The marked propensity of complement deficient individuals to acquire systemic Neisseria infections is a powerful clinical illustration of the importance of the complement system in the host defense against these organisms. In addition, substantial evidence links the complement system to the pathogenesis, clinical manifestations and morbidity of infections caused by Neisseria gonorrhoeae. Strains from patients with uncomplicated symptomatic local disease are sensitive to complement mediated killing in normal serum. Patients with disseminated infection are usually asymptomatic at the genital site and harbor strains resistant to complement mediated attack. Both types of isolates activate and fix complement but this reaction occurs slowly on serum resistant strains. More importantly when examined at equivalent degrees of binding to serum sensitive and serum resistant strains, C3 affixed to the latter is functionally bereft. Central to this proposal is the postulate that there are discrete acceptor sites for C3 on the gonococcal surface and that the chemical structure of these sites determine whether the C3 will be functionally effective or susceptible to inactivation by cleavage.
Its specific aims are: 1) to elucidate the basis for the different functional effect of C3 bound to serum sensitive and serum resistant gonococci; 2) to define the mechanism of membrane attack complex associated regulation of factor B binding; and 3) to examine the effect of unstable serum resistance on complement fixation to these strains and to determine the basis for this type of resistance to complement mediated attack. These studies will employ carefully controlled conditions to quantitate the proportion of the total C3 bound to the organism located on lipooligosaccharide (LOS), outer membrane proteins I and II as well as to anti-gonococcal immunoglobulin. Diluted, high titered bactericidal serrum or monoclonal antibodies specific for the LOS cidal locus will be employed to compare the killing kinetics with the kinetics of C3 deposition and cleavage to determine the effectiveness of C3 deposition at each of these sites. Molecules or classes of molecules, postulated to be present on the gonococcal surface, which modulate the function of C3 will be sought, indentified and their mechanism of action defined. Growth conditions known to affect LOS structure will be used to evaluate changes on C3 deposition and function.
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