Regulation of Francisella virulence by sRNAs

项目总结 图拉氏方济氏菌是一种潜在的生物恐怖、兼性胞内病原菌和致病菌。 图拉热症的制剂。基于其几个属性，Ft已被疾控中心指定为一级特工。而当 在过去的15年里，关于这种病原体的细胞生物学及其方法已经取得了一些进展 对毒力的基因调控仍不完全清楚。在常常充满敌意的环境中生存并茁壮成长 环境中，细菌必须监测其周围环境，并调整其基因表达和生理 相应地。这对病原菌来说尤其重要，因为它们在 一种感染。传统上，基因调控是由蛋白质调节因子介导的，但Ft含有的蛋白质很少 监管因素，缺乏经典的两元监管体系，但却起到了中介作用 复杂的宿主-病原体过程，如宿主接触后早期免疫反应的抑制和 从含有弗朗西塞氏菌的液泡中逃逸到细胞质中。数量有限的孤立双部件 成员存在，包括反应监管机构PmrA。PmrA是弗氏杆菌致病的关键因素，因为它 已被证明可以调节Ft生物膜的形成、巨噬细胞的存活和动物的毒力。小的 RNAs(SRNAs)也越来越多地与病原体的毒力调节有关，我们已经 共鉴定出661个Ft sRNA，包括PmrA调控的亚群(n=81)。这项研究的总体目标是 了解这种重要病原菌的毒力的转录/转录后控制。整体而言 目的是鉴定毒力相关的sRNA(PmrA调控的以及差异表达的sRNAs 在巨噬细胞中)。中心假设是Ft sRNAs受PmrA和巨噬细胞的影响 环境来调节毒力。我们目标的实现将发现Ft疫苗或Ft的新目标 治疗以对抗这种危险的病原体。

PROJECT SUMMARY Francisella tularensis (Ft) is a potential agent of bioterror, facultative intracellular pathogen and the causative agent of tularemia. Based on several of its attributes, Ft has been named by the CDC as a Tier 1 agent. While several advances have been made in the last ~15 years regarding the cell biology of this pathogen, its method of virulence gene regulation remains incompletely understood. To survive and thrive in often hostile environments, a bacterium has to monitor its surroundings and adjust its gene expression and physiology accordingly. This is especially important for pathogenic bacteria that continuously interact with the host during an infection. Gene regulation is traditionally mediated by protein regulatory factors, but Ft contains few protein regulatory factors and is devoid of classically arranged two-component regulatory systems, yet mediates complex host-pathogen processes such as suppression of the immune response early after host contact and escape from the Francisella-containing vacuole into the cytosol. A limited number of orphan two-component members exist including the response regulator PmrA. PmrA is a key factor in Francisella pathogenesis, as it has been demonstrated to regulate Ft biofilm formation, intramacrophage survival and animal virulence. Small RNAs (sRNAs) are also increasingly associated with the regulation of virulence in pathogens, and we have identified 661 Ft sRNAs, including the subset regulated by PmrA (n=81). The overall goal of this research is to understand the transcriptional/post-transcriptional control of virulence in this important pathogen. The overall objective is to identify virulence-associated sRNAs (PmrA-regulated as well as those differentially expressed in macrophages). The central hypothesis is that Ft sRNAs are influenced by PmrA and the macrophage environment to regulate virulence. The achievement of our goals will uncover new targets for Ft vaccines or for therapeutics to counteract this dangerous pathogen.