Editors' ChoiceHost-Pathogen Interactions

Pattern Recognition Receptor Antagonism

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Science Signaling  15 Apr 2014:
Vol. 7, Issue 321, pp. ec97
DOI: 10.1126/scisignal.2005371

Pathogen-associated molecules trigger immune responses through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), both of which are present on dendritic cells (DCs) (see Rivera). Wevers et al. report a mechanism by which Fonseca monophora, a pathogenic fungus that causes the chronic skin infection chromoblastomycosis, subverted the antifungal response through the stimulation of two CLRs with antagonistic activity. In coculture experiments, DCs stimulated with the TLR4 agonist lipopolysaccharide (LPS) promoted the differentiation of T helper 1 (TH1) cells, whereas DCs stimulated with F. monophora alone or F. monophora plus LPS promoted TH2 differentiation. Although F. monophora stimulated primary human DCs to produce various cytokines, it did not trigger production of interleukin (IL)-12p35, a subunit of the TH1-inducing cytokine IL-12. DCs stimulated with LPS produced IL-12p35, and production of this cytokine subunit was inhibited by the presence of F. monophora. Analysis of the cytokine profile of DCs lacking either the CLR dectin-1 or the CLR Mincle showed that the production of IL-6, IL-1β, IL-12p40, and IL-23 in response to F. monophora required dectin-1, and the suppression of IL-12p35 production required Mincle. Activation of Mincle by F. monophora promoted the degradation of interferon regulatory factor 1 (IRF1), which is activated by dectin-1 or TLR4 signaling and remodels nucleosomes to promote transcription of IL12A. Mincle triggered IRF2 degradation through Akt-dependent activation of the ubiquitin E3 ligase Mdm2. This antagonism of dectin-1–mediated IL12A expression by Mincle benefits the pathogen by favoring the differentiation of TH2 cells at the expense of TH1 cells. TH1 cells are critical for activation of pathogen-destroying phagocytes. In contrast, TH2 cells, which are present in chromoblastomycosis lesions, dampen the TH1 response. This may be a common strategy for evading the antifungal response, because several other species of fungi related to F. monophora also bound to recombinant Mincle, inhibited LPS-induced TH1 differentiation, and promoted TH2 differentiation.

B. A. Wevers, T. M. Kaptein, E. M. Zijlstra-Willems, B. Theelen, T. Boekhout, T. B. H. Geijtenbeek, S. I. Gringhuis, Fungal engagement of the C-type lectin Mincle suppresses dectin-1-induced antifungal immunity. Cell Host Microbe 15, 494–505 (2014). [Online Journal]

A. Rivera, When PRRs collide: Mincle meddles with dectin and Toll. Cell Host Microbe 15, 397–399 (2014). [Online Journal]

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