SWI/SNF complex-mediated chromatin remodelling is vital for cell surface adhesin repression and immune evasion

Immune evasion is critical for fungal virulence. However, how the human opportunistic pathogen Candida 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-internalized Cg, 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 adhesin EPA1 genes, respectively. Consistently, EPA1 overexpression and CgMT-C deletion led to increased IL-1{beta} (pro-inflammatory cytokine) production and reduced Cg proliferation in macrophages. Further, CgSNF2 deletion evoked increased IL-1{beta} secretion, and the consequent killing of macrophage-internalized Cg, with elevated IL-1{beta} levels being partially reversed in Akt-, p38-, NF-{kappa}B- or NLRP3 inflammasome-inhibited macrophages. Importantly, macrophages respond to multiple Candida pathogens via NF-{kappa}B-dependent IL-1{beta} production, underscoring NF-{kappa}B signallings role in fungal diseases. Finally, we present the first genome-wide nucleosome map of macrophage-internalized Cg consisting 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 dictates Cg fate in host immune cells.