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Journal of Virology, July 2008, p. 6820-6828, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00246-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Annexin II Incorporated into Influenza Virus Particles Supports Virus Replication by Converting Plasminogen into Plasmin

Fanny LeBouder,^1, Eric Morello,^1, Guus F. Rimmelzwaan,² Françoise Bosse,¹ Christine Péchoux,³ Bernard Delmas,¹ and Béatrice Riteau^1*

Unité de Virologie et Immunologie Moléculaires, UR 892 INRA, Domaine de Vilvert, 78352 Jouy-en-Josas, France,¹ Department of Virology and Postgraduate School of Molecular Medicine, Erasmus Medical Center, Rotterdam, The Netherlands,² Unité UR1196 Génomique et Physiologie de la Lactation, INRA, Plateau de Microscopie Electronique, 78352 Jouy-en-Josas cedex, France³

Received 4 February 2008/ Accepted 24 April 2008

For influenza viruses to become infectious, the proteolytic cleavage of hemagglutinin (HA) is essential. This usually is mediated by trypsin-like proteases in the respiratory tract. The binding of plasminogen to influenza virus A/WSN/33 leads to the cleavage of HA, a feature determining its pathogenicity and neurotropism in mice. Here, we demonstrate that plasminogen also promotes the replication of other influenza virus strains. The inhibition of the conversion of plasminogen into plasmin blocked influenza virus replication. Evidence is provided that the activation of plasminogen is mediated by the host cellular protein annexin II, which is incorporated into the virus particles. Indeed, the inhibition of plasminogen binding to annexin II by using a competitive inhibitor inhibits plasminogen activation into plasmin. Collectively, these results indicate that the annexin II-mediated activation of plasminogen supports the replication of influenza viruses, which may contribute to their pathogenicity.

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* Corresponding author. Mailing address: Unité de Virologie et Immunologie Moléculaires, UR 892 INRA, Domaine de Vilvert, 78352 Jouy-en-Josas, France. Phone and Fax: (33) 1 34 65 26 24. E-mail: beatrice.riteau{at}jouy.inra.fr

Published ahead of print on 30 April 2008.

F.L.B. and E.M. contributed equally to this work.

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Journal of Virology, July 2008, p. 6820-6828, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00246-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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