Control of ExPEC virulence by small RNAs

描述(由申请人提供)：为了有效地在宿主上定居并引起疾病，细菌病原体必须具有感知和响应快速变化的环境条件的手段。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。然而，细菌也编码许多调节性的小RNA(SRNA)分子，这些分子可以深刻地影响细菌的反应和毒力潜力。这些sRNA中的大多数通过与靶mRNA转录本进行碱基配对来发挥作用，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，包括在胃肠道内外引起疾病的大肠杆菌病原体，sRNAs可能是应激抗性、定植和持久性以及毒力的关键调节因子，但sRNAs在这些具有医学和经济意义的重要微生物中的功能作用尚未引起足够的重视。单个sRNA和目标转录本之间的有效相互作用通常需要RNA伴侣Hfq的输入。最近，我们发现Hfq对肠外致病性大肠埃希菌(ExPEC)的适合性和毒力潜力至关重要。这些病原体导致一系列疾病，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之一。我们关于HfQ的发现表明sRNA参与了ExPEC的发病机制，并为更好地定义这些调控分子在感染过程中的功能提供了动力。该R21应用的主要目的是确定ExPEC在感染过程中在体外和体内响应相关环境应激而表达的sRNAs的谱和功能属性。这些研究的结果应该会加强我们对ExPEC如何在面对众多先天防御的情况下设法定植宿主组织和导致疾病的理解，突出了ExPEC诱导感染的预防和治疗方法开发的新靶点。 公共卫生相关性：肠外致病性大肠杆菌(ExPEC)菌株可导致一系列严重疾病，每年影响数百万人，造成数十亿美元的医疗成本和工作时间损失。我们建议ExPEC利用调节的小RNA分子来适应感染过程中快速变化的环境条件，使这些病原体能够更好地在宿主体内定植和持续存在。

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.