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 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.

Differential host circRNA expression profiles in human lung epithelial cells infected with SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging and highly pathogenic coronavirus that causes coronavirus disease (COVID-19), and might even lead to death. Circular RNAs (circRNAs), a new type of RNAs, are implicated in viral pathogenesis and host immune responses. However, their dynamic expression patterns and functions during SARS-CoV-2 infection remain to be unclear. We herein performed genome-wide dynamic analysis of circRNAs in human lung epithelial cells infected with SARS-CoV-2 at four time points. A total of 6118 circRNAs were identified at different genomic locations, including 5641 known and 477 novel circRNAs. Notably, a total of 42 circRNAs were significantly dysregulated, wherein 17 were up-regulated and 25 were down-regulated following infection at multiple phases. The gene ontology and KEGG enrichment analyses revealed that the parental genes of circRNAs were mainly involved in immune and inflammatory responses. Further, the RNA binding protein (RBP) prediction analysis indicated that the dysregulated circRNAs could regulate mRNA stability, immunity, cell death by binding specific proteins. Additionally, the circRNA-miRNA-gene network analysis showed that circRNAs indirectly regulated gene expression by absorbing their targeted miRNAs. Collectively, these results shed light on the roles of circRNAs in virus-host interactions, facilitating future studies on SARS-CoV-2 infection and pathogenesis.