PAR1 contributes to influenza A virus pathogenicity in mice
Khaled Khoufache, Fatma Berri, Wolfgang Nacken, Annette B. Vogel, Marie Delenne, Eric Camerer, Shaun R. Coughlin, Peter Carmeliet, Bruno Lina, Guus F. Rimmelzwaan, Oliver Planz, Stephan Ludwig, Béatrice Riteau
Khaled Khoufache, Fatma Berri, Wolfgang Nacken, Annette B. Vogel, Marie Delenne, Eric Camerer, Shaun R. Coughlin, Peter Carmeliet, Bruno Lina, Guus F. Rimmelzwaan, Oliver Planz, Stephan Ludwig, Béatrice Riteau
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Research Article Inflammation

PAR1 contributes to influenza A virus pathogenicity in mice

Abstract

Influenza causes substantial morbidity and mortality, and highly pathogenic and drug-resistant strains are likely to emerge in the future. Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces. The role of PAR1 in pathogenesis of virus infections is unknown. Here, we demonstrate that PAR1 contributed to the deleterious inflammatory response after influenza virus infection in mice. Activating PAR1 by administering the agonist TFLLR-NH2 decreased survival and increased lung inflammation after influenza infection. Importantly, both administration of a PAR1 antagonist and PAR1 deficiency protected mice from infection with influenza A viruses (IAVs). Treatment with the PAR1 agonist did not alter survival of mice deficient in plasminogen (PLG), which suggests that PLG permits and/or interacts with a PAR1 function in this model. PAR1 antagonists are in human trials for other indications. Our findings suggest that PAR1 antagonism might be explored as a treatment for influenza, including that caused by highly pathogenic H5N1 and oseltamivir-resistant H1N1 viruses.

Authors

Khaled Khoufache, Fatma Berri, Wolfgang Nacken, Annette B. Vogel, Marie Delenne, Eric Camerer, Shaun R. Coughlin, Peter Carmeliet, Bruno Lina, Guus F. Rimmelzwaan, Oliver Planz, Stephan Ludwig, Béatrice Riteau

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Figure 3

Effect of PLG and PLG deficiency on IAV production and PAR1-AP effects.

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Effect of PLG and PLG deficiency on IAV production and PAR1-AP effects. ...
(A) ERK phosphorylation after stimulation of A549 cells with the indicated PAR1-AP concentrations. Anti–phospho-Erk and anti-Erk antibodies were used. (B) Infectious virus titers in the supernatant of infected cells after stimulation with 40 μM PAR1-AP or control peptide in the presence or absence of PLG. (C) Noninfected (NI) or infected (INF) cells were stimulated with 40 μM PAR1-AP or control peptide in the presence or absence of PLG. After cell lysis, proteins were analyzed by Western blot for HA cleavage. (D) Time course of IAV-induced pathogenesis in Plg–/– and WT littermates after treatment or not with PAR1-AP (n = 9–10 mice per group from 2 experiments). (E) Virus titers 48 hours after infection (50 PFU) in lungs of WT or Plg–/– mice stimulated or not with 50 μM PAR1-AP. Data are average ± SD from 5 individual animals per group from 2 experiments. *P < 0.05, treated vs. untreated, Kaplan-Meier test (D), Mann Whitney test (B and E).