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

Jin Zhao,Minchao Li,Genhong Cheng,Zirong Han,Caijun Sun,Yajie Liu,Ruiting Li,Jiaoshan Chen,Yanjun Li,Ling Chen,Yuelong Shu,Congcong Wang,Junjian Wang,Jun Zhao

doi:10.1371/journal.ppat.1010366

Abstract

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.

Highlights

Frequent outbreaks of emerging infectious diseases, including SARS-CoV-2, avian influenza H5N8, Zika virus (ZIKV), and Ebola virus (EBOV), have become a serious threat to global public health [1–6], and an urgent need in clinical practice is to explore the efficient and broad-spectrum antiviral agents against various viral infections
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 identified for the first time that KMO and its enzymatic product quinolinic acid (QUIN) could act as a novel broad-spectrum antiviral factor against emerging pathogenic viruses

Summary

Introduction

Frequent outbreaks of emerging infectious diseases, including SARS-CoV-2, avian influenza H5N8, Zika virus (ZIKV), and Ebola virus (EBOV), have become a serious threat to global public health [1–6], and an urgent need in clinical practice is to explore the efficient and broad-spectrum antiviral agents against various viral infections. Increasing studies indicated the potential cross-talk between the immune responses to viral infections and the cellular metabolism in host cells [7,8]. In-depth investigation of the relationship between immune response and cellular metabolism may reveal novel targets to develop antiviral agents. Kynurenine biosynthesis in macrophages was increased in response to stimulation by the herpes simplex virus (HSV) as well as bacterial lipopolysaccharides [21]. Another metabolite of KP-picolinic acid effectively induced the apoptosis of human immunodeficiency virus (HIV) or HSV-infected cells [22]. It is important to investigate further the host-pathogen interactions through the KP metabolites to explore the novel anti-infection targets

Methods

Discussion

Conclusion