Institute of Experimental Medicine, 197376 Saint Petersburg, Russia.
Viruses. 2022 Feb 3;14(2):317. doi: 10.3390/v14020317.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to have a significant impact on global public health. Multiple mechanisms for SARS-CoV-2 cell entry have been described; however, the role of transferrin receptor 1 (TfR1) in SARS-CoV-2 infection has received little attention. We used ferristatin II to induce the degradation of TfR1 on the surface of Vero cells and to study the consequences of such treatment on the viability of the cells and the replication of SARS-CoV-2. We demonstrated that ferristatin II is non-toxic for Vero cells in concentrations up to 400 µM. According to confocal microscopy data, the distribution of the labeled transferrin and receptor-binding domain (RBD) of Spike protein is significantly affected by the 18h pretreatment with 100 µM ferristatin II in culture medium. The uptake of RBD protein is nearly fully inhibited by ferristatin II treatment, although this protein remains bound on the cell surface. The findings were well confirmed by the significant inhibition of the SARS-CoV-2 infection of Vero cells by ferristatin II with IC values of 27 µM (for Wuhan D614G virus) and 40 µM (for Delta virus). A significant reduction in the infectious titer of the Omicron SARS-CoV-2 variant was noted at a ferristatin II concentration as low as 6.25 µM. We hypothesize that ferristatin II blocks the TfR1-mediated SARS-CoV-2 host cell entry; however, further studies are needed to elucidate the full mechanisms of this virus inhibition, including the effect of ferristatin II on other SARS-CoV-2 receptors, such as ACE2, Neuropilin-1 and CD147. The inhibition of viral entry by targeting the receptor on the host cells, rather than the viral mutation-prone protein, is a promising COVID-19 therapeutic strategy.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）继续对全球公共卫生产生重大影响。已经描述了多种 SARS-CoV-2 进入细胞的机制；然而，转铁蛋白受体 1（TfR1）在 SARS-CoV-2 感染中的作用却很少受到关注。我们使用铁抑素 II 诱导 Vero 细胞表面 TfR1 的降解，并研究这种处理对细胞活力和 SARS-CoV-2 复制的影响。我们证明，铁抑素 II 在高达 400 µM 的浓度下对 Vero 细胞是无毒的。根据共聚焦显微镜数据，用 100 µM 铁抑素 II 在培养基中预处理 18 小时后，标记的转铁蛋白和 Spike 蛋白受体结合域（RBD）的分布受到显著影响。RBD 蛋白的摄取几乎完全被铁抑素 II 处理所抑制，尽管该蛋白仍保留在细胞表面。这些发现通过铁抑素 II 对 Vero 细胞中 SARS-CoV-2 感染的显著抑制得到了很好的证实，其 IC 值分别为 27 µM（武汉 D614G 病毒）和 40 µM（Delta 病毒）。在低至 6.25 µM 的铁抑素 II 浓度下，观察到对奥密克戎 SARS-CoV-2 变体的传染性滴度的显著降低。我们假设铁抑素 II 阻断了 TfR1 介导的 SARS-CoV-2 宿主细胞进入；然而，需要进一步的研究来阐明这种病毒抑制的全部机制，包括铁抑素 II 对 ACE2、Neuropilin-1 和 CD147 等其他 SARS-CoV-2 受体的影响。通过靶向宿主细胞上的受体而不是病毒易突变的蛋白来抑制病毒进入是一种有前途的 COVID-19 治疗策略。
