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C4bp binding to porin mediates stable serum resistance of Neisseria gonorrhoeae

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Author

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

Screening of 29 strains of Neisseria gonorrhoeae revealed that 16/21 serum resistant strains and 0/8 serum sensitive strains bound C4bp. suggesting that C4bp binding to gonococci could contribute to serum resistance. C4bp bound to gonococci retained cofactor (C4b-degrading) function. Using allelic exchange to construct strains with hybrid Por1A/B molecules, we demonstrate that the N-terminal loop (loop 1) of Por1A is required for C4bp binding. Serum resistant Por1B gonococcal strains also bind C4bp via their For molecule. Using allelic exchange and site-directed mutagenesis, we have shown that loops 5 and 7 together form a negatively charged C4bp binding domain. C4bp-Por1B interactions are ionic in nature (inhibited by high salt as well as by heparin), while the C4bp-Por1A bond is hydrophobic. mAbs directed against SCR1 of the alpha -chain of C4bp inhibit C4bp binding to both Por1A and Por1B. Furthermore. only recombinant C4bp mutant molecules that contain alpha -chain SCR1 bind both PorlA and Por1B gonococci, confirming that SCR1 contains For binding sites. C4bp alpha -chain monomers do not bind strains with either For molecule, suggesting that the polymeric form of C4bp is required for binding to gonococci, Inhibition of C4bp binding to serum resistant Por1A and Por1B strains in a serum bactericidal assay using fAb fragments against C4bp SCR1 results in complete killing at 30 min of otherwise fully serum resistant strains in only 10% normal serum, underscoring the role of C4bp in mediating gonococcal serum resistance. (C) 2001 Elsevier Science B,V. All rights reserved.

Publishing year

2001

Language

English

Pages

423-432

Publication/Series

International Immunopharmacology

Volume

1

Issue

3

Document type

Journal article review

Publisher

Elsevier

Topic

  • Pharmacology and Toxicology

Keywords

  • Neisseria gonorrhoeae
  • C4b-binding protein
  • Porin
  • Serum resistance

Status

Published

Research group

  • Protein Chemistry, Malmö
  • Clinical Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 1878-1705