title: Properdin is critical for antibody-dependent bactericidal activity against Neisseria gonorrhoeae that recruit C4b-binding protein.
abstract: Gonorrhea, a sexually transmitted disease caused by Neisseria gonorrhoeae, is an important cause of morbidity worldwide. A safe and effective vaccine against gonorrhea is needed because of emerging resistance of gonococci to almost every class of antibiotic. A gonococcal lipooligosaccharide epitope defined by the mAb 2C7 is being evaluated as a candidate for development of an Ab-based vaccine. Immune Abs against N. gonorrhoeae need to overcome several subversive mechanisms whereby gonococcus evades complement, including binding to C4b-binding protein (C4BP; classical pathway inhibitor) and factor H (alternative pathway [AP] inhibitor). The role of AP recruitment and, in particular, properdin in assisting killing of gonococci by specific Abs is the subject of this study. We show that only those gonococcal strains that bind C4BP require properdin for killing by 2C7, whereas strains that do not bind C4BP are efficiently killed by 2C7 even when AP function is blocked. C3 deposition on bacteria mirrored killing. Recruitment of the AP by mAb 2C7, as measured by factor B binding, occurred in a properdin-dependent manner. These findings were confirmed using isogenic mutant strains that differed in their ability to bind to C4BP. Immune human serum that contained bactericidal Abs directed against the 2C7 lipooligosaccharide epitope as well as murine antigonococcal antiserum required functional properdin to kill C4BP-binding strains, but not C4BP-nonbinding strains. Collectively, these data point to an important role for properdin in facilitating immune Ab-mediated complement-dependent killing of gonococcal strains that inhibit the classical pathway by recruiting C4BP.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sunita
authors.initials: S
authors.lastname: Gulati
authors.forename: Sarika
authors.initials: S
authors.lastname: Agarwal
authors.forename: Shreekant
authors.initials: S
authors.lastname: Vasudhev
authors.forename: Peter A
authors.initials: PA
authors.lastname: Rice
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
mesh_terms: D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology*; D000918:Antibody Specificity; D000942:Antigens, Bacterial / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology; D050716:Complement C4b-Binding Protein; D003170:Complement Pathway, Alternative; D003171:Complement Pathway, Classical; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D009344:Neisseria gonorrhoeae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D018272:Porins / Q000235:genetics / Q000276:immunology; D011414:Properdin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014774:Virulence
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; C055609:C4BPA protein, human; C489166:C4bp protein, mouse; D050716:Complement C4b-Binding Protein; D000939:Epitopes; D006649:Histocompatibility Antigens; D008070:Lipopolysaccharides; D018272:Porins; C023023:lipid-linked oligosaccharides; C057699:porin protein, Neisseria; D011414:Properdin