Regulation of virulence factors in Bartonella henselae

描述（由申请人提供）：henselae巴尔通体（Bartonella henselae）细菌可引起多种疾病综合征，包括一些患者，特别是免疫功能低下个体的严重全身性感染。这种新出现的传染性病原体的一种表现是细菌性血管瘤病，其特征是在感染患者的皮肤和内脏器官中存在血管增生性病变。本课题的目的是验证鸡翅通过协调调节多个毒力因子基因来增强其促进血管生成能力的中心假设。至少有两种重要的毒力因子已被确定在B. henselae中起引起血管生成的作用。第一个是virB操纵子，它编码IV型分泌系统，负责传递作用于内皮细胞的效应蛋白，以促进内皮细胞的延长生存。第二种是主要的粘附素BadA，存在于亨selae表面，已被证明在诱导感染细胞分泌血管内皮生长因子方面起重要作用。我们的初步数据表明，B. henselae的双组分调控系统OmpR/EnvZ至少部分负责这些基因的调控。为了检验这一假设，提出了以下具体目标：1)明确ompR与envZ表达及virB操纵子表达的相关性；2)明确ompR/envZ上调virB的机制；3)鉴定受ompR/envZ调控的其他毒力因子基因。这些研究将帮助我们了解这种细菌如何以及为什么在一些患者中引起轻微疾病，而在其他患者中引起危及生命的感染，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一个有价值的目标。本项目的一个应用成果是virB IV型分泌系统基因调控机制的描述。这些信息可能在未来的尝试中证明是有价值的，利用这种分泌系统将DNA和蛋白质输送到靶细胞进行基因治疗。henselae巴尔通体（Bartonella henselae）细菌可引起多种疾病综合征，包括一些患者，特别是免疫功能低下的个体中严重危及生命的感染。这种严重疾病的独特之处在于血管增生或血管生成。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抗微生物治疗预防由henselae引起的感染的有价值的靶标。

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.