Neisseria gonorrhoea, the exclusively human pathogen that is the causative agent of gonorrhea produces an IgA1 protease that specifically cleaves human immunoglobulin A subclass 1 at its hinge region to yield the fragments Fab and Fc. Because closely related non-pathogenic Neisserial species do not produce this enzyme, it may be a virulence factor, but its role in pathogenesis has not been as extensively explored as numerous other gonococcal virulence factors. This proposal addresses the hypothesis that IgA1 protease contributes to the pathogenesis of human gonococcal infection by interfering with protective function of specific IgA1 antibodies at the mucosal surface and subverting these responses for the pathogen's own protection against the host's immune defenses. A critical aspect of testing this hypothesis is an evaluation of the development of the mucosal antibodies in the genital tract in response to infection. The relative proportions of protease-susceptible IgA1 and protease-resistant IgA2 subclasses of antibodies that are directed at gonococcal surface antigens in genital secretions and serum will be evaluated in individuals who are naturally infected with N. gonorrhoea, in relation to their clinical syndrome (nonsymptomatic vs. symptomatic infection in males; cervical vs. upper genital tract infection in females). Responses will, also, be evaluated in relation to the secondary involvement of the rectum that occurs in 40-50 percent of women, to test the hypothesis that this route of infection results in an additional stimulus of the mucosal immune system that may augment genital immunity. The dissemination of mucosal antibody responses through the common mucosal immune system will be evaluated in terms of circulating IgA antibody-secreting cells and the development of IgA antibodies in a remote secretion such as saliva. The relationship of gonococcal IgA1 protease to specific clinical syndromes will be assessed by correlation of clinical syndrome with the presence of IgA1 protease or its typical cleavage products in genital secretions, with the presence and level of inhibitory antibodies to gonococcal IgA1 protease in secretions and sera, and with IgA1 antibodies to gonococcal surface antigens in secretions and sera. To investigate potential mechanisms by which gonococcal IgA1 protease might act as a virulence factor, the effect of Fab fragments of IgA1 antibodies to gonococcal antigens on adherence of gonococci to cultured human epithelial cells, and on phagocytosis of gonococci by human neutrophils, will be determined in the absence or presence of antibodies of the same or different isotype. Furthermore, the effect of Fc fragments of IgA1 on the metabolic activation of neutrophils will be determined. If the hypothesis that gonococcal IgA1 protease contributes to virulence is sustained, then it might be considered as a potential vaccine component, and chemotherapeutic measures might be devised to inhibit its activity.
