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* Department of Laboratory Medicine, Section of Medical Protein Chemistry, University Hospital Malmö, Lund University, Malmö, Sweden;
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland;
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602;
Department of Medical Microbiology, University Hospital of Jena, Jena, Germany;
¶ Westmead Centre for Oral Health, Institute of Dental Research, Sydney, Australia; and
|| Department of Laboratory Medicine, Section of Medical Microbiology, University Hospital Malmö, Lund University, Malmö, Sweden
The periodontal pathogen Porphyromonas gingivalis is highly resistant to the bactericidal activity of human complement, which is present in the gingival crevicular fluid at 70% of serum concentration. All thirteen clinical and laboratory P. gingivalis strains tested were able to capture the human complement inhibitor C4b-binding protein (C4BP), which may contribute to their serum resistance. Accordingly, in serum deficient of C4BP, it was found that significantly more terminal complement component C9 was deposited on P. gingivalis. Moreover, using purified proteins and various isogenic mutants, we found that the cysteine protease high molecular weight arginine-gingipain A (HRgpA) is a crucial C4BP ligand on the bacterial surface. Binding of C4BP to P. gingivalis appears to be localized to two binding sites: on the complement control protein 1 domain and complement control protein 6 and 7 domains of the 
-chains. Furthermore, the bacterial binding of C4BP was found to increase with time of culture and a particularly strong binding was observed for large aggregates of bacteria that formed during culture on solid blood agar medium. Taken together, gingipains appear to be a very significant virulence factor not only destroying complement due to proteolytic degradation as we have shown previously, but was also inhibiting complement activation due to their ability to bind the complement inhibitor C4BP.
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 the Swedish Foundation for Strategic Research (INGVAR), Swedish Medical Research Council; the foundations of Österlund, Kock, King Gustav V’s 80th Anniversary, Knut and Alice Wallenberg, and Inga-Britt and Arne Lundberg; research grants from the University Hospital in Malmö (to A.M.B.); grants from the Ministry of Science and Higher Education (1642/B/P01/2008/35 Warsaw, Poland); and National Institutes of Health Grant DE 09761 (to J.P.).
2 Address correspondence and reprint requests to Dr. Anna M. Blom, Department of Laboratory Medicine, Division of Medical Protein Chemistry University Hospital Malmö entrance 46, The Wallenberg Laboratory floor 4; Lund University, S-205 02 Malmö, Sweden. E-mail address: Anna.Blom{at}med.lu.se
3 Abbreviations used in this paper: Kgp, lysine-gingipain; Rgp, arginine-gingipain; HRgp, high molecular weight arginine-gingipain; MAC, membrane attack complex; C4BP, C4b-binding protein; CCP, complement control protein (domain); FH, factor H; NHS, normal human serum; TSB, tryptic soy broth; RT, room temperature; L-BAPNA, N-benzoyl-L-arginine p-nitroanilide hydrochloride.
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