HDAC-driven autophagy repression aids macrophage immune evasion bystrains displaying classical, MDR, and hypervirulent phenotypes
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Summary The global emergence of multidrug-resistant (MDR) and hypervirulent (hvKp)strains poses a major clinical challenge. Here, we compared representative classical (cKp), MDR-Kp, and hvKp isolates to define host epigenetic responses during infection. At 24 h post-infection (hpi), infection with all three strains induced HDAC2 upregulation and H3K18 deacetylation, with chromatin immunoprecipitation (ChIP) analysis revealing HDAC2 enrichment at thepromoter, linking epigenetic remodeling to autophagy suppression. Functionally, cKp and MDR-Kp isolates promoted M1-like macrophage polarization, whereas hvKp isolate induced an immunosuppressive M2-like phenotype associated with enhanced intracellular bacterial survival and elevatedexpression.gene knockdown reduced intracellular bacterial survival, while pharmacological inhibition using CI994 and SAHA restored autophagy, normalized cytokine responses, enhanced bacterial clearance, and reversed M2-like polarization induced by hvKp-isolate. Collectively, these findings identify HDAC-mediated epigenetic reprogramming as a central mechanism underlying immune evasion duringinfection and support HDAC inhibition as a potential host-directed therapeutic strategy. abs0010 Graphical abstract http://www.w3.org/1999/xlink float portrait ga1.jpg undfig1 anchor portrait graphical abs0015 Highlights • Representative cKp, MDR-Kp, and hvKp isolates exhibit distinct host responses u0010 • HDAC2-mediated autophagy repression and intracellular surviv
Abstract
Summary The global emergence of multidrug-resistant (MDR) and hypervirulent (hvKp)strains poses a major clinical challenge. Here, we compared representative classical (cKp), MDR-Kp, and hvKp isolates to define host epigenetic responses during infection. At 24 h post-infection (hpi), infection with all three strains induced HDAC2 upregulation and H3K18 deacetylation, with chromatin immunoprecipitation (ChIP) analysis revealing HDAC2 enrichment at thepromoter, linking epigenetic remodeling to autophagy suppression. Functionally, cKp and MDR-Kp isolates promoted M1-like macrophage polarization, whereas hvKp isolate induced an immunosuppressive M2-like phenotype associated with enhanced intracellular bacterial survival and elevatedexpression.gene knockdown reduced intracellular bacterial survival, while pharmacological inhibition using CI994 and SAHA restored autophagy, normalized cytokine responses, enhanced bacterial clearance, and reversed M2-like polarization induced by hvKp-isolate. Collectively, these findings identify HDAC-mediated epigenetic reprogramming as a central mechanism underlying immune evasion duringinfection and support HDAC inhibition as a potential host-directed therapeutic strategy. abs0010 Graphical abstract http://www.w3.org/1999/xlink float portrait ga1.jpg undfig1 anchor portrait graphical abs0015 Highlights • Representative cKp, MDR-Kp, and hvKp isolates exhibit distinct host responses u0010 • HDAC2-mediated autophagy repression and intracellular survival u0015 • HvKp isolates promote immunosuppressive M2-like macrophage polarization u0020 • HDAC inhibition restores host defense and enhances intracellular bacterial clearance u0025 simple ulist0010 author-highlights abs0020 Microbiome; Metabolomics; Transcriptomics teaser abs0025