HDAC-driven autophagy repression aids macrophage immune evasion by K. pneumoniae strains displaying classical, MDR, and hypervirulent phenotypes.

The global emergence of multidrug-resistant (MDR) and hypervirulent (hvKp) Klebsiella pneumoniae 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 the ATG5 promoter, 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 elevated IL-10 expression. HDAC1/2 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 during K. pneumoniae infection and support HDAC inhibition as a potential host-directed therapeutic strategy.