Gefitinib Results in Robust Host-Directed Immunity Against Infection Through Proteo-Metabolomic Reprogramming.

The global rise of antibiotic-resistant strains of has necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against . Further, using the proteome analysis of -infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against infection and might be useful for the treatment of other intracellular infections.