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.
Highlights
Influenza A viruses (IAV) are an important cause of outbreaks of respiratory tract infections and are responsible for significant morbidity and mortality in the human population [1]
Our findings show that plasminogen plays an important role in lung inflammation upon IAV infections, mainly through fibrinolysis
Influenza viruses, including H5N1 bird influenza viruses continue to form a major threat for public health
Summary
Influenza A viruses (IAV) are an important cause of outbreaks of respiratory tract infections and are responsible for significant morbidity and mortality in the human population [1]. Upon infection with IAV, innate and adaptive immune responses are induced that restrict viral replication and that afford protection against infection with these viruses. The sites of virus replication in the respiratory tract represent complex microenvironments, in which extracellular proteases are present abundantly [5,6]. Some of these proteases can play a role in innate immune responses since they are important mediators of inflammatory processes [7] and influence virus replication [8,9]. The elucidation of host proteases contributing to pathogenesis of IAV infections in vivo has been hampered by the lack of experimental models
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