Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.
Bottom Line: Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9.Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production.These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.
Affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany. Electronic address: firstname.lastname@example.org.Show MeSH
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Mentions: We adoptively transferred T cell-suppressive neutrophilic MDSCs and monitored their impact on survival in fungal infection. While a single dose of adoptively transferred MDSCs was protective in systemic C. albicans infection, MDSCs had no impact on A. fumigatus infection (Figure 1E). Septic shock determines mortality in candidiasis (Spellberg et al., 2005), and the interplay of fungal growth and renal immunopathology was shown to correlate with host survival (Lionakis et al., 2011, 2013; Lionakis and Netea, 2013; Spellberg et al., 2003). Adoptively transferred MDSCs dampened renal T and NK cell activation and systemic Th17 and TNF-α cytokine responses (Figures S1F and S1G). Conversely, supplementing IL-17A dampened the MDSC-mediated protective effect (Figure 2A). Besides these immunomodulatory effects, MDSCs might also act directly antifungal, as our in vitro studies showed that they can phagocytose and kill fungi (Figure 2B). However, direct antifungal effects could hardly explain the beneficial effect of MDSCs in candidiasis: (i) adoptively transferred MDSCs had no effect on fungal burden in vivo (Figure 2A), (ii) inhibition of phagocytosis only partially diminished the protection conferred by MDSCs (Figure 2A), and (iii) MDSCs were exclusively protective in immunocompetent mice (C. albicans infection model), with no effect in immunosuppressed (neutropenic) mice (A. fumigatus infection model).
Affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany. Electronic address: email@example.com.