The emergence of a series of SARS-CoV-2 variants has necessitated the search for broad-spectrum antiviral targets. The aryl hydrocarbon receptor (AhR) senses tryptophan metabolites and is an immune regulator. However, the role of AhR in SARS-CoV-2 infection and whether AhR can be used as the target of antiviral therapy against SARS-CoV-2 and its variants are yet unclear. Here, we show that infection with SARS-CoV-2 activates AhR signaling and facilitates viral replication by interfering with IFN-I–driven antiviral immunity and up-regulating ACE2 receptor expression. The pharmacological AhR blockade or AhR knockout reduces SARS-CoV-2 and its variants’ replication in vitro. Drug targeting of AhR with AhR antagonists markedly reduced SARS-CoV-2 and its variants’ replication in vivo and ameliorated lung inflammation caused by SARS-CoV-2 infection in hamsters. Overall, AhR was a SARS-CoV-2 proviral host factor and a candidate host-directed broad-spectrum target for antiviral therapy against SARS-CoV-2 and its variants, including Delta and Omicron, and potentially other variants in the future.

中文翻译：

---

芳基烃受体是前病毒宿主因子和候选泛 SARS-CoV-2 治疗靶点

一系列 SARS-CoV-2 变种的出现使得寻找广谱抗病毒靶点成为必要。芳烃受体 (AhR) 感知色氨酸代谢物，是一种免疫调节剂。然而，AhR 在 SARS-CoV-2 感染中的作用以及 AhR 是否可以作为针对 SARS-CoV-2 及其变种的抗病毒治疗的靶点尚不清楚。在这里，我们发现 SARS-CoV-2 感染会激活 AhR 信号传导，并通过干扰 IFN-I 驱动的抗病毒免疫和上调 ACE2 受体表达来促进病毒复制。药理学 AhR 阻断或 AhR 敲除可减少 SARS-CoV-2 及其变体的体外复制。使用 AhR 拮抗剂靶向 AhR 的药物可显着减少 SARS-CoV-2 及其变体在体内的复制，并改善仓鼠中由 SARS-CoV-2 感染引起的肺部炎症。总体而言，AhR 是 SARS-CoV-2 前病毒宿主因子，也是针对 SARS-CoV-2 及其变体（包括 Delta 和 Omicron，以及未来可能的其他变体）抗病毒治疗的候选宿主导向广谱靶点。