Regulation of virulence factors in Bartonella henselae

描述(申请人提供)：亨氏巴尔通氏杆菌可引起多种疾病综合征，包括一些患者的严重全身感染，特别是免疫功能低下的患者。这种新出现的感染性病原体的一个表现是细菌性血管瘤病，其特征是感染患者的皮肤和内脏器官出现血管增生性病变。该项目的目的是验证汉氏不动杆菌利用几个毒力因子基因的协调调节来增强其促进血管生成的能力这一中心假设。至少有两个重要的毒力因子已经在亨塞氏杆菌中被确定，它们在导致血管生成中发挥作用。第一个是VIRB操纵子，它编码一个IV型分泌系统，负责传递作用于内皮细胞的效应蛋白，以促进其延长存活。第二种是主要的黏附素Bada，它位于亨氏假单胞菌表面，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OmpR/EnvZ双组分调控系统至少部分负责对这些基因的调控。为了验证这一假说，我们提出了以下几个具体目标：1)确定ompR和envZ表达与VIRB操纵子表达之间的相关性；2)研究ompR/envZ上调VIRB的机制；3)鉴定ompR/envZ调控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导致轻度疾病，在其他患者中导致危及生命的感染，从而导致血管新生损害。此外，控制细菌毒力因子的基因调控系统的特征可能被证明是抗菌治疗的一个有价值的目标。该项目的一个应用成果是对VIRB IV型分泌系统基因的调节机制的描述。这些信息可能在未来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的尝试中被证明是有价值的。亨氏巴尔通体细菌会引起各种疾病综合征，包括一些患者的严重威胁生命的感染，特别是在免疫功能低下的人中。这种严重疾病的独特之处在于血管的增殖，或称血管生成。这个项目试图更好地了解这种细菌的基因是如何被控制来导致血管生成的。控制细菌毒力因子的基因调控系统的特征可能被证明是预防亨塞氏杆菌感染的抗菌治疗的一个有价值的目标。

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.