The hyphal and yeast forms of Candida albicans bind the complement regulator C4b-binding protein.
Candida albicans, an important pathogenic yeast, activates all three pathways of the complement system. To understand how this yeast evades the effects of the activated system, we have analyzed the binding of the classical pathway inhibitor C4b-binding protein (C4BP) by C. albicans. Purified native as well as recombinant C4BP bound dose dependently to the yeast and hyphal forms, as shown by multiple methods, such as confocal microscopy, flow cytometry, a novel enzyme-linked immunosorbent assay, absorption from human serum, and direct binding assays with purified proteins. A prominent binding site was identified at the tip of the germ tube, a structure that is considered important for tissue penetration and pathogenesis. The binding site in C4BP was localized to the two N-terminal complement control protein domains by using recombinant deletion constructs and site-specific monoclonal antibodies. As the alternative pathway inhibitors factor H and FHL-1 also bind to C. albicans, the binding of all three plasma proteins was compared. Simultaneous binding of the classical regulator C4BP and the alternative pathway regulator factor H was demonstrated by confocal microscopy. In addition, FHL-1 competed for binding with C4BP, suggesting that these two related complement regulators bind to the same structures on the yeast surface. The surface-attached C4BP maintains its complement regulatory activities and inactivates C4b. The surface-attached human C4BP serves multiple functions relevant for immune evasion and likely pathogenicity. It inhibits complement activation at the yeast surface and, in addition, mediates adhesion of C. albicans to host endothelial cells.
Meri
T
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Hans Knöll Institute for Natural Products Research, D-07745 Jena, Germany.
Blom
A M
AM
Hartmann
A
A
Lenk
D
D
Meri
S
S
Zipfel
P F
PF
D001665:Binding Sites; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D002176:Candida albicans / Q000254:growth & development* / Q000378:metabolism / Q000472:pathogenicity*; D003180:Complement C3b Inactivator Proteins; D015935:Complement C4b / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal
D001798:Blood Proteins; C493495:CFH protein, human; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D015935:Complement C4b; D017242:Complement Factor H