SWI/SNF complex-mediated chromatin remodeling in Candida glabrata promotes immune evasion

Immune evasion is critical for fungal virulence. However, how the human opportunistic pathogen Candida glabrata (Cg) accomplishes this is unknown. Here, we present the first genome-wide nucleosome map of the macrophage-internalized Cg consisting of ∼12,000 dynamic and 70,000 total nucleosomes. We demonstrate that CgSnf2 (SWI/SNF chromatin remodeling complex-ATPase subunit)-mediated chromatin reorganization in macrophage-internalized Cg upregulates and downregulates the immunosuppressive seven-gene mannosyltransferase-cluster (CgMT-C) and immunostimulatory cell surface adhesin-encoding EPA1 gene, respectively. Consistently, EPA1 overexpression and CgMT-C deletion elevated IL-1β (pro-inflammatory cytokine) production and diminished Cg proliferation in macrophages. Further, Cgsnf2Δ had higher Epa1 surface expression, and evoked increased IL-1β secretion, and was killed in macrophages. Akt-, p38-, NF-κB- or NLRP3 inflammasome-inhibition partially reversed increased IL-1β secretion in Cgsnf2Δ-infected macrophages. Importantly, macrophages responded to multiple Candida pathogens via NF-κB-dependent IL-1β production, underscoring NF-κB signaling's role in fungal diseases. Altogether, our findings directly link the nucleosome positioning-based chromatin remodeling to fungal immunomodulatory molecule expression.