title: Regulation of kynurenine biosynthesis during influenza virus infection.
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.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Lana
authors.initials: L
authors.lastname: Gaelings
authors.affiliation: Institute of Biotechnology (BI), University of Helsinki, Finland.|Finnish Institute of Occupational Health (TTL), Helsinki, Finland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Söderholm
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Finland.
authors.forename: Andrii
authors.initials: A
authors.lastname: Bugai
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Jatin
authors.initials: J
authors.lastname: Nandania
authors.affiliation: Medical Biotechnology Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Schepens
authors.affiliation: Finnish Institute of Occupational Health (TTL), Helsinki, Finland.
authors.forename: Martina B
authors.initials: MB
authors.lastname: Lorey
authors.affiliation: National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Tynell
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Finland.|Medical Biotechnology Center, VIB, Ghent, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Vande Ginste
authors.affiliation: Centre de Recherche de Jouy-en-Josas UR0892 Unité VIM - Virologie & Immunologie Moléculaires, Domaine de Vilvert, Jouy-en-Josas, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Le Goffic
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Institute for Infectious Diseases Research, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Miller
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Kuisma
authors.affiliation: Department of Biological and Environmental Science, Nanoscience Center, University of Jyväskylä, Finland.
authors.forename: Varpu
authors.initials: V
authors.lastname: Marjomäki
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Jef
authors.initials: J
authors.lastname: De Brabander
authors.affiliation: Finnish Institute of Occupational Health (TTL), Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
authors.affiliation: Institute of Clinical Medicine, Rikshospitalet, Oslo, Norway.
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.affiliation: Institute of Biotechnology (BI), University of Helsinki, Finland.
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Bamford
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, University of Helsinki, Finland.|Medical Biotechnology Center, VIB, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.affiliation: National Institute for Health and Welfare (THL), Helsinki, Finland.|Department of Virology, University of Turku, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.affiliation: Department of Virology, University of Turku, Finland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Paavilainen
authors.affiliation: Department of Virology, University of Turku, Finland.
authors.forename: Veijo
authors.initials: V
authors.lastname: Hukkanen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
authors.forename: Denis E
authors.initials: DE
authors.lastname: Kainov
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007211:Indoles; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000276:immunology; D007737:Kynurenine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D053858:Metabolic Networks and Pathways / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D010080:Oxazoles / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D061251:Primary Cell Culture; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D059467:Transcriptome; D014364:Tryptophan / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; C576710:IDO1 protein, human; C085820:INS1 protein, influenza virus; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D010091:Oximes; D011758:Pyrroles; D013449:Sulfonamides; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; D007737:Kynurenine; C000613752:epacadostat; D014364:Tryptophan; D007372:Interferons; C520962:obatoclax
keywords: host-pathogen interaction; indoleamine-pyrrole 2,3-dioxygenase (IDO1); influenza virus; innate immunity; interferon