Dysregulation of Host Histone Acetylation by <i>Acinetobacter baumannii</i>: A Novel Mechanism for Autophagy Inhibition and Bacterial Survival

Widespread antimicrobial resistance in <i>Acinetobacter baumannii</i> necessitates the development of new treatment approaches. Host-directed therapies have emerged as a promising strategy to combat these multidrug-resistant bacteria. Many studies investigated whether bacteria evade the immune response by modulating host histone proteins to persist intracellularly. However, studies focusing on changes in histone protein modifications due to <i>A. baumannii</i> are lacking. In this investigation, we explored the role of <i>A. baumannii</i> in altering host histone proteins for its survival. Our findings revealed decreased acetylation levels of histone proteins (H3K9ac, H3K27ac, and H2AK5ac) and upregulation of histone deacetylases (HDACs) in human cell lines THP-1 and PBMC infected with <i>A. baumannii</i> strains compared to uninfected cells. Since H3K9ac is known to regulate the transcription of autophagy-related genes, we used vorinostat (SAHA), a pan-HDAC inhibitor, to restore H3K9ac levels during <i>A. baumannii</i> infection. Vorinostat successfully induced autophagy by increasing ATG9B, ATG16L1, ATG5, and ATG4C expression and decreasing the accumulation of LC3-II/I. Additionally, we observed that SAHA promotes the fusion of autophagosomes and lysosomes mediated by SNARE proteins, enhancing the intracellular clearance of <i>A. baumannii</i>. This study highlights the epigenetic modulations induced by <i>A. baumannii</i> and suggests targeting the host histone acetylation machinery as a potential alternative treatment strategy to combat multidrug-resistant isolates.