Control of ExPEC virulence by small RNAs

小 RNA 控制 ExPEC 毒力

基本信息

批准号：
8075058
负责人：
MATTHEW A MULVEY
金额：
$ 18.62万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8075058
关键词：
Address Affect Animal Model Attention Bacteria Bacterial Infections Base Pairing Binding Bioinformatics Biological Assay Biological Models Communicable Diseases Coupled Development Disease Escherichia coli Gastrointestinal tract structure Gene Expression Genetic Transcription Growth Healthcare In Vitro Individual Infection Knock-out Laboratories Meningitis Messenger RNA Microbe Microbial Biofilms Modeling Molecular Chaperones Mus Nature Northern Blotting Pathogenesis Preventive Protein Inhibition RNA Repression Resistance Role SECTM1 gene Small RNA Stress Technology Testing Therapeutic Time Tissues Transcript Urinary tract Urinary tract infection Uropathogenic E. coli Virulence Work Zebrafish cell motility cost environmental change fitness genetic regulatory protein in vivo mutant neonatal sepsis next generation novel overexpression pathogen pathogenic Escherichia coli public health relevance response

项目摘要

DESCRIPTION (provided by applicant): In order to effectively colonize a host and cause disease, bacterial pathogens must have the means to sense and respond to rapidly changing environmental conditions. The adaptable nature of these microbes is largely attributed to the activation or inhibition of proteins that directly or indirectly modulate gene transcription. However, bacteria also encode many regulatory small RNA (sRNA) molecules that can profoundly affect bacterial responses and virulence potential. Most of these sRNAs act by base pairing with target mRNA transcripts, allowing for the post-transcriptional induction or repression of gene expression. In wild type E. coli strains, including E. coli pathogens that cause disease either within or outside of the gastrointestinal tract, sRNAs are likely key regulators of stress resistance, colonization and persistence, and virulence, but the functional roles of sRNAs within these medically and economically important microbes have received slight attention. Productive interactions between individual sRNAs and target transcripts often require input from the RNA chaperone Hfq. Recently, we found that Hfq is critical to the fitness and virulence potential of extraintestinal pathogenic Escherichia coli (ExPEC). These pathogens cause an array of diseases including, sepsis, neonatal meningitis, and urinary tract infections, the latter of which rank among the most common of infectious diseases. Our findings concerning Hfq implicate sRNAs in ExPEC pathogenesis and provide an impetus for better defining the functionality of these regulatory molecules during infection. The primary objectives of this R21 application are to identify the spectrum and functional attributes of sRNAs that are expressed by ExPEC in response to relevant environmental stresses both in vitro and in vivo during the course of an infection. Results obtained from these studies should enhance our understanding of the how ExPEC manages to colonize host tissues and cause disease in the face of numerous innate defenses, highlighting novel targets for the development of both preventive and therapeutic treatments of ExPEC-induced infections. PUBLIC HEALTH RELEVANCE: Strains of Extraintestinal pathogenic Escherichia coli (ExPEC) cause an array of serious illnesses that affect several million individuals each year, costing billions in health care and time loss at work. We propose that ExPEC utilize small regulatory RNA molecules to adapt to rapidly changing environmental conditions during the course of an infection, enabling these pathogens to better colonize and persist within the host.

描述（由申请人提供）：为了有效地定居宿主并引起疾病，细菌病原体必须具有感知和应对迅速变化的环境状况的方法。这些微生物的适应性很大程度上归因于直接或间接调节基因转录的蛋白质的激活或抑制。但是，细菌还编码许多可以深远影响细菌反应和毒力潜力的调节性小RNA（SRNA）分子。这些SRNA中的大多数通过碱基与靶mRNA转录物配对，从而允许转录后诱导或抑制基因表达。在野生型大肠杆菌菌株中，包括在胃肠道内部或外部引起疾病的大肠杆菌病原体，SRNA可能是压力抗性，定殖和持久性和毒力的关键调节剂，但是SRNA在这些医学和经济上重要的微生物中的功能作用受到了略有关注。单个SRNA和目标转录本之间的生产性相互作用通常需要RNA伴侣HFQ的输入。最近，我们发现HFQ对于肠外致病性大肠杆菌（Expec）的适应性和毒力潜力至关重要。这些病原体引起一系列疾病，包括败血症，新生儿脑膜炎和尿路感染，后者是最常见的传染病。我们关于HFQ的发现暗示了SRNA在Expec发病机理中，并为更好地定义感染过程中这些调节分子的功能提供了动力。该R21应用程序的主要目标是确定Expec在感染过程中由Expec表达的SRNA的光谱和功能属性。从这些研究中获得的结果应增强我们对Expec如何在众多先天防御中殖民组织并引起疾病的方式的理解，这突出了开发预防性和治疗性治疗的新型目标。公共卫生相关性：肠外致病性大肠杆菌（EXPEC）引起的一系列严重疾病，每年影响数百万个人，造成数十亿美元的医疗保健和工作时间损失。我们建议指出，使用小的调节RNA分子来适应感染过程中迅速变化的环境条件，从而使这些病原体能够更好地在宿主内殖民和持续存在。