Respiratory syncytial virus downregulates the airway aryl hydrocarbon receptor pathway: implication for the development of a novel therapeutic target

Despite recent advances in preventative options, respiratory syncytial virus (RSV) infection is still a major cause of hospitalizations of young children and older adults, with no specific treatment available. The aryl hydrocarbon receptor (AHR) is a transcription factor originally identified as the mediator of the toxic effects of environmental pollutants but later shown to be also activated by dietary and endogenous ligands. AHR is involved in various physiological and pathophysiological processes, including host response to infections. Many clinically relevant viruses have been shown to induce AHR activation as a strategy to evade antiviral immunity and promote replication, including the severe acute respiratory syndrome coronavirus 2. It is currently not known whether RSV infection affects the AHR pathway. In this study, we investigated the effects of RSV infection on the AHR signaling pathway by using in vitro and in vivo experimental models. We found that RSV infection led to inhibition of the AHR-dependent gene transcription in human airway epithelial cells and in the lungs of mice. Human lung epithelial cells lacking AHR showed upregulation of genes related to inflammatory response and airway remodeling, as well as increased production of proinflammatory mediators in response to RSV infection. In contrast, administration of the dietary AHR ligand indole-3-carbinol to mice led to beneficial effects on RSV-associated disease, including anti-inflammatory and antiviral activity. Collectively, our results suggest that the AHR has a protective role during RSV infection, and therefore its modulation can be explored as a novel therapeutic target for RSV-induced disease.<b>NEW & NOTEWORTHY</b> Our study reveals that respiratory syncytial virus (RSV) downregulates the aryl hydrocarbon receptor (AHR) pathway in human airway epithelial cells and mouse lungs. Loss of the AHR in lung cells led to an exacerbated inflammatory response, and the AHR ligand indole-3-carbinol (I3C) showed in vivo anti-inflammatory and antiviral activity during RSV infection. Our data suggest that AHR plays a protective role during RSV infection and can be explored as a novel therapeutic target.