The main and long term goal of this application is to understand the mechanism of action of bactericidal antibodies in Borrelia infections. A number of monoclonal antibodies have been discovered that can kill Borrelia burgdorferi without the assistance of complement, and the Fab fragments of the antibodies have the same bactericidal activity. Earlier studies showed that these antibodies function by lysis of the outer membrane in a Ca++ dependent medium process. This application is based on the hypothesis that complement independent bactericidal antibodies represent a novel and fundamental mechanism of host resistance in infections with Borrelia, and possibly in infections with other bacteria. The Research Plan is based on three underlying hypotheses that support the main goal of this application to characterize the mechanisms by which bactericidal antibodies can destroy Borrelia spp. The first approach will be to examine the antibodies themselves for possible catalytic properties which could result in a breakdown of the antigen leading to changes in the physical association of the antigen with other outer membrane molecules. The possibility that the antibodies could induce unique conformational changes in their antigens, which in turn could affect the topology and integrity of the outer membrane will also be evaluated. The second approach will be to test the hypothesis that the antibody-antigen complex induces the activation of lytic enzymes through an outer membrane signal transduction mechanism. Specifically, the identification and role of lipases and phospholipases in Borrelia will be evaluated. Such enzymes exist in these organisms and should be involved in the lysis of the outer membrane. If this mechanism of killing Borrelia is found to occur, it will represent a novel, and overlooked form of host defense. The third approach will be to test the possibility that bactericidal antibodies are a major form of host defense in Borrelia infections. Passive immunization studies will be conducted with the bactericidal antibodies in complement deficient (transgenic) mice to determine their role in preventing infection in a complement independent manner. Other studies will be involved in raising targeted bactericidal antibodies to antigens expressed in vivo. The possibility that the bactericidal antibodies may select more invasive phenotypes will also be evaluated.
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