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

Abstract

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