Factor H and factor H-related protein 1 bind to human neutrophils via complement receptor 3, mediate attachment to Candida albicans, and enhance neutrophil antimicrobial activity.
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.
Losse
Josephine
J
Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
Zipfel
Peter F
PF
Józsi
Mihály
M
D001053:Apolipoproteins / Q000378:metabolism; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism*; D002176:Candida albicans / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement; D003167:Complement Activation; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000378:metabolism*; D006801:Humans; D007781:Lactoferrin / Q000276:immunology / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology*
D001053:Apolipoproteins; D001798:Blood Proteins; C517621:CFHR1 protein, human; C105092:CFHR4 protein, human; D003180:Complement C3b Inactivator Proteins; D016177:Macrophage-1 Antigen; C100631:factor H-related protein 1; D017242:Complement Factor H; D007781:Lactoferrin