PAR1 contributes to influenza A virus pathogenicity in mice
Journal of Clinical Investigation , Volume 123 - Issue 1 p. 206- 214
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.
|Influenza virus A, Influenza virus A H1N1, Influenza virus A H3N2, Influenza virus A H5N1, animal cell, animal experiment, animal model, animal tissue, article, controlled study, cytokine release, cytokine response, enzyme inactivation, enzyme linked immunosorbent assay, histopathology, human, human cell, inflammation, influenza A, influenza A (H1N1), influenza A (H3N2), influenza A (H5N1), mouse, neutrophil chemotaxis, nonhuman, priority journal, protein function, receptor binding, signal transduction, survival rate, virus pathogenesis, virus pneumonia, virus replication, virus virulence, weight reduction|
|Journal of Clinical Investigation|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Khoufache, K, Berri, F, Nacken, W, Vogel, A.B, Delenne, M, Camerer, E, … Riteau, B. (2013). PAR1 contributes to influenza A virus pathogenicity in mice. Journal of Clinical Investigation, 123(1), 206–214. doi:10.1172/JCI61667