳动物胃肠道。此外，我们的数据表明这些 sRNA 调节靶基因通过不寻常的机制表达。在此应用中，我们将研究分子机制 DicF 和 MavR 依赖性基因调控的研究，并全面鉴定 DicF 的直接靶标和马夫R。拟议的研究不仅将揭示肠出血性大肠杆菌的毒力，而且还将揭示 sRNA- 依赖的调控机制可能对多种细菌的基因调控很重要病原体。