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Binding of C4b-binding protein: A molecular mechanism of serum resistance of Neisseria gonorrhoeae

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Author

  • Sanjay Ram
  • Meabh Cullinane
  • Anna Blom
  • Sunita Gulati
  • Daniel P. McQuillen
  • Brian G. Monks
  • Catherine O'Connell
  • Ryan Boden
  • Christopher Elkins
  • Michael K. Pangburn
  • Björn Dahlbäck
  • Peter A. Rice
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Summary, in English

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 surfacebound 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. C4bpPor1B interactions were ionic in nature (inhibited by high salt or by heparin), whereas the C4bpPor1A 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.

Publishing year

2001

Language

English

Pages

281-295

Publication/Series

Journal of Experimental Medicine

Volume

193

Issue

3

Document type

Journal article

Publisher

Rockefeller University Press

Topic

  • Medicinal Chemistry

Status

Published

Research group

  • Clinical Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 1540-9538