Aryl hydrocarbon receptor is a proviral host factor and a candidate pan-SARS-CoV-2 therapeutic target

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 ac-tivates 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 ham-sters. 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.

Automated summary

The activation of the AhR signaling pathway during SARS-CoV-2 infection interferes with antiviral immune responses and enhances viral replication by upregulating ACE2 receptor expression. Pharmacological inhibition or genetic knockout of AhR reduces the replication of SARS-CoV-2 and its variants in vitro and in vivo, and alleviates lung inflammation. AhR is therefore a pro-viral host factor and a potential broad-spectrum target for antiviral therapy against SARS-CoV-2 and its variants.