Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection

doi:10.1073/pnas.0506471102

Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae and results in species-specific infection

^*Section of Infectious Diseases, Department of Medicine, Boston University Medical Center, Boston, MA 02118; ^†Department of Laboratory Medicine, Section of Clinical Chemistry, Lund University, S-205 202, Malmö, Sweden; ^‡Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, 00014, Helsinki, Finland; ^§Uniformed Services University of Health Sciences, Bethesda, MD 20814; and ^¶Division of Infectious Diseases and Immunology, Department of Medicine, and ^∥Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01605

Edited by Emil C. Gotschlich, The Rockefeller University, New York, NY (received for review August 1, 2005)

Abstract

Neisseria gonorrhoeae is the causative agent of gonorrhea, a disease that is restricted to humans. Complement forms a key arm of the innate immune system that combats gonococcal infections. N. gonorrhoeae uses its outer membrane porin (Por) molecules to bind the classical pathway of complement down-regulatory protein C4b-binding protein (C4bp) to evade killing by human complement. Strains of N. gonorrhoeae that resisted killing by human serum complement were killed by serum from rodent, lagomorph, and primate species, which cannot be readily infected experimentally with this organism and whose C4bp molecules did not bind to N. gonorrhoeae. In contrast, we found that Yersinia pestis, an organism that can infect virtually all mammals, bound species-specific C4bp and uniformly resisted serum complement-mediated killing by these species. Serum resistance of gonococci was restored in these sera by human C4bp. An exception was serotype Por1B-bearing gonococcal strains that previously had been used successfully in a chimpanzee model of gonorrhea that simulates human disease. Por1B gonococci bound chimpanzee C4bp and resisted killing by chimpanzee serum, providing insight into the host restriction of gonorrhea and addressing why Por1B strains, but not Por1A strains, have been successful in experimental chimpanzee infection. Our findings may lead to the development of better animal models for gonorrhea and may also have implications in the choice of complement sources to evaluate neisserial vaccine candidates.

Footnotes

↵ ** To whom correspondence should be addressed at: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Lazare Research Building, Room 321, 364 Plantation Street, Worcester, MA 01605. E-mail: peter.rice{at}umassmed.edu.
Author contributions: J.N., S.R., and P.A.R. designed research; J.N., S.R., and S.G. performed research; A.M.B., H.J., E.L., and J.G. contributed new reagents/analytic tools; J.N., S.R., A.E.J., S.G., and P.A.R. analyzed data; and J.N., S.R., E.L., and P.A.R. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: C4bp, C4b-binding protein; Por, porin; CCP, complement control protein; NHS, normal human serum; NCS, normal chimpanzee serum.