BINDING OF COMPLEMENT FACTOR-H TO LOOP-5 OF PORIN PROTEIN 1A - A MOLECULAR MECHANISM OF SERUM RESISTANCE OF NONSIALYLATED NEISSERIA-GONORRHOEAE

Neisseria gonorrhoeae isolated from patients with disseminated infecti on are often of the porin (Por1A) serotype and resist killing by nonim mune normal human serum. The molecular basis of this resistance (terme d stable serum resistance) in these strains has not been fully defined but is not related to sialylation of lipooligosaccharide Here we demo nstrate that Por1A bearing gonococcal st rains bind more factor H, a c ritical downregulator of the alternative complement pathway, than thei r Por1B counterparts. This results in a sevenfold reduction in C3b, wh ich is >75% converted to iC3b. Factor H binding to isogenic gonococcal strains that differed only in their porin serotype, confirmed that Po r1A was the acceptor molecule for factor H. We identified a surface ex posed re,region on the Por1A molecule that served as the binding site for factor H. We used gonococcal strains with hybrid Por1A/B molecules that differed in their surface exposed domains to localize the factor H binding site to loop 5 of`Por1A. This was confirmed by inhibition o f factor H binding using synthetic peptides corresponding to the putat ive exposed regions of the porin loops. The addition of Por1A loop 5 p eptide in a serum bactericidal assay, which inhibited binding of facto r H to the bacterial surface, permitted 50% killing of an otherwise co mpletely serum resistant gonococcal strain. Collectively, these data p rovide a molecular basis to explain serum resistance of Por1A strains of N. gonorrhocae.