ARYL HYDROCARBON RECEPTOR IS ACTIVATED BY INFECTION WITH CANINE CORONAVIRUS

Objectives: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that interacts with endogenous and exogenous substrates including bilirubin, biliverdin, tryptophan metabolites, environmental pollutants, and microbial metabolites. The activation of AhR by these substances induces the control of the expression of target genes such as AhR repressor, detoxifying monooxygenases, and cytokines. Recent advances reveal that AhR signaling regulates aspects of the intrinsic, innate and adaptive immune response to diverse microorganisms. AhR is involved in the host response to Coronaviruses (CoVs) (i.e. MCoV, SARS-CoV-2, HCoV 229E) infection. Particularly, AhR agonists decrease the expression of ACE2 via AhR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells. Here, we report that AhR is activated by infection with genotype II of canine coronavirus (CCoV-II), an alphacoronavirus. Moreover, pharmacological inhibition of AhR suppresses in vitro replication of CCoV. Methods used: Infection of CCoV (378/strain) in canine fibrosarcoma (A72) cell line was performed in the presence of CH223191, an AhR antagonist. Bioscreen, immunofluorescence, and virus yield analyses were carried out. Results: Following CCoV infection, we found a considerable stimulation of AhR, a receptor expressed in A72 cells. At non-toxic concentration, CH223191 noticeably reduced cell death signs and increased cell viability. Furthermore, the AhR antagonist induced a meaningful decline in virus yield, accompanied by the inhibition of the expression of viral nuclear protein. Conclusions: Taken together, our findings show that infection with CCoV activates AhR. Furthermore, pharmacologic AhR inhibition reduces CoVs replication in vitro, identifying AhR as a possible candidate target for antiviral therapy.