SWI/SNF complex-mediated chromatin remodelling inCandida glabratais vital for immune evasion

Abstract

AbstractImmune evasion is critical for fungal virulence. However, how the human opportunistic pathogenCandida glabrata(Cg) accomplishes this is unknown. Here, using micrococcal nuclease-sequencing, RNA-sequencing, macrophage-signalling and genetic analyses, we demonstrate that chromatin reorganization in macrophage-internalizedCg, via CgSnf2 (ATPase subunit of the SWI/SNF chromatin remodelling complex), leads to upregulation and downregulation of immunosuppressive seven mannosyltransferase-cluster (CgMT-C) and immunostimulatory cell surface adhesinEPA1genes, respectively. Consistently,EPA1overexpression andCgMT-Cdeletion led to increased IL-1β (pro-inflammatory cytokine) production and reducedCgproliferation in macrophages. Further,CgSNF2deletion evoked increased IL-1β secretion, and the consequent killing of macrophage-internalizedCg, with elevated IL-1β levels being partially reversed in Akt-, p38-, NF-κB- or NLRP3 inflammasome-inhibited macrophages. Importantly, macrophages respond to multipleCandidapathogens via NF-κB-dependent IL-1β production, underscoring NF-κB signalling’s role in fungal diseases. Finally, we present the first genome-wide nucleosome map of macrophage-internalizedCgconsisting of ∼12,000 dynamic and 70,000 total nucleosomes. Altogether, our findings directly link the nucleosome positioning-based chromatin remodelling to fungal immunomodulatory molecule expression, which dictatesCgfate in host immune cells.