Mechanisms of Bartonella Virulence in AIDS Patients

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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.