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J Clin Invest. PAR1 contributes to influenza A virus pathogenicity in mice

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  • J Clin Invest. PAR1 contributes to influenza A virus pathogenicity in mice

    [Source: The Journal of Clinical Investigation, full page: (LINK). Abstract, edited.]

    Published in Volume 123, Issue 1 (January 2, 2013)

    J Clin Invest. 2013;123(1):206?214. doi:10.1172/JCI61667.

    Copyright ? 2013, American Society for Clinical Investigation

    Research Article

    PAR1 contributes to influenza A virus pathogenicity in mice

    Khaled Khoufache<SUP>1,</SUP><SUP>2</SUP>, Fatma Berri<SUP>1</SUP>, Wolfgang Nacken<SUP>3</SUP>, Annette B. Vogel<SUP>4,</SUP><SUP>5</SUP>, Marie Delenne<SUP>1</SUP>, Eric Camerer<SUP>6,</SUP><SUP>7</SUP>, Shaun R. Coughlin<SUP>8</SUP>, Peter Carmeliet<SUP>9,</SUP><SUP>10</SUP>, Bruno Lina<SUP>1</SUP>, Guus F. Rimmelzwaan<SUP>11</SUP>, Oliver Planz<SUP>4</SUP>, Stephan Ludwig<SUP>3</SUP> and B?atrice Riteau<SUP>1,</SUP><SUP>2</SUP>
    <SUP>1</SUP>Virologie et Pathologie Humaine, EA 4610, Universit? Lyon1, Facult? de M?decine RTH Laennec, Lyon, France. <SUP>2</SUP>INRA Tours, Nouzilly, France.
    <SUP>3</SUP>Institute of Molecular Virology, ZMBE, Westf?lische-Wilhelms-University, M?nster, Germany. <SUP>4</SUP>Friedrich-Loeffler-Institute, Institute of Immunology, University Hospital, Tuebingen, Germany. <SUP>5</SUP>Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
    <SUP>6</SUP>INSERM U970, Paris Cardiovascular Centre, Paris, France. <SUP>7</SUP>Universit? Paris-Descartes, Paris, France. <SUP>8</SUP>Cardiovascular Research Institute, UCSF, San Francisco, California, USA. <SUP>9</SUP>Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium. <SUP>10</SUP>Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, KU Leuven, Leuven, Belgium. <SUP>11</SUP>Department 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:

    Authorship note: Khaled Khoufache and Fatma Berri contributed equally to this work.

    First 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-NH<SUB>2</SUB> 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.