Coronaviruses exacerbate pulmonary fibrosis via altered tryptophan metabolism and activation of non-canonical AHR signaling 3690

Abstract Description SARS-CoV-2 infections can be very severe in patients with pre-existing lung conditions. Evidence suggests that patients with existing interstitial lung disease (ILD), e.g., pulmonary fibrosis, have a 2- to 3-fold increased risk of in-hospital mortality and increased incidence of life threating fibrotic and inflammatory exacerbations. SARS-CoV-2 lung pathophysiology has features in common with ILD, i.e., reprogramming of lung antigen presenting cells to a pro-fibrotic state and altered tryptophan (trp) metabolism. Inflammatory cytokines stimulate the production of the oxygenases IDO1/2 which metabolize trp into an endogenous immunomodulatory compound, kynurenine (kyn), a potent ligand for the aryl-hydrocarbon receptor (AHR). Non-canonical AHR signaling has been described where AHR dimerizes with inflammatory transcription factors like NFkB modulating expression of immune genes including cytokines and chemokines from professional antigen presenting cells, i.e., dendritic cells (DCs) and macrophages. Using a murine model of bleomycin pulmonary fibrosis, we demonstrate that coronavirus superinfection exacerbates fibrosis and alters trp metabolism. Mice with a genetic ablation of canonical AHR signaling in CD11c+ DCs exhibit decreased antiviral IFNγ signaling and increased IL-6 / IL-17 responses leading to tissue injury and fibroproliferation. We conclude that coronaviruses exacerbate fibrosis via augmentation of tryptophan metabolism and activation of non-canonical AHR signaling. Funding Sources Pulmonary Fibrosis Foundation Fellowship, NIH R35HL144481 Topic Categories Mucosal and Regional Immunology (MUC)