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* Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden; and
Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
Complement evasion by various mechanisms is important for microbial virulence and survival in the host. One strategy used by some pathogenic bacteria is to bind the complement inhibitor of the classical pathway, C4b-binding protein (C4BP). In this study, we have identified a novel interaction between nontypeable Haemophilus influenzae (NTHi) and C4BP, whereas the majority of the typeable H. influenzae (a-f) tested showed no binding. One of the clinical isolates, NTHi 506, displayed a particularly high binding of C4BP and was used for detailed analysis of the interaction. Importantly, a low C4BP-binding isolate (NTHi 69) showed an increased deposition of C3b followed by reduced survival as compared with NTHi 506 when exposed to normal human serum. The main isoform of C4BP contains seven identical 
-chains and one 
-chain linked together with disulfide bridges. Each -chain is composed of eight complement control protein (CCP) modules and we have found that the NTHi 506 strain did not interact with rC4BP lacking CCP2 or CCP7 showing that these two CCPs are important for the binding. Importantly, C4BP bound to the surface of H. influenzae retained its cofactor activity as determined by analysis of C3b and C4b degradation. Taken together, NTHi interferes with the classical complement activation pathway by binding to 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 grants from the Swedish Medical Research Council, the Swedish Foundation for Strategic Research (INGVAR), and the Foundations of Anna and Edwin Berger, Kock, Österlund, Bergvall, King Gustav V’s 80th Anniversary, and a research grant from the University Hospital in Malmö.
2 Address correspondence and reprint requests to Dr. Anna M. Blom, Department of Laboratory Medicine, Medical Protein Chemistry, Lund University, Malmö University Hospital, The Wallenberg Laboratory, Floor 4, SE-205 02 Malmö, Sweden. E-mail address: anna.blom{at}med.lu.se
3 Abbreviations used in this paper: NTHi, nontypeable Haemophilus influenzae; Hsf, Haemophilus surface fibril; MAC, membrane attack complex; C4BP, C4b-binding protein; CCP, complement control protein; BHI, brain heart infusion; pAb, polyclonal Ab; FH, factor H; VBS, Veronal-buffered saline; NHS, normal human serum; C3, complement factor 3; GVB, gelatin-Veronal buffer; DGVB, dextrose-GVB.
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