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* Medical Microbiology and
Clinical Chemistry, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden; and
Leibniz Institute for Natural Product Research and Infectious Biology, Hans Knoell Institute, Friedrich Schiller University, Jena, Germany
Pathogenic microbes acquire human complement inhibitors to circumvent the innate immune system. In this study, we identify two novel host-pathogen interactions, factor H (FH) and factor H-like protein 1 (FHL-1), the inhibitors of the alternative pathway that binds to Hib. A collection of clinical Haemophilus influenzae isolates was tested and the majority of encapsulated and unencapsulated bound FH. The isolate Hib 541 with a particularly high FH-binding was selected for detailed analysis. An increased survival in normal human serum was observed with Hib 541 as compared with the low FH-binding Hib 568. Interestingly, two binding domains were identified within FH; one binding site common to both FH and FHL-1 was located in the N-terminal short consensus repeat domains 6–7, whereas the other, specific for FH, was located in the C-terminal short consensus repeat domains 18–20. Importantly, both FH and FHL-1, when bound to the surface of Hib 541, retained cofactor activity as determined by analysis of C3b degradation. Two H. influenzae outer membrane proteins of 
32 and 40 kDa were detected with radiolabeled FH in Far Western blot. Taken together, in addition to interactions with the classical, lectin, and terminal pathways, H. influenzae interferes with the alternative complement activation pathway by binding FH and FHL-1, and thereby reducing the complement-mediated bactericidal activity resulting in an increased survival. In contrast to incubation with active complement, H. influenzae had a reduced survival in FH-depleted human serum, thus demonstrating that FH mediates a protective role at the bacterial surface.
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 foundations of Alfred Österlund, Anna and Edwin Berger, Crafoord, and Kock.
2 Address correspondence and reprint requests to Dr. Kristian Riesbeck, Medical Microbiology, Department of Laboratory Medicine, Malmö University Hospital, Lund University, SE-205 02 Malmö, Sweden. E-mail address: kristian.riesbeck{at}med.lu.se
3 Abbreviations used in this paper: Hib, Haemophilus influenzae type b; NTHi, non-typeable Haemophilus influenzae; OMP, outer membrane protein; Hsf, Haemophilus surface fibrils; MAC, membrane attack complex; FH, factor H; FHL-1, fH-like protein-1; C4BP, C4b-binding protein; SCR, short consensus repeats; BHI, brain heart infusion; RT, room temperature; pAb, polyclonal Ab.
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