Kynurenine-3-monooxygenase (KMO) broadly inhibits viral infections via triggering NMDAR/Ca2+ influx and CaMKII/ IRF3-mediated IFN-β production.
Jin ZhaoJiaoshan ChenCongcong WangYajie LiuMinchao LiYanjun LiRuiting LiZirong HanJunjian WangLing ChenYuelong ShuGenhong ChengCaijun SunPublished in: PLoS pathogens (2022)
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.
Keyphrases
- dendritic cells
- protein kinase
- sars cov
- immune response
- hydrogen peroxide
- high fat diet induced
- drug induced
- papillary thyroid
- multiple sclerosis
- transcription factor
- signaling pathway
- high glucose
- small molecule
- diabetic rats
- squamous cell carcinoma
- type diabetes
- nitric oxide
- metabolic syndrome
- depressive symptoms
- combination therapy
- binding protein
- sleep quality