tetano
Editor, Senior Moderator
J Clin Invest. doi:10.1172/JCI61667.
Copyright ? 2012, The American Society for Clinical Investigation.
Research Article
PAR1 contributes to influenza A virus pathogenicity in mice
Khaled Khoufache1,2, Fatma Berri1, Wolfgang Nacken3, Annette B. Vogel4,5, Marie Delenne1, Eric Camerer6,7, Shaun R. Coughlin8, Peter Carmeliet9,10, Bruno Lina1, Guus F. Rimmelzwaan11, Oliver Planz4, Stephan Ludwig3 and B?atrice Riteau1,2
1Virologie et Pathologie Humaine, EA 4610, Universit? Lyon1, Facult? de M?decine RTH Laennec, Lyon, France.
2INRA Tours, Nouzilly, France.
3Institute of Molecular Virology, ZMBE, Westf?lische-Wilhelms-University, M?nster, Germany.
4Friedrich-Loeffler-Institute, Institute of Immunology, University Hospital, Tuebingen, Germany.
5Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
6INSERM U970, Paris Cardiovascular Centre, Paris, France.
7Universit? Paris-Descartes, Paris, France.
8Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
9Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
10Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, KU Leuven, Leuven, Belgium.
11Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands.
Address correspondence to: Beatrice Riteau, EMR 4610 VirPath, Virologie et Pathologie Humaine, Facult? de m?decine RTH Laennec, Universit? Claude Bernard Lyon 1, Universit? de Lyon, F-69008, Lyon, France. Phone: 33.1.0478771008; Fax: 33.1.0478778751; E-mail: beatrice.riteau@univ-lyon1.fr.
Authorship note: Khaled Khoufache and Fatma Berri contributed equally to this work.
Published December 3, 2012
Received for publication November 7, 2011, and accepted in revised form October 4, 2012.
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.
full text
http://www.jci.org/articles/view/61667
Copyright ? 2012, The American Society for Clinical Investigation.
Research Article
PAR1 contributes to influenza A virus pathogenicity in mice
Khaled Khoufache1,2, Fatma Berri1, Wolfgang Nacken3, Annette B. Vogel4,5, Marie Delenne1, Eric Camerer6,7, Shaun R. Coughlin8, Peter Carmeliet9,10, Bruno Lina1, Guus F. Rimmelzwaan11, Oliver Planz4, Stephan Ludwig3 and B?atrice Riteau1,2
1Virologie et Pathologie Humaine, EA 4610, Universit? Lyon1, Facult? de M?decine RTH Laennec, Lyon, France.
2INRA Tours, Nouzilly, France.
3Institute of Molecular Virology, ZMBE, Westf?lische-Wilhelms-University, M?nster, Germany.
4Friedrich-Loeffler-Institute, Institute of Immunology, University Hospital, Tuebingen, Germany.
5Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
6INSERM U970, Paris Cardiovascular Centre, Paris, France.
7Universit? Paris-Descartes, Paris, France.
8Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
9Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
10Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, KU Leuven, Leuven, Belgium.
11Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands.
Address correspondence to: Beatrice Riteau, EMR 4610 VirPath, Virologie et Pathologie Humaine, Facult? de m?decine RTH Laennec, Universit? Claude Bernard Lyon 1, Universit? de Lyon, F-69008, Lyon, France. Phone: 33.1.0478771008; Fax: 33.1.0478778751; E-mail: beatrice.riteau@univ-lyon1.fr.
Authorship note: Khaled Khoufache and Fatma Berri contributed equally to this work.
Published December 3, 2012
Received for publication November 7, 2011, and accepted in revised form October 4, 2012.
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.
full text
http://www.jci.org/articles/view/61667