Protective role of cross-reactive anti-enteric antibody

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DESCRIPTION (provided by applicant): We hypothesize that the indigenous flora primes adaptive immune responses that can be recruited during primary infection with pathogens that share common or similar cell surface antigens with commensals. We use Citrobacter rodentium, a mucosal pathogen of mice, to study the nature and recruitment of these responses. Prior studies by our group have identified that an early T cell-dependent serum antibody response is critical for surviving the acute phase of infection while pre-existing secretory IgA appears to impact early events in colonization, which influence the subsequent severity of infection. This proposal outlines a series of experiments to define antigens from normal flora that elicit immunoglobulin responses against Citrobacter rodentium, an attaching and effacing pathogen similar to the EPEC and other class B bioterrorism agents. We will determine the role of serum and mucosal antibody against these shared antigens with the following aims:(1) identify antigens shared between C. rodentium and commensal species to which mice naive to infection generate an antibody response, (2) develop monoclonal mucosal (IgA) and serum (IgG or IgM) antibodies against these antigens and assess the ability of administered immunoglobulin to impact colonization and the development of symptomatic infection (3) ascertain protection conferred in wild-type and immunodeficient mice by systemic vaccination strategies using cross-reactive antigens. The results from these experiments will provide a molecular basis for understanding the immunoprotective functions of the indigenous flora, and can assist in the development of better vaccines and therapeutics to provide broad protection against many enteric pathogens of human and veterinary importance.