Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a ‘highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是一种“高度传播的呼吸道病原体，可导致严重的多器官损伤”。然而，有关 SARS-CoV-2 诱导的细胞改变的知识有限。在这项研究中，我们报告说，SARS-CoV-2 在病毒感染的早期阶段异常升高线粒体生物能并激活 EGFR 介导的细胞生存信号级联。 SARS-CoV-2 通过 SARS-CoV-2 RNA 核衣壳簇引起线粒体跨膜电位增加，从而异常促进线粒体伸长和 OXPHOS 过程，随后增强 ATP 产生。此外，SARS-CoV-2 激活 EGFR 信号级联，随后诱导线粒体 EGFR 运输，导致异常 OXPHOS 过程和病毒传播。已批准的 EGFR 抑制剂可显着减少 SARS-CoV-2 的传播，其中凡德他尼的抗病毒功效最高。用凡德他尼治疗 SARS-CoV-2 感染的细胞可减少 SARS-CoV-2 诱导的 EGFR 向线粒体的运输，并恢复 SARS-CoV-2 诱导的 OXPHOS 过程和 ATP 生成的异常升高，从而减少 SARS -CoV-2 传播。此外，对感染 SARS-CoV-2 的 hACE2 转基因小鼠口服凡德他尼可减少 SARS-CoV-2 在肺组织中的传播，并减轻 SARS-CoV-2 诱导的肺部炎症。在体外细胞培养实验中，Vandetanib 还对各种令人关注的 SARS-CoV-2 变体（包括 α、β、δ 和 omicron）表现出有效的抗病毒活性。总而言之，我们的研究结果为病毒感染早期阶段 SARS-CoV-2 诱导的线粒体动力学和 EGFR 运输的改变及其在 SARS-CoV-2 强劲传播中的作用提供了新的见解，表明 EGFR 是一个有吸引力的宿主靶点抗击新冠肺炎 (COVID-19)。