The goals of this project are to examine the role of a pilus accessory protein designated PilC in adherence of Neisseria gonorrhoeae to human epithelial cells, and in infection of male human volunteers. Adherence of N gonorrhoeae is known to be mediated by a combination of pili and PilC, but it is unclear what are their separate roles because PilC is ordinarily required for expression of pili. Mutants of N gonorrhoeae will be constructed that express various combinations of pili, PilC, or a mutant form of pilC that allows expression of pili but prevents adherence. These will be used to challenge male human volunteers so as to determine for the first time whether pili or PilC [or both] are required to initiate infection. We will determine the domains of PilC that are crucial to adherence, and whether antibodies against these domains will prevent adherence. If a transgenic CD46-expressing mouse model of female genital tract infection supports growth of piliated, PilC expressing N gonorrhoeae, we will determine whether a vaccine against PilC prevents infection in the mouse model. These experiments are important to discovering vaccine candidates for prevention of gonorrhea, an important cause of morbidity in women and a cofactor for transmission of HIV.