Regulation of virulence factors in Bartonella henselae

描述（由申请方提供）：汉赛巴尔通体细菌可引起多种疾病综合征，包括某些患者的严重全身感染，特别是免疫功能低下的个体。这种新出现的感染因子的一种表现是杆菌性血管瘤病，其特征在于感染患者的皮肤和内脏器官的血管增生性病变的存在。这个项目的目标是测试中心假设，即B。henselae利用几种毒力因子基因的协调调节来增强其促进血管生成的能力。在B中至少鉴定了两个重要的毒力因子。在引起血管生成中起作用的Henselae。第一个是virB操纵子，其编码IV型分泌系统，该IV型分泌系统负责递送作用于内皮细胞以促进其延长存活的效应蛋白。第二个是位于B表面的主要粘附素BadA。Henselae，并且已经显示在感染细胞中诱导血管内皮生长因子分泌方面是重要的。我们的初步数据表明，B的双组分调节系统OmpR/EnvZ。henselae至少部分负责这些基因的调节。提出了以下具体目标来检验该假设：1）确定ompR和envZ表达与virB操纵子表达之间的相关性，2）表征ompR/envZ上调virB的机制，3）鉴定ompR/envZ控制下的其他毒力因子基因。这些研究应该有助于我们了解这种细菌如何以及为什么会在一些患者中引起轻微疾病，而在其他患者中导致危及生命的感染，从而导致血管生成病变。此外，控制细菌毒力因子的基因调控系统的表征可能被证明是抗菌治疗的有价值的靶点。本项目的一个应用成果是描述了virB IV型分泌系统基因的调控机制。这些信息可能在未来尝试利用这种分泌系统将DNA和蛋白质递送到靶细胞进行基因治疗时证明是有价值的。叙事 项目描述汉赛巴尔通体（Bartonella henselae）细菌可引起多种疾病综合征，包括某些患者的严重危及生命的感染，特别是免疫功能低下的个体。这种严重疾病的独特方面是血管增殖或血管生成。该项目旨在更好地了解这种细菌的基因是如何被控制以引起这种血管生成的。控制细菌毒力因子的基因调控系统的表征可能被证明是预防B引起的感染的抗菌治疗的有价值的靶点。亨瑟莱

DESCRIPTION (provided by applicant): The bacterium Bartonella henselae causes a variety of disease syndromes including severe systemic infections in some patients, particularly in immunocompromised individuals. One manifestation of this emerging infectious agent is bacillary angiomatosis which is characterized by the presence of vascular proliferative lesions of the skin and visceral organs in infected patients. The goal of this project is to test the central hypothesis that B. henselae utilizes coordinate regulation of several virulence factor genes to enhance it's ability to promote angiogenesis. At least two important virulence factors have been identified in B. henselae that play a role in causing angiogenesis. The first is the virB operon that encodes a type IV secretion system that is responsible for delivery of the effector proteins that act on endothelial cells to promote their extended survival. The second is the major adhesin BadA that is on the surface of B. henselae and has been shown to be important in inducing vascular endothelial growth factor secretion in infected cells. Our preliminary data suggest that the two-component regulatory system OmpR/EnvZ of B. henselae is at least in part responsible for regulation of these genes. The following specific aims are proposed to test the hypothesis; 1) define the correlation between ompR and envZ expression and expression of the virB operon, 2) characterize the mechanism involved in ompR/envZ upregulation of virB, and 3) identify other virulence factor genes under control of ompR/envZ . These studies should help us understand how and why this bacterium causes mild disease in some patients and life-threatening infections in other patients resulting in angiogenic lesions. Furthermore, characterization of a gene regulatory system that controls bacterial virulence factors may prove to be a valuable target for antimicrobial therapy. An applied product of this project is the description of the regulatory mechanism of the virB type IV secretion system genes. Such information may prove valuable in future attempts to harness the use of this secretion system for delivery of DNA and protein to target cells for gene therapy. Narrative Project Description The bacterium Bartonella henselae causes a variety of disease syndromes including severe life-threatening infections in some patients, particularly in immunocompromised individuals. The unique aspect of this severe disease is the proliferation of blood vessels, or angiogenesis. This project seeks to better understand how the genes of this bacterium are controlled to cause this angiogenesis. Characterization of a gene regulatory system that controls bacterial virulence factors may prove to be a valuable target for antimicrobial therapy to prevent infections caused by B. henselae.