Plasminogen controls inflammation and pathogenesis of influenza virus infections via fibrinolysis

Fatma Berri; Guus F Rimmelzwaan; Michel Hanss; Emmanuel Albina; Marie-Laure Foucault-Grunenwald; Vuong B Lê; Stella E Vogelzang-van Trierum; Patrica Gil; Eric Camerer; Dominique Martinez; Bruno Lina; Roger Lijnen; Peter Carmeliet; Béatrice Riteau

doi:10.1371/journal.ppat.1003229

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.

Authors

Fatma Berri¹, Guus F Rimmelzwaan, Michel Hanss, Emmanuel Albina, Marie-Laure Foucault-Grunenwald, Vuong B Lê, Stella E Vogelzang-van Trierum, Patrica Gil, Eric Camerer, Dominique Martinez, Bruno Lina, Roger Lijnen, Peter Carmeliet, Béatrice Riteau

Affiliation

¹ VirPath, EA4610 Virologie et Pathologie Humaine, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Lyon, France.

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

Grants and funding

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.