Infection and Immunobiology, Translational Health Science and Technology Institute, Faridabad, India.
Department of Biotechnology and Biochemistry, SRM University, Sonepat, India.
Front Immunol. 2021 Mar 31;12:648710. doi: 10.3389/fimmu.2021.648710. eCollection 2021.
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.
全球抗生素耐药菌株的出现使得开发替代治疗策略变得必要。最近的研究表明，靶向宿主因素可能为治疗细胞内病原体提供一种替代方法。宿主导向治疗（HDT）调节宿主细胞因子，这些因子对于支持细胞内病原体的复制至关重要。在本研究中，我们鉴定出吉非替尼是一种针对的潜在宿主导向治疗药物。此外，通过对感染巨噬细胞的蛋白质组分析，我们鉴定出 EGFR，一种宿主因子，促进 mTOR-HIF-1α 轴的细胞内生存。阻断 EGFR、mTOR 或 HIF-1α 可抑制细胞内巨噬细胞和小鼠中 的存活。全局蛋白质组代谢组学分析表明，宿主因子上调，主要与 ATP 周转、糖酵解、尿素循环相关，这些因子最终在感染时激活 EGFR-HIF1α 信号。重要的是，EGFR 和 HIF1α 的抑制恢复了 感染引起的蛋白质组和代谢组学变化。总之，这项研究鉴定出吉非替尼是一种宿主导向药物，具有针对 感染的潜在转化价值，可能对治疗其他细胞内感染有用。
