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

Brigitte A Wevers; Tanja M Kaptein; Esther M Zijlstra-Willems; Bart Theelen; Teun Boekhout; Teunis B H Geijtenbeek; Sonja I Gringhuis

doi:10.1016/j.chom.2014.03.008

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

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

Authors

Brigitte A Wevers¹, Tanja M Kaptein¹, Esther M Zijlstra-Willems¹, Bart Theelen², Teun Boekhout², Teunis B H Geijtenbeek¹, Sonja I Gringhuis³

Affiliations

¹ Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The 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, The Netherlands. Electronic address: [email protected].

PMID: 24721577
DOI: 10.1016/j.chom.2014.03.008

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CARD Signaling Adaptor Proteins / immunology
Cell Differentiation / immunology
Cells, Cultured
Chromoblastomycosis / immunology
Dendritic Cells / immunology
Humans
Interferon Regulatory Factor-1 / biosynthesis
Interferon Regulatory Factor-1 / genetics
Interleukin-12 Subunit p35 / biosynthesis*
Interleukin-12 Subunit p35 / genetics
Interleukin-12 Subunit p35 / immunology
Intracellular Signaling Peptides and Proteins / immunology
Lectins, C-Type / immunology*
Protein-Tyrosine Kinases / immunology
Proto-Oncogene Proteins c-mdm2 / immunology
RNA Interference
RNA, Small Interfering
Receptors, Immunologic / immunology*
Saccharomycetales / immunology*
Syk Kinase
Th1 Cells / immunology
Th17 Cells / immunology

Substances

CARD Signaling Adaptor Proteins
CARD9 protein, human
CLEC4D protein, human
IL12A protein, human
IRF1 protein, human
Interferon Regulatory Factor-1
Interleukin-12 Subunit p35
Intracellular Signaling Peptides and Proteins
Lectins, C-Type
RNA, Small Interfering
Receptors, Immunologic
dectin 1
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
Protein-Tyrosine Kinases
SYK protein, human
Syk Kinase