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Defining Targets for Complement Components C4b and C3b on the Pathogenic Neisseriae ^,

Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,¹ Dionex Corporation, Sunnyvale, California 94088,² Universität Würzburg, 97080 Würzburg, Germany,³ Department of Laboratory Medicine, Medical Protein Chemistry, University of Lund, Malmö, Sweden⁴

Received 30 April 2007/ Returned for modification 8 June 2007/ Accepted 25 October 2007

Complement is a key arm of the innate immune defenses against the pathogenic neisseriae. We previously identified lipooligosaccharide on Neisseria meningitidis as an acceptor for complement C4b. Little is known about other neisserial targets for complement proteins C3 and C4, which covalently attach to bacterial surfaces and initiate opsonization and killing. In this study we demonstrate that Neisseria gonorrhoeae porin (Por) 1B selectively binds C4b via amide linkages and C3b via ester linkages. Using strains expressing hybrid Por1A/1B molecules, a region spanned by loops 4 and 5 of Por1B was identified as the preferred binding site for C4b. We also identified the opacity protein (Opa), a major adhesin of pathogenic neisseriae, as a target for C4b and C3b on both N. meningitidis and N. gonorrhoeae. Using N. gonorrhoeae variants that predominantly expressed individual Opa proteins, we found that all Opa proteins tested (A, B, C, D, E, F, and I) bound C4b and C3b via amide and ester linkages, respectively. Amide linkages with Por1B and Opa were confirmed using serum containing only the C4A isoform, which exclusively forms amide linkages with targets. While monomers and heterodimers of C4Ab were detected on bacterial targets, C4Bb appeared to preferentially participate in heterodimer (C5 convertase) formation. Our data provide another explanation for the enhanced serum sensitivity of Por1B-bearing gonococci. The binding of C3b and C4b to Opa provides a rationale for the recovery of predominantly "transparent" (Opa-negative) neisserial isolates from persons with invasive disease, where the bacteria encounter high levels of complement.

Published ahead of print on 5 November 2007.

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Editor: J. N. Weiser