Tryptophan metabolism reprogramming potentially contributes to the prothrombotic milieu in mice and humans with SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disturbs the coagulation balance in the blood, triggering thrombosis and contributing to organ failure. The role of prothrombotic metabolites in COVID-19-associated coagulopathy remains elusive. Leveraging K18-hACE2 mice infected with SARS-CoV-2, we observed higher levels of the tryptophan metabolite, kynurenine, than in controls. SARS-CoV-2-infected mice showed a significant upregulation of enzymes controlling kynurenine biogenesis, such as indoleamine 2,3-dioxygenase 1 (IDO-1) and tryptophan 2,3-dioxygenase in the kidney and liver, respectively, as well as changes in the enzymes involved in kynurenine catabolism, including kynurenine monooxygenase and kynurinase. Consistent with the agonistic role of these metabolites in aryl hydrocarbon receptor (AHR) signaling, AHR activation and its downstream mediator, tissue factor (TF), a highly potent procoagulant factor, was observed in endothelial cells (ECs) of lungs and kidneys of infected mice. These findings were validated in humans. Compared with controls, sera of patients with COVID-19 showed increased levels of kynurenine, kynurenic acid, anthranilic acid, and quinolinic acid. Activation of the AHR-TF axis was noted in the kidneys and lungs of patients with COVID-19, and sera from patients infected with SARS-CoV-2 showed higher IDO-1 activity than controls. Kynurenine levels in patients with COVID-19 correlated strongly with the TF-inducing activity of sera from patients infected with SARS-CoV-2 on ECs. A specific IDO-1 inhibitor or AHR inhibitor separately or in combination suppressed sera from induced TF activity in ECs from patients with COVID-19. Together, we identified IDO-1 as upregulated by SARS-CoV-2 infection, resulting in augmented kynurenine and its prothrombotic catabolites, thereby suggesting the kynurenine-AHR-TF axis as a potential new diagnostic and therapeutic target.