Clinical Center for Bio-Therapy, Zhongshan Hospital, Fudan University (Xiamen Branch), Shanghai, China.
Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
mSphere. 2022 Aug 31;7(4):e0021122. doi: 10.1128/msphere.00211-22. Epub 2022 Jul 12.
The innate interferon (IFN) response constitutes the first line of host defense against viral infections. It has been shown that IFN-I/III treatment could effectively contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication . However, how SARS-CoV-2 survives through the innate antiviral mechanism remains to be explored. Our study uncovered that human angiotensin-converting enzyme 2 (ACE2), identified as a primary receptor for SARS-CoV-2 entry, can disturb the IFN-I signaling pathway during SARS-CoV-2 infection in human lung cells. We identified that ACE2 was significantly upregulated by SARS-CoV-2 and Sendai virus (SeV) infection, and exogenous expression of ACE2 suppressed IFN-I production in a dose-dependent manner. Mechanistically, ACE2 disrupted poly (I:C)-mediated inhibition of SARS-CoV2 replication by antagonizing IFN-I production by blocking IRF3 phosphorylation and nuclear translocation. Moreover, ACE2 quenched the IFN-mediated antiviral immune response by degrading endogenous STAT2 protein, inhibiting STAT2 phosphorylation and nuclear translocation. Interestingly, IFN-inducible short ACE2 (dACE2 or MIRb-ACE2) can also be induced by virus infection and inhibits the IFN signaling. Thus, our findings provide mechanistic insight into the distinctive role of ACE2 in promoting SARS-CoV-2 infection and enlighten us that the development of interventional strategies might be further optimized to interrupt ACE2-mediated suppression of IFN-I and its signaling pathway. Efficient antiviral immune responses against SARS-CoV-2 infection play a key role in controlling the coronavirus diseases 2019 (COVID-19) caused by this virus. Although SARS-CoV-2 has developed strategies to counteract the IFN-I signaling through the virus-derived proteins, our knowledge of how SARS-CoV-2 survives through the innate antiviral mechanism remains poor. We herein discovered the distinctive role of ACE2 as a restraining factor of the IFN-I signaling in facilitating SARS-CoV-2 infection in human lung cells. Both full-length ACE2 and truncated dACE2 can antagonize IFN-mediated antiviral response. These findings are key to understanding the counteraction between SARS-CoV-2 pathogenicity and the host antiviral defenses.
先天干扰素 (IFN) 反应构成了宿主防御病毒感染的第一道防线。已经表明 IFN-I/III 治疗可以有效地抑制严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的复制。然而，SARS-CoV-2 如何通过先天抗病毒机制存活仍有待探索。我们的研究发现，人类血管紧张素转换酶 2 (ACE2) 被鉴定为 SARS-CoV-2 进入的主要受体，它可以在 SARS-CoV-2 感染人类肺细胞期间干扰 IFN-I 信号通路。我们发现 ACE2 被 SARS-CoV-2 和仙台病毒 (SeV) 感染显著上调，外源性表达 ACE2 以剂量依赖的方式抑制 IFN-I 的产生。从机制上讲，ACE2 通过阻断 IRF3 磷酸化和核易位来拮抗 IFN-I 的产生，从而破坏了聚 (I:C) 介导的对 SARS-CoV2 复制的抑制。此外，ACE2 通过降解内源性 STAT2 蛋白、抑制 STAT2 磷酸化和核易位来抑制 IFN 介导的抗病毒免疫反应。有趣的是，病毒感染也可以诱导 IFN 诱导的短 ACE2 (dACE2 或 MIRb-ACE2)，并抑制 IFN 信号。因此，我们的研究结果为 ACE2 在促进 SARS-CoV-2 感染中的独特作用提供了机制见解，并启发我们可以进一步优化干预策略的开发，以阻断 ACE2 介导的 IFN-I 及其信号通路的抑制。针对这种病毒引起的 2019 年冠状病毒病 (COVID-19)，高效的抗病毒免疫反应在控制 SARS-CoV-2 感染中起着关键作用。尽管 SARS-CoV-2 已经通过病毒衍生蛋白开发了对抗 IFN-I 信号的策略，但我们对 SARS-CoV-2 如何通过先天抗病毒机制存活的认识仍然有限。我们在此发现了 ACE2 在促进 SARS-CoV-2 感染中的独特作用，作为 IFN-I 信号的抑制因子，在人类肺细胞中发挥作用。全长 ACE2 和截断的 dACE2 均可拮抗 IFN 介导的抗病毒反应。这些发现对于理解 SARS-CoV-2 致病性与宿主抗病毒防御之间的相互作用至关重要。
