O antigen is the target of bactericidal Weil-Felix antibodies.

Rickettsial diseases have long been diagnosed with serum antibodies cross-reactive against (Weil-Felix reaction). Although Weil-Felix antibodies are associated with the development of immunity, their rickettsial target and contribution to disease pathogenesis are not established. Here, we developed a transposon for insertional mutagenesis of , isolating variants defective for replication in cultured cells and in spotted fever pathogenesis. Mutations in the () abolish lipopolysaccharide O-antigen synthesis and Weil-Felix serology and alter outer-membrane protein assembly. Unlike wild-type , mutants cannot elicit bactericidal antibodies that bind O antigen. The operon is conserved among rickettsial pathogens, suggesting that bactericidal antibodies targeting O antigen may generate universal immunity that could be exploited to develop vaccines against rickettsial diseases.