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

Abstract

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, compared to controls. SARS-CoV-2 infected mice showed a significant upregulation of enzymes controlling Kynurenine biogenesis, such as indoleamine 2,3-dioxygenase (IDO-1) and tryptophan 2,3-dioxygenase levels in kidneys 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, where compared to controls, sera of COVID-19 patients 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 COVID-19 patients, and COVID-19 sera showed higher IDO-1 activity than controls. Levels of Kyn in COVID-19 patients correlated strongly with the TF-inducing activity of COVID-19 sera on ECs. A specific IDO-1 inhibitor or AHR inhibitor separately or in combination suppressed COVID-19 sera-induced TF activity in ECs. Together, we identified IDO-1 as upregulated by SARS-CoV-2 infection, resulting in augmented Kyn and its prothrombotic catabolites, thereby suggesting the Kyn-AHR-TF axis as possibly a new diagnostic and/or therapeutic target. Key pointsO_LISARS-CoV-2-infection upregulates kynurenine biogenesis in the liver and diminishes kynurenine catabolism in the lungs and kidneys. C_LIO_LIAn increase in kynurenine stimulates the AHR-TF axis in the microvasculature in COVID-19 patients, which is inhibited by pharmacological manipulation. C_LI