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 1

Effect of PAR1 activation and PAR1 deficiency on IAV pathogenicity.

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Effect of PAR1 activation and PAR1 deficiency on IAV pathogenicity. (A) ...
(A) Time course of IAV-induced pathogenesis and death in mice in response to PAR1 stimulation. Mice were inoculated intranasally with H1N1 (50 PFU, n = 22 per group; 500 PFU, n = 18 per group) and treated with either vehicle or 50 μM PAR1-AP. (B) Time course of uninfected mice treated or not with 50 μM PAR1-AP (n = 13 per group). (C) Mice were infected with 50 PFU H1N1 and treated with control peptide or vehicle (n = 10 per group). Results are average percent survival or weight loss from 3 independent experiments. (D) Survival and weight loss of Par1–/– mice and WT littermates after infection with 100 PFU H1N1 (n = 12 per group). Results are average percent survival or weight loss from 2 experiments. P < 0.05, PAR1-AP vs. untreated or Par1–/– vs. WT, Kaplan-Meier test.