Regulation of virulence factors in Bartonella henselae

汉赛巴尔通体毒力因子的调控

• 批准号: 7523995
• 负责人: BURT E ANDERSON
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7523995
• 关键词: Angiogenic Factor; Antigens; Bacillary Angiomatosis; Bacteria; Bacterial Adhesins; Bacterial Genes; Bacterial Typing; Bartonella; Bartonella henselae; Binding; Biological Assay; Blood Vessels; Cat-Scratch Disease; Cells; Clinical; DNA; DNA Microarray Chip; DNA Microarray format; DNA delivery; Data; Disease; Effector Cell; Endothelial Cells; Environment; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Immunocompromised Host; Individual; Infection; Infection prevention; Infectious Agent; Laboratories; Lesion; Life; Mediating; Modeling; Operon; Organ; Pathogenesis; Patients; Peptides; Phenotype; Play; Process; Production; Protein Overexpression; Proteins; Range; Recruitment Activity; Regulation; Regulator Genes; Reporting; Research; Role; Signal Transduction; Skin; Surface; Syndrome; System; Systemic infection; Testing; Transcriptional Regulation; Type IV Secretion System Pathway; Up-Regulation; Vascular Endothelial Growth Factors; Virulence; Virulence Factors; Visceral; angiogenesis; antimicrobial; base; gene therapy; genetic regulatory protein; in vivo; knockout gene; mutant; promoter

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.

描述（由申请人提供）：汉塞巴尔通体细菌引起多种疾病综合征，包括在一些患者中，特别是在免疫功能低下的个体中引起严重的全身感染。这种新出现的传染原的一个表现是杆菌性血管瘤病，其特征是感染患者的皮肤和内脏器官出现血管增殖性病变。该项目的目标是检验汉赛芽孢杆菌利用多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的中心假设。汉赛芽孢杆菌中至少已鉴定出两种重要的毒力因子，它们在引起血管生成中发挥作用。第一个是 virB 操纵子，编码 IV 型分泌系统，负责传递作用于内皮细胞的效应蛋白，以促进其延长存活时间。第二种是汉赛芽孢杆菌表面的主要粘附素 BadA，已被证明在诱导感染细胞中血管内皮生长因子分泌方面发挥重要作用。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。提出以下具体目标来检验假设； 1) 定义 ompR 和 envZ 表达与 virB 操纵子表达之间的相关性，2) 表征 virB 的 ompR/envZ 上调所涉及的机制，以及 3) 识别 ompR/envZ 控制下的其他毒力因子基因。这些研究应该帮助我们了解这种细菌如何以及为何在一些患者中引起轻度疾病，而在其他患者中引起危及生命的感染，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。该项目的一个应用产品是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利用这种分泌系统将 DNA 和蛋白质递送至靶细胞进行基因治疗的尝试中有价值。叙述性项目描述 汉赛巴尔通体细菌会引起多种疾病综合症，包括对一些患者（尤其是免疫功能低下的个体）造成严重危及生命的感染。这种严重疾病的独特之处是血管增殖或血管生成。该项目旨在更好地了解如何控制这种细菌的基因以引起血管生成。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汉赛芽孢杆菌引起的感染的抗菌治疗的一个有价值的目标。