Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity.
Recognition of fungal pathogens by C-type lectin receptor (CLR) dectin-1 on human dendritic cells is essential for triggering protective antifungal TH1 and TH17 immune responses. We show that Fonsecaea monophora, a causative agent of chromoblastomycosis, a chronic fungal skin infection, evades these antifungal responses by engaging CLR mincle and suppressing IL-12, which drives TH1 differentiation. Dectin-1 triggering by F. monophora activates transcription factor IRF1, which is crucial for IL12A transcription via nucleosome remodeling. However, simultaneous F. monophora binding to mincle induces an E3 ubiquitin ligase Mdm2-dependent degradation pathway, via Syk-CARD9-mediated PKB signaling, that leads to loss of nuclear IRF1 activity, hence blocking IL12A transcription. The absence of IL-12 leads to impaired TH1 responses and promotes TH2 polarization. Notably, mincle is similarly exploited by other chromoblastomycosis-associated fungi to redirect TH responses. Thus, mincle is a fungal receptor that can suppress antifungal immunity and, as such, is a potential therapeutic target.
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Brigitte A
BA
Wevers
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Tanja M
TM
Kaptein
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Esther M
EM
Zijlstra-Willems
Centraalbureau voor Schimmelcultures, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Bart
B
Theelen
Centraalbureau voor Schimmelcultures, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Teun
T
Boekhout
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Teunis B H
TB
Geijtenbeek
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Electronic address: s.i.gringhuis@amc.uva.nl.
Sonja I
SI
Gringhuis
D053468:CARD Signaling Adaptor Proteins / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002862:Chromoblastomycosis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic / Q000276:immunology*; D004718:Saccharomycetales / Q000276:immunology*; D000072377:Syk Kinase; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D000099181:Dectin-1
D053468:CARD Signaling Adaptor Proteins; D050856:Interferon Regulatory Factor-1; D053765:Interleukin-12 Subunit p35; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D000072377:Syk Kinase; D000099181:Dectin-1; C505855:CARD9 protein, human; C482593:CLEC4D protein, human; C508858:IL12A protein, human; C494257:IRF1 protein, human; C497206:MDM2 protein, human; C000606896:SYK protein, human