[PDF] SWI/SNF complex-mediated chromatin remodelling in Candida glabrata is vital for immune evasion-论文阅读讨论-ReadPaper

摘要

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 signalling's 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.

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