Mechanisms of Bartonella Virulence in AIDS Patients

描述（由申请人提供）：拟议研究的长期目标是深入了解巴尔通体的致病机制，巴尔通体是艾滋病患者的机会致病菌。B. quintana是一种挑剔的革兰氏阴性细菌，可引起细菌性血管瘤病，这是一种影响hiv感染患者的血管增生性病变。复发性和/或持续性血液感染是金塔纳芽孢杆菌感染的常见表现，发生在HIV感染的所有阶段的患者中，可在人类中持续数月，导致衰弱甚至致命的后遗症。我们发现了一个编码巴尔通体外膜蛋白（OMP）的基因家族，该基因家族随着时间的推移而表达变化，并且在长时间的血流感染过程中，会经历一个或多个串联排列的旁系基因的重排和/或删除。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已被充分研究的OMP粘附素的同源物，包括耶尔森氏菌的YadA。Vomp是三聚体autotransporter adhesion （TAA）毒力决定因子家族的成员，是一种参与人类巴尔通体发病的多功能蛋白。我们已经确定的呕吐物的毒力特性包括相变化、自聚集、血凝和与宿主细胞的结合。本研究的直接目的是通过阐明昆塔纳巴尔通体的毒力特性来研究巴尔通体的发病机制，包括表征：1。黄刺苋TAA的分子结构及自动转运机制研究2. 体外表面表达的呕吐物黏附素与内皮细胞的相互作用和3。个体Vomp在确定黄颡鱼与宿主细胞（RBC， EC）和宿主细胞成分（细胞外基质，胶原）结合特异性中的作用。综上所述，mmp家族的100 kDa TAA成员是介导人类宿主发病机制的多功能毒力决定因素。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家族和个体Vomp粘附素在hiv感染者巴尔通体介导的发病机制中的作用。7. 巴尔通体是一种细菌，可导致免疫系统较弱的患者患上严重疾病，包括艾滋病患者、癌症患者和器官移植患者。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。

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.