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Human Factor H Interacts Selectively with Neisseria gonorrhoeae and Results in Species-Specific Complement Evasion¹

Jutamas Ngampasutadol^2,*, Sanjay Ram^*, Sunita Gulati^*, Sarika Agarwal^*, Chongqing Li, Alberto Visintin^*, Brian Monks^*, Guillermo Madico and Peter A. Rice^*

^* Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and Section of Infectious Diseases, Department of Medicine, Evans Biomedical Research Center, Boston University Medical Center, Boston, MA 02118

Complement forms a key arm of innate immune defenses against gonococcal infection. Sialylation of gonococcal lipo-oligosaccharide, or expression of porin 1A (Por1A) protein, enables Neisseria gonorrhoeae to bind the alternative pathway complement inhibitor, factor H (fH), and evade killing by human complement. Using recombinant fH fragment-murine Fc fusion proteins, we localized two N. gonorrhoeae Por1A-binding regions in fH: one in complement control protein domain 6, the other in complement control proteins 18–20. The latter is similar to that reported previously for sialylated Por1B gonococci. Upon incubation with human serum, Por1A and sialylated Por1B strains bound full-length human fH (HufH) and fH-related protein 1. In addition, Por1A strains bound fH-like protein 1 weakly. Only HufH, but not fH from other primates, bound directly to gonococci. Consistent with direct HufH binding, unsialylated Por1A gonococci resisted killing only by human complement, but not complement from other primates, rodents or lagomorphs; adding HufH to these heterologous sera restored serum resistance. Lipo-oligosaccharide sialylation of N. gonorrhoeae resulted in classical pathway regulation as evidenced by decreased C4 binding in human, chimpanzee, and rhesus serum but was accompanied by serum resistance only in human and chimpanzee serum. Direct-binding specificity of HufH only to gonococci that prevents serum killing is restricted to humans and may in part explain species-specific restriction of natural gonococcal infection. Our findings may help to improve animal models for gonorrhea while also having implications in the choice of complement sources to evaluate neisserial vaccine candidates.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI32725 (to P.A.R.) and AI054544 (to S.R.).

² Address correspondence and reprint requests to Dr. Jutamas Ngampasutadol, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts, Lazare Research Building, Room 370T, 364 Plantation Street, Worcester, MA 01605. E-mail address: jutamas.shaughnessy{at}umassmed.edu

³ Abbreviations used in this paper: NHS, normal human serum; C4BP, C4b-binding protein; LNT, lacto-N-neotetraose; LOS, lipo-oligosaccharide; CMP-NANA, 5'-cytidinemonophospho-N-acetylneuraminic acid; CCP, complement control protein domain; fH, factor H; HufH, human fH; NChS, normal chimpanzee serum; FHL-1, fH-like protein 1; FHR-1, fH-related protein; NRhS, normal rhesus serum; ChfH, chimpanzee fH; Por, porin.