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Original Article

Sanjay Ram^a, Meabh Cullinane^a, Anna M. Blom^b, Sunita Gulati^a, Daniel P. McQuillen^a, Brian G. Monks^a, Catherine O'Connell^a, Ryan Boden^a, Christopher Elkins^c, Michael K. Pangburn^d, Björn Dahlbäck^b, and Peter A. Rice^a

^a Evans Biomedical Research Center, Boston Medical Center, Boston, Massachusetts 02118
^b Lund University, Malmö S-20502, Sweden
^c University of North Carolina, Chapel Hill, North Carolina 27599
^d University of Texas Health Sciences Center, Tyler, Texas 75708
Evans Biomedical Research Center, Boston Medical Center, Room 604, 650 Albany St., Boston, MA 02118.617-414-5280617-414-7917

sram{at}bu.edu

We screened 29 strains of Neisseria gonorrhoeae and found 16/21 strains that resisted killing by normal human serum and 0/8 serum sensitive strains that bound the complement regulator, C4b-binding protein (C4bp). Microbial surface–bound C4bp demonstrated cofactor activity. We constructed gonococcal strains with hybrid porin (Por) molecules derived from each of the major serogroups (Por1A and Por1B) of N. gonorrhoeae, and showed that the loop 1 of Por1A is required for C4bp binding. Por1B loops 5 and 7 of serum-resistant gonococci together formed a negatively charged C4bp-binding domain. C4bp–Por1B interactions were ionic in nature (inhibited by high salt or by heparin), whereas the C4bp–Por1A bond was hydrophobic. Only recombinant C4bp mutant molecules containing the NH₂-terminal -chain short consensus repeat (SCR1) bound to both Por1A and Por1B gonococci, suggesting that SCR1 contained Por binding sites. C4bp -chain monomers did not bind gonococci, indicating that the polymeric form of C4bp was required for binding. Using fAb fragments against C4bp SCR1, C4bp binding to Por1A and Por1B strains was inhibited in a complement-dependent serum bactericidal assay. This resulted in complete killing of these otherwise fully serum resistant strains in only 10% normal serum, underscoring the importance of C4bp in mediating gonococcal serum resistance.

Key Words: Neisseria gonorrhoeae • C4b-binding protein • porin • serum resistance • short consensus repeat

© 2001 The Rockefeller University Press

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