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* Department of Laboratory Medicine, Medical Microbiology, and
Department of Laboratory Medicine, Medical Protein Chemistry, Lund University, Malmö, Sweden;
Department of Bacteriology and Immunology, Haartman Institute, Helsinki, Finland;
Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden; and
¶ Department of Microbiology, Tumorbiology and Cell Biology, Karolinska Institutet, Stockholm, Sweden
The complement system constitutes an important component of the innate immune system. To colonize their host and/or to cause disease, many pathogens have evolved strategies to avoid complement-mediated bacterial lysis and opsonophagocytosis. In this study, using a collection of 55 clinical isolates of Streptococcus pneumoniae, we demonstrate for the first time that pneumococci bind the complement inhibitor C4b-binding protein (C4BP). C4BP binding seems to be restricted to certain serotypes such as serotype 4, 6B, 7F, and 14, of which the strains of serotype 14 are the strongest binders. We show that bacteria-bound C4BP retains its functional activity and down-regulates the activation of the classical pathway. Thus, this major respiratory pathogen may escape immune recognition and eradication by the complement system. Furthermore, we show that C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4. The study of the distribution of group 4 pspC locus shows that most of high-binder serotype 14 isolates harbor an allelic variant of group 4 pspC. Using PspC-negative mutant strains, we identified a new allelic variant of PspC (PspC4.4) as a major ligand for C4BP, revealing a new function for this important pneumococcal virulence factor. Thus pneumococci exploit host C4BP for complement evasion in a PspC allele-dependent manner.
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1 B.A. was supported by grants from the Swedish Medical Research Council, Crafoord Foundation, the Swedish Society of Medicine, Lars Hiertas Memory Funds, Alfred Österlund Foundation, Längmanska Culture Foundation, and O. E. & Edda Johansson Scientific Foundation. A.M.B. received grants from the Swedish Medical Research Council and the Swedish Foundation for Strategic Research. B.H.N. was financed by the Swedish Medical Research Council, Torsten and Ragnar Söderbergs Foundation, the Swedish Royal Academy of Science, and by the European Union project Pneumococcal Resistance Epidemicity and Virulence—An International Study funded by Directorate General research with the Sixth Framework Program. S.M. was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, and the Helsinki University Hospital Funds (EVO).
2 Address correspondence and reprint requests to Dr. Barbara Albiger, Department of Laboratory Medicine, Medical Microbiology, Malmö University Hospital, Lund University, Malmö, SE-205 02 Sweden. E-mail address: Barbara.Albiger{at}med.lu.se
3 Abbreviations used in this paper: MAC, membrane attack complex; C4BP, C4b-binding protein; CCP, complement control protein; SCR, short consensus repeat; NHS, normal human serum; IPD, invasive pneumococcal disease; PspC, pneumococcal surface protein C; MLST, multilocus sequence typing; ST, sequence type; wt, wild type; CSP, competence stimulatory peptide; FH, factor H; FI, factor I; RT, room temperature; GVB, gelatin-veronal buffer; pC4BP, plasma-purified C4BP; sIgA, secretory IgA; PAF-R, platelet-activating factor receptor; pIgR, polymeric IgG receptor.
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