School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.
mBio. 2024 Apr 10;15(4):e0039224. doi: 10.1128/mbio.00392-24. Epub 2024 Feb 27.
SARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search of effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) has been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped CsA-suppressed nuclear factor of activated T cells (NFAT) signaling to drive the expression of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 (RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic antiviral effects when used in combination with nirmatrelvir. Our study delineated the molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the anti-SARS-CoV-2 action of calcineurin inhibitors.
Cyclosporine A (CsA), commonly used to inhibit immune responses, is also known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in combination with Paxlovid.
导致 COVID-19 的 SARS-CoV-2 已被深入研究，以寻找有效的抗病毒治疗方法。免疫抑制剂环孢素 A（CsA）被认为是一种泛冠状病毒抑制剂，但它的潜在机制在很大程度上仍不清楚。在这里，我们发现，SARS-CoV-2 的非结构蛋白 1（Nsp1）篡夺了 CsA 抑制的活化 T 细胞核因子（NFAT）信号通路，以驱动细胞 DEAD 框解旋酶 5（DDX5）的表达，从而促进病毒复制。Nsp1 与钙调神经磷酸酶 A（CnA）相互作用，取代 CnA 的钙调神经磷酸酶调节蛋白 3（RCAN3）以激活 NFAT。通过使用缺乏 Nsp1 的突变病毒也验证了 NFAT 激活对 SARS-CoV-2 复制的影响。钙调神经磷酸酶抑制剂，如 CsA 和 VIVIT，抑制 SARS-CoV-2 复制，并与奈玛特韦联合使用时表现出协同抗病毒作用。我们的研究描绘了 CsA 介导的抑制 SARS-CoV-2 复制的分子机制和钙调神经磷酸酶抑制剂的抗 SARS-CoV-2 作用。
环孢素 A（CsA），通常用于抑制免疫反应，也被认为具有抗 SARS-CoV-2 活性，但它的作用方式仍不清楚。在这里，我们提供了一个模型来解释 CsA 如何通过三种关键蛋白来拮抗 SARS-CoV-2：DDX5、NFAT1 和 Nsp1。DDX5 是 SARS-CoV-2 复制的细胞促进剂，NFAT1 控制 DDX5 的产生。Nsp1 是一种不存在于成熟病毒颗粒中的病毒蛋白，能够激活 NFAT1 和 DDX5 的功能。CsA 和类似药物通过抑制 Nsp1、NFAT1 和 DDX5 来发挥其抗 SARS-CoV-2 活性，无论是单独使用还是与帕罗韦德联合使用。
