Mechanisms of Bartonella Virulence in AIDS Patients

艾滋病患者巴尔通体的毒力机制

• 批准号: 7554614
• 负责人: JANE E KOEHLER
• 金额: $ 45.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554614
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Animal Model; Architecture; Bacillary Angiomatosis; Bacillus (bacterium); Bacteria; Bacterial Adhesins; Bartonella; Bartonella Infections; Binding; Blood; Blood Circulation; Blood Vessels; Cells; Cellular Structures; Chronic; Class; Clinical; Collagen; DNA Sequence Rearrangement; Data; Endocarditis; Endothelial Cells; Erythrocytes; Extracellular Matrix; Family; Gene Family; Genes; Goals; Gram-Negative Bacteria; HIV Infections; Heart Valves; Hemagglutination; Homelessness; Homologous Gene; Homologous Protein; Human; Immune system; In Vitro; Individual; Infection; Knowledge; Lesion; Malignant Neoplasms; Mediating; Membrane Proteins; Membrane Transport Proteins; Molecular; Organ Transplantation; Orthologous Gene; Pathogenesis; Patients; Phase; Population; Property; Protein Family; Proteins; Public Health; Range; Relapse; Role; Sepsis; Specificity; Staging; Stream; Surface; System; Time; Translating; Variant; Virulence; Virulence Factors; Yersinia; cell type; improved; in vivo; insight; member; paralogous gene; pathogen; prevent; protein function

DESCRIPTION (provided by applicant): The long range objective of the proposed study is to gain insight into the pathogenic mechanisms of Bartonella, an opportunistic pathogen of AIDS patients. B. quintana is a fastidious, gram-negative bacterium that causes bacillary angiomatosis, a vascular proliferative lesion affecting HIV-infected patients. Relapsing and/or persistent bloodstream infection is a frequent manifestation of B. quintana infection that occurs in patients at all stages of HIV infection and can last for months in humans, causing debilitating and even fatal sequelae. We identified a gene family encoding outer membrane proteins (OMP) of Bartonella that are variably expressed over time, and that undergo rearrangement and/or deletion of one or more of the tandemly-arranged, paralogous genes during prolonged blood stream infection. Members of this variably-expressed outer membrane protein (Vomp) family are orthologs of several well-studied OMP adhesins in other gram-negative bacteria, including the YadA of Yersinia. The Vomp are members of the trimeric autotransporter adhesin (TAA) family of virulence determinants, and the Vomp represent a multifunctional protein involved in Bartonella pathogenesis in humans. The virulence properties of the Vomp that we have identified include phase variation, autoaggregation, hemagglutination and binding to host cells. The immediate objective of this proposal is to study the mechanisms of Bartonella pathogenesis by elucidating the virulence properties of the B. quintana Vomp including characterization of the: 1. Molecular architecture and mechanism of autotransport by the B. quintana Vomp TAA; 2. Interaction of surface-expressed Vomp adhesins with endothelial cells (EC) in vitro; and 3. Role of the individual Vomp in determining binding specificity of B. quintana to host cells (RBC, EC) and host cell components (extracellular matrix, collagens). In summary, the 100 kDa TAA members of the Vomp family are multifunctional virulence determinants that mediate pathogenesis in the human host. The ultimate goal of this project is to characterize at the molecular, bacterial and host cellular levels, the contribution of the Vomp family and the individual Vomp adhesins to Bartonella-mediated pathogenesis in the HIV-infected human. 7. PUBLIC HEALTH RELEVANCE Bartonella is a bacterium that causes severe illness in patients with a weakened immune system, including those with AIDS, cancer and transplanted organs. We are investigating how this bacterium is able to cause long-term infections in the blood of humans, sometimes for years, so that infection can be prevented.

描述（由申请方提供）：拟议研究的长期目标是深入了解巴尔通体（一种艾滋病患者的机会致病菌）的致病机制。B。昆塔纳是一种难养的革兰氏阴性细菌，其引起杆菌性血管瘤病，一种影响HIV感染患者的血管增生性病变。复发性和/或持续性血流感染是B的常见表现。在艾滋病毒感染的所有阶段，患者都会发生五他那感染，在人类中可持续数月，造成衰弱甚至致命的后遗症。我们鉴定了编码巴尔通体外膜蛋白（OMP）的基因家族，所述外膜蛋白随时间推移而表达，并且在长时间血流感染期间经历一个或多个串联排列的旁系同源基因的重排和/或缺失。这个可变表达的外膜蛋白（Vomp）家族的成员是其他革兰氏阴性菌中几种研究充分的OMP粘附素的直系同源物，包括耶尔森氏菌的YadA。Vomp是毒力决定簇的三聚体自转运粘附素（TAA）家族的成员，并且Vomp代表参与人类巴尔通体致病的多功能蛋白。我们已经确定的Vomp的毒力特性包括相位变化，自动聚集，血凝和结合宿主细胞。该建议的直接目标是通过阐明B的毒力特性来研究巴尔通体的致病机制。quintana Vomp包括表征：1.分子结构和B自转运机制。quintana Vomp TAA; 2.表面表达的Vomp粘附素与内皮细胞（EC）的体外相互作用;和3.个体Vomp在确定B结合特异性中的作用。quintana对宿主细胞（RBC、EC）和宿主细胞成分（细胞外基质、胶原）的作用。总之，Vomp家族的100 kDa TAA成员是介导人类宿主发病的多功能毒力决定因子。该项目的最终目标是在分子、细菌和宿主细胞水平上表征Vomp家族和单个Vomp粘附素对HIV感染者中Bartonella介导的发病机制的贡献。7.公共卫生相关性巴尔通体是一种细菌，可导致免疫系统减弱的患者患上严重疾病，包括艾滋病、癌症和器官移植患者。我们正在研究这种细菌如何能够在人类血液中引起长期感染，有时长达数年，以便预防感染。