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The global rise of antibiotic-resistant strains of  Salmonella  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  Salmonella . Further, using the proteome analysis of  Salmonella -infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of  Salmonella via  mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of  Salmonella  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  Salmonella  infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against  Salmonella  infection and might be useful for the treatment of other intracellular infections.

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