title: Secreted aspartic protease 2 of Candida albicans inactivates factor H and the macrophage factor H-receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18).
abstract: The opportunistic pathogenic yeast Candida albicans employs several mechanisms to interfere with the human complement system. This includes the acquisition of host complement regulators, the release of molecules that scavenge complement proteins or block cellular receptors, and the secretion of proteases that inactivate complement components. Secreted aspartic protease 2 (Sap2) was previously shown to cleave C3b, C4b and C5. C. albicans also recruits the complement inhibitor factor H (FH), but yeast-bound FH can enhance the antifungal activity of human neutrophils via binding to complement receptor type 3 (CR3). In this study, we characterized FH binding to human monocyte-derived macrophages. Inhibition studies with antibodies and siRNA targeting CR3 (CD11b/CD18) and CR4 (CD11c/CD18), as well as analysis of colocalization of FH with these integrins indicated that both function as FH receptors on macrophages. Preincubation of C. albicans yeast cells with FH induced increased production of IL-1β and IL-6 in macrophages. Furthermore, FH enhanced zymosan-induced production of these cytokines. C. albicans Sap2 cleaved FH, diminishing its complement regulatory activity, and Sap2-treatment resulted in less detectable CR3 and CR4 on macrophages. These data show that FH enhances the activation of human macrophages when bound on C. albicans. However, the fungus can inactivate both FH and its receptors on macrophages by secreting Sap2, which may represent an additional means for C. albicans to evade the host innate immune system.
authors: Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.
authors: Eliška
authors: E
authors: Svoboda
authors: MTA-ELTE "Lendület" Complement Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Andrea E
authors: AE
authors: Schneider
authors: MTA-ELTE Immunology Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Noémi
authors: N
authors: Sándor
authors: Junior Research Group Fundamental Molecular Biology of Pathogenic Fungi, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.
authors: Ulrich
authors: U
authors: Lermann
authors: Junior Research Group Fundamental Molecular Biology of Pathogenic Fungi, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany; Research and Development, Kneipp GmbH, Würzburg, Germany.
authors: Peter
authors: P
authors: Staib
authors: MTA-ELTE Immunology Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Mariann
authors: M
authors: Kremlitzka
authors: Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Zsuzsa
authors: Z
authors: Bajtay
authors: Institute for Transfusion Medicine, University Hospital of Jena, Germany.
authors: Dagmar
authors: D
authors: Barz
authors: MTA-ELTE Immunology Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary; Department of Immunology, Eötvös Loránd University, Budapest, Hungary.
authors: Anna
authors: A
authors: Erdei
authors: Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany; MTA-ELTE "Lendület" Complement Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary. Electronic address: mihaly.jozsi@gmx.net.
authors: Mihály
authors: M
authors: Józsi
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002176:Candida albicans / Q000201:enzymology / Q000276:immunology* / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017242:Complement Factor H / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005656:Fungal Proteins / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen; D018821:CD18 Antigens; D016207:Cytokines; D005656:Fungal Proteins; D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen; D017242:Complement Factor H; D016282:Aspartic Acid Endopeptidases; C090753:SAP2 protein, Candida
keywords: CR3; Candida albicans; Complement; Factor H; Fungal pathogen; Immune evasion; Protease; Sap2