Pathogenic rickettsiae are the causative agents of Rocky Mountain spotted fever, typhus, and other human diseases with high mortality and an important impact on society. Although survivors of rickettsial infections are considered immune to disease, the molecular basis of this immunity or the identification of protective antigens that enable vaccine development was hitherto not known. By exploring the molecular pathogenesis of Rickettsia conorii, the agent of Mediterranean spotted fever, we report here that the autotransporter protein, rickettsial outer membrane protein B (rOmpB), constitutes a protective antigen for this group of pathogens. A recombinant, purified rOmpB passenger domain fragment comprised of amino acids 36 to 1334 is sufficient to elicit humoral immune responses that protect animals against lethal disease. Protective immunity requires folded antigen and production of antibodies that recognize conformational epitopes on the rickettsial surface. Monoclonal antibodies (MAbs) 5C7.27 and 5C7.31, which specifically recognize a conformation present in the folded, intact rOmpB passenger domain, are sufficient to confer immunity in vivo. Analyses in vitro indicate this protection involves a mechanism of complement-mediated killing in mammalian blood, a means of rickettsial clearance that has not been previously described. Considering the evolutionary conservation of rOmpB and its crucial contribution to bacterial invasion of host cells, we propose that rOmpB antibody-mediated killing confers immunity to rickettsial infection
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