The Role of BBI36/38 in Lyme Disease Pathogenesis

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DESCRIPTION (provided by applicant): The proposal describes a 5-year training program designed to provide the educational experiences and laboratory training for a successful career as an independent investigator in basic research in infectious diseases. The candidate has a long history of prior research activities, and this proposal includes formal coursework in biostatistics and study design that will complement the candidate's previous graduate work. The laboratory work will encompass areas of current competency and allow further training in immunohistochemistry, genetic manipulation of spirochetes, and animal models of infectious diseases. Dr. James Carroll, an expert in the area of experimental proteomics and molecular pathogenesis, will mentor the candidate, in close cooperation with an advisory committee of senior investigators from the institution. Lyme disease is the most common vector-borne infection reported in the United States, and has doubled in incidence in the past 10 years. Borrelia burgdorferi, the spirochete agent of Lyme disease, modulates its membrane proteins in the cycle of tick-mammal infection. We have observed that BBA71, a member of the pgf family of membrane proteins, is increased in expression at conditions which mimic mammalian infection. We hypothesize that BBA71 is a surface exposed outer membrane protein expressed during mammalian infection, which will provide protective immunity in tick-mouse infection with B. burgdorferi. We will focus early experiments on the expression of BBA71 in tick and specific tissues in the murine model of mammalian infection. We will be using homologous recombination to delete expression of BBA71 in the parent B31 strain to test the absolute requirement for BBA71 in mammalian infection. Finally, we will assess the protection from infection with B. burgdorferi conferred by passive and active immunization with BBA71. Lyme disease is of increasing relevance to public health worldwide with cases numbers mounting and diagnosis typically delayed. The development of new diagnostic and vaccine approaches is crucial, and this proposal gives the opportunity to develop these new therapies while providing an ideal research environment for the candidate. The University of Pittsburgh and the mentoring support proposed here offer excellent tools for the development of a career in basic research.