Gefitinib Results in Robust Host-Directed Immunity Against Salmonella Infection Through Proteo-Metabolomic Reprogramming
| Autor: | Zaigham Abbas Rizvi, Rajdeep Dalal, Deepak K. Rathore, Atul Kumar Johri, Yashwant Kumar, Ashutosh Tiwari, Manitosh Pandey, Bhoj Kumar, Tushar Kanti Maiti, Amit Awasthi, Srikanth Sadhu, Renu Goel, Ramendra Pati Pandey, Amit K. Pandey |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine Proteomics Salmonella THP-1 Cells EGFR Immunology gefitinib HIF-1α Salmonella infection Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Gefitinib Immunity medicine Immunology and Allergy Animals Humans Metabolomics Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cells Cultured Host factor Original Research Microbial Viability Intracellular parasite Macrophages acriflavin medicine.disease ErbB Receptors Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Host-Pathogen Interactions Salmonella Infections Cancer research mTOR host directed therapeutics lcsh:RC581-607 Intracellular medicine.drug proteo-metabolomic changes Signal Transduction |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 12 (2021) |
| ISSN: | 1664-3224 |
| Popis: | The global rise of antibiotic-resistant strains ofSalmonellahas 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 againstSalmonella. Further, using the proteome analysis ofSalmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival ofSalmonella viamTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival ofSalmonellawithin 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 bySalmonellainfection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values againstSalmonellainfection and might be useful for the treatment of other intracellular infections. |
| Databáze: | OpenAIRE |
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