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J. Biol. Chem., Vol. 278, Issue 51, 50853-50862, December 19, 2003

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Neisserial Lipooligosaccharide Is a Target for Complement Component C4b

INNER CORE PHOSPHOETHANOLAMINE RESIDUES DEFINE C4b LINKAGE SPECIFICITY^*

Sanjay Ram, Andrew D. Cox¶, J. Claire Wright||, Ulrich Vogel**, Silke Getzlaff**, Ryan Boden, Jianjun Li¶, Joyce S. Plested||, Seppo Meri, Sunita Gulati, Daniel C. Stein, James C. Richards¶, E. Richard Moxon||, and Peter A. Rice

From the Section of Infectious Diseases, Evans Biomedical Research Center, Boston University Medical Center, Boston, Massachusetts 02118, the ^¶Institute for Biological Sciences, National Research Council, Ottawa, Ontario K1A 0R6, Canada, ^||Molecular Infectious Diseases Group, Oxford University Department of Pediatrics, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom, ^**Institute for Hygiene and Microbiology, University of Würzburg, 97080 Würzburg, Germany, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland-00014, and Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742

We identified Neisseria meningitidis lipooligosaccharide (LOS) as an acceptor for complement component C4b (C4b). Phosphoethanolamine (PEA) residues on the second heptose (HepII) residue in the LOS core structure formed amide linkages with C4b. PEA at the 6-position of HepII (6-PEA) was more efficient than 3-PEA in binding C4b. Strains bearing 6-PEA bound more C4b than strains with 3-PEA and were more susceptible to complement-mediated killing in serum bactericidal assays. Deleting 3-PEA from a strain that expressed both 3- and 6-PEA simultaneously on HepII did not decrease C4b binding. Glycose chain extension of the first heptose residue (HepI) influenced the nature of the C4b-LOS linkage. Predominantly ester C4b-LOS bonds were seen when lacto-N-neotetraose formed the terminus of the glycose chain extension of HepI with 3-PEA on HepII in the LOS core. Related LOS species with more truncated chain extensions from HepI bound C4b via amide linkages to 3-PEA on HepII. However, 6-PEA in the LOS core bound C4b even when the glycose chain from HepI bore lacto-N-neotetraose at the terminus. The C4A isoform exclusively formed amide linkages, whereas C4B bound meningococci preferentially via ester linkages. These data may serve to explain the preponderance of 3-PEA-bearing meningococci among clinical isolates, because 6-PEA enhances C4b binding that may facilitate clearance of 6-PEA-bearing strains resulting from enhanced serum killing by the classical pathway of complement.

Received for publication, July 31, 2003

^* This work was supported by National Institutes of Health Grants AI32725 and AI054544, and by National Institutes of Health Grant AI24452 (to D. C. S.); the Graduate College 520 of Deutsche Forschungsgemeinschaft (University of Würzburg) (to S. G.); the Academy of Finland and the Helsinki University Center Hospital (EVO) (to S. M.); and Chiron Vaccines S.p.a., Medical Research Council and National Meningitis Trust, UK (to J. C. W., J. S. P., and E. R. M.). 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.

To whom correspondence should be addressed: Section of Infectious Diseases, Evans Biomedical Research Center, Boston Medical Center, Boston, MA 02118. Tel.: 617-414-7917; Fax: 617-414-5280; E-mail: sram{at}bu.edu.

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