Kynurenine-3-monooxygenase (KMO) broadly inhibits viral infections via triggering NMDAR/Ca2+ influx and CaMKII/ IRF3-mediated IFN-beta production

Author summaryThe outbreaks of emerging infectious diseases have become a severe challenge worldwide, and therefore it is a public health priority to explore novel broad-spectrum antiviral agents with various mechanisms. This study reported that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme during tryptophan metabolism, showed promise as a novel broad-spectrum antiviral factor against emerging pathogenic viruses. We further found that quinolinic acid (QUIN), an enzymatic product of KMO, could also act as a novel broad-spectrum antiviral agent. We then systematically studied the underlying mechanisms and broadly antiviral function of KMO and QUIN in vitro and in vivo. Our data highlight the importance of exploring novel antiviral targets from the key enzymes and their metabolites in tryptophan metabolism. Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo(-/-) mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses.