Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is a recently emerged respiratory coronavirus that has infected >23 million people worldwide with >800,000 deaths. Few COVID-19 therapeutics are available, and the basis for severe infections is poorly understood. Here, we investigated properties of type I (β), II (γ), and III (λ1) interferons (IFNs), potent immune cytokines that are normally produced during infection and that upregulate IFN-stimulated gene (ISG) effectors to limit virus replication. IFNs are already in clinical trials to treat COVID-19. However, recent studies highlight the potential for IFNs to enhance expression of host angiotensin-converting enzyme 2 (ACE2), suggesting that IFN therapy or natural coinfections could exacerbate COVID-19 by upregulating this critical virus entry receptor. Using a cell line model, we found that beta interferon (IFN-β) strongly upregulated expression of canonical antiviral ISGs, as well as ACE2 at the mRNA and cell surface protein levels. Strikingly, IFN-λ1 upregulated antiviral ISGs, but ACE2 mRNA was only marginally elevated and did not lead to detectably increased ACE2 protein at the cell surface. IFN-γ induced the weakest ISG response but clearly enhanced surface expression of ACE2. Importantly, all IFN types inhibited SARS-CoV-2 replication in a dose-dependent manner, and IFN-β and IFN-λ1 exhibited potent antiviral activity in primary human bronchial epithelial cells. Our data imply that type-specific mechanisms or kinetics shape IFN-enhanced ACE2 transcript and cell surface levels but that the antiviral action of IFNs against SARS-CoV-2 counterbalances any proviral effects of ACE2 induction. These insights should aid in evaluating the benefits of specific IFNs, particularly IFN-λ, as repurposed therapeutics.

中文翻译：

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I，II和III型干扰素的抗病毒活性可抵消ACE2的诱导能力并限制SARS-CoV-2。

严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）是2019年冠状病毒病的病因（COVID-19），是最近出现的呼吸道冠状病毒，已感染全球2300万人，死亡> 80万人。很少有COVID-19治疗剂可用，并且对严重感染的基础了解甚少。在这里，我们研究了I型（β），II型（γ）和III型（λ1）干扰素（IFN）的特性，这些干扰素是在感染过程中通常产生的有效免疫细胞因子，它们会上调IFN刺激基因（ISG）效应子以限制病毒复制。干扰素已经在治疗COVID-19的临床试验中。但是，最近的研究强调了IFN增强宿主血管紧张素转化酶2（ACE2）表达的潜力，提示IFN治疗或自然共感染可通过上调该关键病毒进入受体而加剧COVID-19。使用细胞系模型，我们发现β干扰素（IFN-β）在mRNA和细胞表面蛋白水平上强烈上调了典型抗病毒ISG以及ACE2的表达。令人惊讶的是，IFN-λ1上调了抗病毒ISG，但ACE2 mRNA仅略微升高，并没有导致细胞表面ACE2蛋白的可检测地增加。IFN-γ诱导了最弱的ISG反应，但明显增强了ACE2的表面表达。重要的是，所有类型的IFN都以剂量依赖的方式抑制SARS-CoV-2复制，并且IFN-β和IFN-λ1在原代人支气管上皮细胞中表现出强大的抗病毒活性。我们的数据暗示类型特异性机制或动力学影响IFN增强的ACE2转录和细胞表面水平，但IFNs对SARS-CoV-2的抗病毒作用抵消了ACE2诱导的任何前病毒作用。这些见解应有助于评估特定IFN（特别是IFN-λ）作为再利用疗法的益处。