Regulation of kynurenine biosynthesis during influenza virus infection

FEBS J. 2017 Jan;284(2):222-236. doi: 10.1111/febs.13966. Epub 2016 Dec 14.

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.

Keywords: host-pathogen interaction; indoleamine-pyrrole 2,3-dioxygenase (IDO1); influenza virus; innate immunity; interferon.

Publication types

  • Editorial

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Female
  • Gene Expression Regulation
  • Host-Pathogen Interactions
  • Humans
  • Immunologic Factors / pharmacology*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Influenza A Virus, H1N1 Subtype / drug effects*
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / growth & development
  • Influenza A Virus, H1N1 Subtype / metabolism
  • Interferons / genetics
  • Interferons / immunology
  • Kynurenine / antagonists & inhibitors*
  • Kynurenine / biosynthesis
  • Lung / drug effects
  • Lung / immunology
  • Lung / virology
  • Macrophages / drug effects
  • Macrophages / virology
  • Metabolic Networks and Pathways / drug effects*
  • Metabolic Networks and Pathways / genetics
  • Metabolic Networks and Pathways / immunology
  • Mice
  • Mice, Inbred BALB C
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Oxazoles / pharmacology
  • Oximes / pharmacology
  • Primary Cell Culture
  • Pyrroles / pharmacology
  • Sulfonamides / pharmacology
  • Thiazoles / pharmacology
  • Transcriptome
  • Tryptophan / metabolism
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication

Substances

  • Antiviral Agents
  • INS1 protein, influenza virus
  • Immunologic Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
  • Oxazoles
  • Oximes
  • Pyrroles
  • Sulfonamides
  • Thiazoles
  • Viral Nonstructural Proteins
  • indoleamine 2,3-dioxygenase 1, human
  • Kynurenine
  • epacadostat
  • Tryptophan
  • Interferons
  • obatoclax