Binding of C4b-binding Protein to Porin: A Molecular Mechanism of Serum Resistance of Neisseria gonorrhoeae

doi:10.1084/jem.193.3.281

Published online 29 January 2001.

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© The Rockefeller University Press, 0022-1007/2001/2/281/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 3, February 5, 2001 281-296

Original Article

Binding of C4b-binding Protein to Porin: A Molecular Mechanism of Serum Resistance of Neisseria gonorrhoeae

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

Correspondence to: Sanjay Ram, Evans Biomedical Research Center, Boston Medical Center, Room 604, 650 Albany St., Boston, MA 02118. Tel:617-414-7917 Fax:617-414-5280 E-mail:sram{at}bu.edu.

We screened 29 strains of Neisseria gonorrhoeae and found 16/21strains that resisted killing by normal human serum and 0/8serum sensitive strains that bound the complement regulator,C4b-binding protein (C4bp). Microbial surface–bound C4bpdemonstrated cofactor activity. We constructed gonococcal strainswith hybrid porin (Por) molecules derived from each of the majorserogroups (Por1A and Por1B) of N. gonorrhoeae, and showed thatthe loop 1 of Por1A is required for C4bp binding. Por1B loops5 and 7 of serum-resistant gonococci together formed a negativelycharged C4bp-binding domain. C4bp–Por1B interactions wereionic in nature (inhibited by high salt or by heparin), whereasthe C4bp–Por1A bond was hydrophobic. Only recombinantC4bp mutant molecules containing the NH₂-terminal ${alpha}$ -chain shortconsensus repeat (SCR1) bound to both Por1A and Por1B gonococci,suggesting that SCR1 contained Por binding sites. C4bp ${alpha}$ -chainmonomers did not bind gonococci, indicating that the polymericform of C4bp was required for binding. Using fAb fragments againstC4bp SCR1, C4bp binding to Por1A and Por1B strains was inhibitedin a complement-dependent serum bactericidal assay. This resultedin complete killing of these otherwise fully serum resistantstrains in only 10% normal serum, underscoring the importanceof C4bp in mediating gonococcal serum resistance.

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

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