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Cell Host Microbe. 2014 Apr 9;15(4):494-505. doi: 10.1016/j.chom.2014.03.008.

Fungal engagement of the C-type lectin mincle suppresses dectin-1-induced antifungal immunity.

Author information

1
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, TheĀ Netherlands.
2
Centraalbureau voor Schimmelcultures, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
3
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, TheĀ Netherlands. Electronic address: s.i.gringhuis@amc.uva.nl.

Abstract

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.

PMID:
24721577
DOI:
10.1016/j.chom.2014.03.008
[Indexed for MEDLINE]
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