Bartonella Vomp adhesins and pathogenesis in AIDS patients

Julie Roden, UC San Francisco
Basic-Applied Clinical

Bartonella quintana is a bacterial pathogen that persists for months in the human bloodstream, and causes relapsing fever, heart valve infection, and vascular proliferative lesions known as bacillary angiomatosis. B. quintana infection produces debilitating or fatal illness in immunocompromised individuals with AIDS, transplanted organs, or undergoing treatment for cancer. It also can cause serious infections in people with a normal immune system. Although the infection occurs worldwide, more cases of HIV-associated B. quintana infection have been reported in San Francisco and California than in any other location. B. quintana was only recently identified as a human pathogen, and little is known about the mechanisms by which Bartonella is able to infect and cause disease. One critical aspect of B. quintana infection is attachment to and infection of red blood cells (RBC). Sequestration within RBC enables the bacterium to infect sites throughout the body and escape detection by the host immune system. We identified a family of four variably-expressed outer membrane protein (Vomp) adhesins that are involved in binding of B. quintana to host cells, including RBC. The Vomp are required for infection in vivo. Vomp share amino acid and functional homology with a family of proteins recently designated as trimeric autotransporter adhesins (TAA). TAA family members include Yersinia YadA and Neisseria NadA, which are critical for the virulence of these pathogens. The functional structure of TAA is a trimer on the bacterial surface. I will characterize the structure of the Vomp to determine if they also form trimers on the bacterial surface. I will also characterize the function of individual Vomp domains in the transport of the Vomp to the B. quintana outer membrane surface. Our lab has previously shown that the Vomp mediate autoaggregation and binding to collagen IV in the extracellular matrix (ECM). I have preliminarily demonstrated that B. quintana binds to RBC, and I will further explore the role of Vomp in mediating B. quintana binding to and infection of RBC, both in vitro and in vivo, using a flow cytometry-based assay. I also will investigate binding of the Vomp to ECM components, such as laminin and collagen, to identify additional binding targets for these adhesins. Finally, I will infect our animal model with the vomp null mutant complemented with individual vomp genes, to determine the contribution of each Vomp to the B. quintana virulence phenotype. The goal of this proposal is to understand the functional structure of Vomp, and to determine the host molecules and cells to which it binds. Because binding to RBC is critical for Bartonella infection, understanding these mechanisms will enable us to better prevent and treat Bartonella infections.