Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
Nat Commun. 2021 Mar 25;12(1):1876. doi: 10.1038/s41467-021-22166-4.
Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.
病毒劫持宿主细胞代谢以获取复制所需的构建块。了解 SARS-CoV-2 如何改变宿主细胞代谢可能会为 COVID-19 带来潜在的治疗方法。在这里，我们分析了 SARS-CoV-2 感染在肾上皮细胞和肺气液界面（ALI）培养物中引起的代谢变化，并表明 SARS-CoV-2 感染通过增加丙酮酸羧化酶表达增加了葡萄糖碳进入 TCA 循环。SARS-CoV-2 还减少了氧化谷氨酰胺代谢，同时保持还原羧化作用。与这些变化一致，SARS-CoV-2 感染增加了细胞系和肺 ALI 培养物中 mTORC1 的活性。最后，我们在 COVID-19 患者的肺组织中证明了 mTORC1 的激活证据，并且 mTORC1 抑制剂可降低肾上皮细胞和肺 ALI 培养物中的病毒复制。我们的研究结果表明，靶向 mTORC1 可能是 COVID-19 患者的一种可行治疗策略，但需要进一步研究以确定其在患者中的抑制机制和潜在疗效。
