Regulation of kynurenine biosynthesis during influenza virus infection. (14th December 2016)

• Record Type: Journal Article
• Authors: Gaelings, Lana; Söderholm, Sandra; Bugai, Andrii; Fu, Yu; Nandania, Jatin; Schepens, Bert; Lorey, Martina B.; Tynell, Janne; Vande Ginste, Liesbeth; Le Goffic, Ronan; Miller, Matthew S.; Kuisma, Marika; Marjomäki, Varpu; De Brabander, Jef; Matikainen, Sampsa; Nyman, Tuula A.; Bamford, Dennis H.; Saelens, Xavier; Julkunen, Ilkka; Paavilainen, Henrik; Hukkanen, Veijo; Velagapudi, Vidya; Kainov, Denis E.
• Is Part Of: FEBS journal. Volume 284:Number 2(2017)
• Page Start: 222
• Page End: 236
• Publication Date: 2016-12-14
• Subjects: host–pathogen interaction -- indoleamine‐pyrrole 2, 3‐dioxygenase (IDO1) -- influenza virus -- innate immunity -- interferon; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13966
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Influenza A virus (IAV) infections inflict a major economic and health burden worldwide; however, effective antiviral treatments are still lacking. Kainov and colleagues now report a potential new therapeutic angle for such drugs. They demonstrate that IAV infection‐induced interferon expression promotes production of the key kynurenine biosynthetic pathway enzyme indoleamine‐2, 3‐dioxygenase (IDO1) that can suppress T‐cell responses. Indeed, infection with IAV, IBV or herpes simplex virus 1/2 also induced kynurenine production in macrophages. IDO inhibitors are in clinical trials as anti‐cancer agents, and this study suggests that they might be beneficial in treating IAV infection as well. Abstract : Influenza A viruses (IAVs) remain serious threats to public health because of the shortage of effective means of control. Developing more effective virus control modalities requires better understanding of virus–host interactions. It has previously been shown that IAV induces the production of kynurenine, which suppresses T‐cell responses, enhances pain hypersensitivity and disturbs behaviour in infected animals. However, the regulation of kynurenine biosynthesis during IAV infection remains elusive. Here we showed that IAV infection induced expression of interferons ( IFNs ), which upregulated production of indoleamine‐2, 3‐dioxygenase (IDO1), which catalysed the kynurenine biosynthesis. Furthermore, IAV attenuated the IDO1 expression and the production of kynurenine through its NS1 protein. Interestingly, inhibition of viral replication prior to IFN induction limited IDO1 expression, while inhibition after did not. Finally, we showed that kynurenine biosynthesis was activated in macrophages in response to other stimuli, such as influenza B virus, herpes simplex virus 1 and 2 as well as bacterial lipopolysaccharides. Thus, the tight regulation of the kynurenine biosynthesis by host cell and, perhaps, pathogen might be a basic signature of a wide range of host–pathogen interactions, which should be taken into account during development of novel antiviral and antibacterial drugs.