SAHA Counteracts Host Response Alterations Driven by Carbapenem-Resistant Acinetobacter baumannii: A Transcriptomic Deep Dive

Bacterial pathogens remodel the host epigenetic programming to surpass host defence mechanisms for their benefit. The studies on carbepenem-resistant A. baumannii (CRAB) circumvention of host defence mechanisms, especially the role of host HDAC inhibition on its survival, have not been investigated. In the current study, we employed comparative transcriptomics to investigate changes in the key host pathways and biological processes during A. baumannii infection and after its treatment with SAHA (pan HDAC inhibitor). Our primary findings highlighted that A. baumannii establishes an immunosuppressive condition by regulating both TNFα and IL10 signaling pathways for its persistence. We found overexpression of the ACOD1 gene during infection, which is reportedly involved in the progression of sepsis. In the presence of SAHA, the mRNA expression of IDO1, ACOD1, IL10RA, IL10, TNFα, IL6, IFNB1, and CCL3L3 genes was found to be decreased during AB infection. Further, we observed that SAHA treatment induces autophagy by regulating the genes involved in phagosome maturation and antigen processing through tubulin binding and MHC class II proteins, respectively. Moreover, SAHA facilitates the autophagosome-lysosome fusion process through upregulation of important autophagy-related and SNARE proteins, causing bacterial clearance. Therefore, our findings provide a comprehensive insight into the A. baumannii immune evasion mechanisms and the potential of SAHA as a host-directed therapeutic against A. baumannii infection.