AHR signaling is induced by infection with coronaviruses

Federico Giovannoni,Zhaorong Li,Andrea V Dugour,Ana Paletta,Juan M Figueroa,Andrea A Barquero,Ana Ceballos,Karen L Mossman,Mercedes Elizalde,Francisco J Quintana,María E Dávola,Federico Remes-Lenicov,Cybele C Garcia,Ali A Ashkar

doi:10.1038/s41467-021-25412-x

Abstract

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy.

Highlights

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure
Similar findings describing aryl hydrocarbon receptor (AHR) activation were recently reported in the context of infection by the murine coronavirus (M-CoV) in vitro and in vivo[22] (Table 1)
In-depth analyses of RNA-Seq data from M-CoV-infected macrophages detected the upregulation of AHR and AHR

Summary

Introduction

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. An AHR antagonist optimized for human use boosted antiviral immunity, interfered with viral replication and ameliorated multiple aspects of Zika congenital syndrome including microcephaly in animal models[18], identifying AHR as a candidate target for therapeutic intervention. Based on these findings and the urgent need for SARS-CoV-2 therapy, we investigated the potential role of AHR in CoV infection. Pharmacologic AHR blockade reduces CoVs replication in vitro, identifying AHR as a candidate target for antiviral therapy

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Conclusion