Arthropod-borne members of the bacterial genus Borrelia cause two human disorders: relapsing fever and Lyme disease. In both infections the etiologic spirochetes avoid immune clearance by the host. The relapsing fever Borrelae achieve this through a polymorphic antigen variation. The Lyme disease agent, B. burgdorferi, by an unknown mechanism, persists in the face of vigorous antibody production. Consequences of bacterial persistence in Lyme disease are chronic arthritis or progressive central nervous system disease. Our efforts are toward understanding the molecular basis of borrelial infections. To this end and in regard to B. hermsii, a relapsing fever species, we have 1) demonstrated the variable antigens, 2) cloned the genes that encode the protein antigens, 3) located the genes on linear plasmids in the borreliae, and 4) shown that there are expressed as well as silent copies of the genes. In studies of the Lyme disease borrelia we identified the major surface proteins that are immunogenic in patients and that differ between strains. The objectives for the proposed period of research are as follows: 1) To study the structure and evolution of the major outer membrane proteins of B. hermsii and B. burgdorferi. The primary tools for this analysis will be DNA sequencing of the genes and precise epitope mapping. 2) To reveal the organization of the linear plasmids that bear the outer membrane protein genes. Important for the initial phases of this particular study will be determination of the structure of the plasmid termini and mapping the location of the membrane protein genes on the plasmids. 3) To identify the actual mechanism out of the group of possible mechanisms that could account for the antigen switching in relapsing fever. A prominent branch point for this discrimination between models will be whether the gene rearrangements are the result of homologous recombination or site-specific recombination. 4) To investigate the role of outer membrane proteins of B. burgdorferi in Lyme disease pathogenesis and immunity. A critical part of this study will be the evaluation of recombinant surface proteins as protective immunogens in B. burgdorferi infections of laboratory animals. The information gained from studies in these four areas should reveal additional details of Borrelia pathogenesis. It is anticipated that the information will be relevant also to gene regulation and protein structure in general.
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