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 infection are often of the porin (Por1A) serotype and resist killing by nonimmune normal human serum. The molecular basis of this resistance (termed stable serum resistance) in these strains has not been fully defined but is not related to sialylation of lipooligosaccharide. Here we demonstrate that Por1A bearing gonococcal strains bind more factor H, a critical downregulator of the alternative complement pathway, than their Por1B counterparts. This results in a sevenfold reduction in C3b, which is >75% converted to iC3b. Factor H binding to isogenic gonococcal strains that differed only in their porin serotype, confirmed that Por1A was the acceptor molecule for factor H. We identified a surface exposed 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 of factor H binding using synthetic peptides corresponding to the putative exposed regions of the porin loops. The addition of Por1A loop 5 peptide in a serum bactericidal assay, which inhibited binding of factor H to the bacterial surface, permitted 50% killing of an otherwise completely serum resistant gonococcal strain. Collectively, these data provide a molecular basis to explain serum resistance of Por1A strains of N. gonorrhoeae.
Ram
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S
The Maxwell Finland Laboratory for Infectious Diseases and the Evans Memorial Department of Clinical Research and Department of Medicine, Boston Medical Center, Boston, Massachusetts 02118, USA. sram@bu.edu
McQuillen
D P
DP
Gulati
S
S
Elkins
C
C
Pangburn
M K
MK
Rice
P A
PA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001770:Blood Bactericidal Activity; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009344:Neisseria gonorrhoeae / Q000276:immunology*; D018272:Porins / Q000276:immunology / Q000378:metabolism*; D011817:Rabbits; D012794:Sialic Acids / Q000378:metabolism
C493495:CFH protein, human; D018272:Porins; D012794:Sialic Acids; C057699:porin protein, Neisseria; D017242:Complement Factor H