RovA regulon of Yersinia pestis

描述（由申请人提供）：鼠疫耶尔森氏菌是一种革兰氏阴性细菌性人类病原体，是鼠疫的病原体。从历史上看，鼠疫杆菌是造成重大人类发病率和死亡率的原因。由于鼠疫杆菌引起的高死亡率和严重疾病，它已成为生物战和生物恐怖主义的代理人。更详细地了解鼠疫杆菌的发病机制将有助于确定疫苗开发和治疗的靶点。目前，除了对III型分泌系统和毒力质粒上编码的效应物的研究外，对鼠疫菌分子水平的发病机制知之甚少。关于耶尔森氏菌的发病机制的大部分已知信息来自对该属的另外两种人类病原体，即小肠结肠炎耶尔森氏菌和假结核耶尔森氏菌的调查，这两种病原体都主要是肠道病原体，但能够像鼠疫耶尔森氏菌一样引起全身感染。肠致病性耶尔森氏菌是一些最具特征的病原体，由于易于遗传操作和使用小鼠作为模型。小鼠耶尔森菌病概括了人类疾病的大多数方面，允许对发病机制进行详细分析。所有三种致病性耶尔森菌都具有完全毒力所必需的毒力质粒。然而，使用小肠结肠炎杆菌，我们采用了多种技术来鉴定染色体上编码的许多毒力因子。其中一个基因是MarR家族的转录调节基因，叫做rovA。RovA存在于所有致病性耶尔森氏菌中，并已被证明可调节小肠结肠炎耶尔森氏菌的许多毒力因子。RovA的沙门氏菌同源物也调节沙门氏菌的几种毒力因子。虽然RovA和SlyA明显是毒力的调控因子，但调控的毒力因子并不相同，这表明RovA调控的基因可能因物种而异。总之，这些观察结果使我们假设鼠疫杆菌RovA是毒力的调节因子，通过研究RovA在鼠疫杆菌毒力中的作用，我们将对鼠疫的发病机制有更深入的了解。具体建议：(1)分析RovA在鼠疫菌毒力中的作用；(2)鉴定鼠疫菌RovA调控基因产物；我们预测其中一些rovA调节基因将是鼠疫杆菌所特有的（与小肠结肠炎或沙门氏菌相比）。

DESCRIPTION (provided by applicant): Yersinia pestis is a Gram-negative bacterial human pathogen that is the causative agent of plague. Historically Y. pestis has been responsible for significant human morbidity and mortality. Due to the high mortality rates and severe disease caused by Y. pestis, it has emerged as an agent of biological warfare and bioterrorism. A more detailed understanding of the pathogenesis of Y. pestis will facilitate the identification of targets for vaccine development and treatment. Currently, aside from studies of the type III secretion system and effectors encoded on the virulence plasmid, very little is known about the pathogenesis of Y. pestis at the molecular level. Much of what is known about the pathogenesis of Yersiniae comes from the investigation of the other two human pathogens in the genus, Y. enterocolitica and Y. pseudotuberculosis, both of which are primarily enteric pathogens but are capable of causing systemic infection much like Y. pestis. The enteropathogenic Yersiniae are some of the best-characterized pathogens due to the ease of genetic manipulation and the use of the mouse as a model. Murine yersiniosis recapitulates most aspects of disease in humans allowing for a detailed analysis of the pathogenesis. All three pathogenic species of Yersinia have virulence plasmids that are required for full virulence. However, using Y. enterocolitica we have employed a wide variety of techniques to identify numerous virulence factors that are encoded on the chromosome. One of these genes is a transcriptional regulator of the MarR family called rovA. RovA is present in all pathogenic species of Yersinia and has been demonstrated to regulate numerous virulence factors in Y. enterocolitica. The Salmonella homologue of RovA also regulates several virulence factors in Salmonella. Although RovA and SlyA are clearly regulators of virulence, the virulence factors regulated are not the same, suggesting that RovA regulated genes may differ depending on the species. Together these observations lead us to hypothesize that the Y. pestis RovA is a regulator of virulence and that by studying the role of RovA in the virulence of Y. pestis we will gain a greater understanding of the pathogenesis of plague. Specifically we propose: (I) Analysis of the role of RovA in the virulence of Y. pestis, and (2) Identification of the Y. pestis RovA regulated gene products; we predict some of these rovA regulated genes will be unique to Y. pestis (compared to Y. enterocolitica or Salmonella).