The opportunistic human pathogenic fungus Aspergillus fumigatus evades the host complement system.
The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinase-type plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
Judith
J
Behnsen
Andrea
A
Hartmann
Jeannette
J
Schmaler
Alexander
A
Gehrke
Axel A
AA
Brakhage
Peter F
PF
Zipfel
D001232:Aspergillus fumigatus / Q000276:immunology*; D001665:Binding Sites; D001798:Blood Proteins / Q000276:immunology / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D010958:Plasminogen / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D013172:Spores, Fungal / Q000276:immunology
D001798:Blood Proteins; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; C100631:factor H-related protein 1; D017242:Complement Factor H; D010958:Plasminogen; D003165:Complement System Proteins