Plasminogen controls inflammation and pathogenesis of influenza virus infections via fibrinolysis

PLoS Pathog. 2013 Mar;9(3):e1003229. doi: 10.1371/journal.ppat.1003229. Epub 2013 Mar 21.

Abstract

Detrimental inflammation of the lungs is a hallmark of severe influenza virus infections. Endothelial cells are the source of cytokine amplification, although mechanisms underlying this process are unknown. Here, using combined pharmacological and gene-deletion approaches, we show that plasminogen controls lung inflammation and pathogenesis of infections with influenza A/PR/8/34, highly pathogenic H5N1 and 2009 pandemic H1N1 viruses. Reduction of virus replication was not responsible for the observed effect. However, pharmacological depletion of fibrinogen, the main target of plasminogen reversed disease resistance of plasminogen-deficient mice or mice treated with an inhibitor of plasminogen-mediated fibrinolysis. Therefore, plasminogen contributes to the deleterious inflammation of the lungs and local fibrin clot formation may be implicated in host defense against influenza virus infections. Our studies suggest that the hemostatic system might be explored for novel treatments against influenza.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Female
  • Fibrin / drug effects
  • Fibrin Clot Lysis Time
  • Fibrinogen / drug effects
  • Fibrinolysis / drug effects
  • Fibrinolytic Agents / pharmacology*
  • Host-Pathogen Interactions
  • Inflammation / chemically induced*
  • Inflammation / prevention & control
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Influenza A Virus, H5N1 Subtype / pathogenicity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / prevention & control
  • Plasminogen / deficiency
  • Plasminogen / genetics
  • Plasminogen / pharmacology*
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / prevention & control
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Fibrinolytic Agents
  • Fibrin
  • Fibrinogen
  • Plasminogen

Grant support

This work was supported by the Agence Nationale de la Recherche (ANR, BR), Long term Structural funding - Methusalem by the Flemish Government (PC), and INSERM avenir (EC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.