Mechanisms of Bartonella Virulence in AIDS Patients

描述(申请人提供)：拟议研究的长期目标是深入了解巴尔通氏杆菌的致病机制，巴尔通氏杆菌是艾滋病患者的一种机会性病原体。昆塔纳杆菌是一种挑剔的革兰氏阴性细菌，会导致杆状血管瘤，这是一种影响艾滋病毒感染患者的血管增生性病变。复发和/或持续的血液感染是昆塔纳杆菌感染的一种常见表现，这种感染发生在艾滋病毒感染的所有阶段，并可在人类持续数月，导致虚弱甚至致命的后遗症。我们鉴定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可变地表达，并且在长期的血流感染过程中经历了一个或多个同源基因的重排和/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细菌中几个研究得很好的OMP粘附素的同源基因，包括耶尔森氏菌的Yada。Vomp是三聚体自身转运蛋白粘附素(TAA)毒力决定因素家族的成员，Vomp代表着一种参与巴尔通体致病的多功能蛋白。我们鉴定的Vomp毒力特性包括时相变异、自身聚集、血凝和与宿主细胞的结合。本建议的直接目的是通过阐明巴尔通体的毒力特性来研究巴尔通体的致病机制，包括表征：1.巴氏杆菌Vomp TAA的分子结构和自转机制；2.体外表面表达的Vomp粘附素与内皮细胞(EC)的相互作用；以及3.单个Vomp在确定B.quintana Vomp与宿主细胞(RBC、EC)和宿主细胞成分(细胞外基质、胶原蛋白)结合特异性中的作用。综上所述，Vomp家族的100 kDa TAA成员是多功能毒力决定因子，介导了人类宿主的发病机制。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粘附素在HIV感染者巴氏杆菌介导的致病机制中的贡献。7.与公共卫生有关的巴尔通氏杆菌是一种细菌，它会在免疫系统减弱的患者中引起严重疾病，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造成长期感染，有时会持续数年，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.