Gene-Specific Rewiring of Type I Interferon Responses by Staphylococcus aureus 2329926

Abstract Introduction Staphylococcus aureus is a Gram-positive pathogen that is a major cause of soft tissue and bloodstream infections in humans. Previous studies have shown that S. aureus triggers myeloid cell-driven innate immune activation including inflammatory signaling and type I interferon (IFN) responses; however, the role type I IFNs remains controversial. Methods Primary human CD14+ monocytes were purified from PBMCs of healthy donors using anti-CD14 magnetic beads. Monocytes were infected with various doses of S. aureus and harvested for RT-qPCR, Western blotting, and integrated bulk RNA sequencing, ATAC-seq and CUT&RUN. Results We observed a dose-dependent dichotomous regulation of the IFN response, which was induced by low doses and suppressed at high doses of S. aureus. Only a subset of interferon-stimulated genes (ISGs) was induced despite intact IFNβ production following S. aureus infection. Intriguingly, S. aureus selectively abrogated the activation and nuclear translocation of STAT1, while activation and nuclear translocation of the other ISGF3 components STAT2 and IRF9 were preserved. Furthermore, RNA profiling revealed a disparate regulation of gene expression, with a distinct subset of genes exhibiting significantly enhanced expression upon combined S. aureus and IFNβ treatment. Epigenomic profiling showed a complete repression of chromatin accessibility as well as STAT1 binding at a subset of ISG loci upon S. aureus infection, whereas another subset of ISGs displayed increased chromatin accessibility and transcriptional activation upon infection. Conclusion Our findings suggest that S. aureus alters activation of the canonical type I IFN-mediated Jak-STAT pathway through suppression of STAT1 activation and altering chromatin remodeling . This change in signaling is associated with gene-specific reprogramming of the type I IFN response by S. aureus that may alter the host response to this pathogen in a context-dependent manner and contribute to difficulty in clearing S. aureus infection. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)