Formyl Peptide Receptor 2 Plays a Deleterious Role During Influenza A Virus Infections

J Infect Dis. 2016 Jul 15;214(2):237-47. doi: 10.1093/infdis/jiw127. Epub 2016 Mar 30.

Abstract

Background: The pathogenesis of influenza A virus (IAV) infections is a multifactorial process that includes the replication capacity of the virus and a harmful inflammatory response to infection. Formyl peptide receptor 2 (FPR2) emerges as a central receptor in inflammatory processes controlling resolution of acute inflammation. Its role in virus pathogenesis has not been investigated yet.

Methods: We used pharmacologic approaches to investigate the role of FPR2 during IAV infection in vitro and in vivo.

Results: In vitro, FPR2 expressed on A549 cells was activated by IAV, which harbors its ligand, annexin A1, in its envelope. FPR2 activation by IAV promoted viral replication through an extracellular-regulated kinase (ERK)-dependent pathway. In vivo, activating FPR2 by administering the agonist WKYMVm-NH2 decreased survival and increased viral replication and inflammation after IAV infection. This effect was abolished by treating the mice with U0126, a specific ERK pathway inhibitor, showing that, in vivo, the deleterious role of FPR2 also occurs through an ERK-dependent pathway. In contrast, administration of the FPR2 antagonist WRW4 protected mice from lethal IAV infections.

Conclusions: These data show that viral replication and IAV pathogenesis depend on FPR2 signaling and suggest that FPR2 may be a promising novel strategy to treat influenza.

Keywords: formyl peptide receptor 2; host immune response; influenza; influenza virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Epithelial Cells / physiology
  • Epithelial Cells / virology
  • Host-Pathogen Interactions*
  • Humans
  • Influenza A virus / pathogenicity*
  • Influenza A virus / physiology
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / pathology*
  • Orthomyxoviridae Infections / virology*
  • Receptors, Formyl Peptide / metabolism*
  • Receptors, Lipoxin / metabolism*
  • Virulence
  • Virus Replication

Substances

  • FPR2 protein, human
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • formyl peptide receptor 2, mouse