The host
complement system plays an important role in protection against
infections. Several human-pathogenic microbes were shown to acquire host
complement regulators, such as
factor H (CFH), that downregulate complement activation at the microbial surface and protect the pathogens from the opsonic and lytic effects of
complement. Because CFH can also bind to host cells, we addressed the role of CFH and CFH-related
proteins as adhesion
ligands in host-pathogen interactions. We show that the CFH family
proteins CFH, CFH-like
protein 1 (CFHL1), CFH-related
protein (CFHR) 1, and CFHR4 long
isoform bind to human neutrophil granulocytes and to the opportunistic human-pathogenic yeast Candida albicans. Two major binding sites, one within the N-terminus and one in the C-terminus of CFH, were found to mediate binding to neutrophils.
Complement receptor 3 (CD11b/CD18; alpha(M)
beta2 integrin) was identified as the major cellular receptor on neutrophils for CFH, CFHL1, and CFHR1, but not for CFHR4 long
isoform. CFH and CFHR1 supported cell migration. Furthermore, CFH, CFHL1, and CFHR1 increased attachment of neutrophils to C. albicans. Adhesion of neutrophils to plasma-opsonized yeasts was reduced when CFH binding was inhibited by specific Abs or when using CFH-depleted plasma. Yeast-bound CFH and CFHR1 enhanced the generation of
reactive oxygen species and the release of the antimicrobial
protein lactoferrin by human neutrophils, and resulted in a more efficient killing of the pathogen. Thus, CFH and CFHR1, when bound on the surface of C. albicans, enhance antimicrobial activity of human neutrophils.