Abstract
Plasmacytoid dendritic cells (pDCs) were initially considered as critical for innate immunity to viruses. However, our group has shown that pDCs bind to and inhibit the growth of Aspergillus fumigatus hyphae and that depletion of pDCs renders mice hypersusceptible to experimental aspergillosis. In this study, we examined pDC receptors contributing to hyphal recognition and downstream events in pDCs stimulated by A. fumigatus hyphae. Our data show that Dectin-2, but not Dectin-1, participates in A. fumigatus hyphal recognition, TNF-α and IFN-α release, and antifungal activity. Moreover, Dectin-2 acts in cooperation with the FcRγ chain to trigger signaling responses. In addition, using confocal and electron microscopy we demonstrated that the interaction between pDCs and A. fumigatus induced the formation of pDC extracellular traps (pETs) containing DNA and citrullinated histone H3. These structures closely resembled those of neutrophil extracellular traps (NETs). The microarray analysis of the pDC transcriptome upon A. fumigatus infection also demonstrated up-regulated expression of genes associated with apoptosis as well as type I interferon-induced genes. Thus, human pDCs directly recognize A. fumigatus hyphae via Dectin-2; this interaction results in cytokine release and antifungal activity. Moreover, hyphal stimulation of pDCs triggers a distinct pattern of pDC gene expression and leads to pET formation.
Highlights
Aspergillus fumigatus is an opportunistic fungal pathogen with a worldwide distribution
Our laboratory has been studying the interplay between Plasmacytoid dendritic cells (pDCs) and the fungal pathogen, Aspergillus fumigatus
As fungal recognition appears to be Toll-like receptors (TLRs)-independent, we investigated the possible involvement of two C-type lectin receptors, Dectin-1 and Dectin-2, which have been demonstrated to bind to A. fumigatus hyphae [5], [6], [21], [22], [23]
Summary
Aspergillus fumigatus is an opportunistic fungal pathogen with a worldwide distribution. Invasive aspergillosis (IA) is seen predominantly in immunocompromised patients and is characterized by hyphal invasion associated with tissue destruction [1]. Innate immune responses of phagocytes, neutrophils, are essential for effective host defenses against A. fumigatus. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) on phagocytes recognize surface ligands on A. fumigatus [3], [4], [5], [6]. Hyphae grow too large to be phagocytosed, phagocytes spread over the hyphal surface and antifungal activity proceeds via both oxidative and non-oxidative mechanisms. Larger fungal morphotypes, including tissueinvading Aspergillus hyphae, can still be controlled [8]. Macrophages, eosinophils, and mast cells release ETs [7], [9] it is unknown whether these cell types can form ETs in response to Aspergillus
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