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Journal of Virology, October 2001, p. 9297-9301, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9297-9301.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Plasminogen-Binding Activity of Neuraminidase Determines the Pathogenicity of Influenza A Virus

Hideo Goto,1,2 Krisna Wells,2 Ayato Takada,1,3 and Yoshihiro Kawaoka1,2,*

Institute of Medical Science, University of Tokyo, Tokyo 108-8639,1 and Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818,3 Japan, and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin---Madison, Madison, Wisconsin 537062

Received 17 April 2001/Accepted 6 July 2001

When expressed in vitro, the neuraminidase (NA) of A/WSN/33 (WSN) virus binds and sequesters plasminogen on the cell surface, leading to enhanced cleavage of the viral hemagglutinin. To obtain direct evidence that the plasminogen-binding activity of the NA enhances the pathogenicity of WSN virus, we generated mutant viruses whose NAs lacked plasminogen-binding activity because of a mutation at the C terminus, from Lys to Arg or Leu. In the presence of trypsin, these mutant viruses replicated similarly to wild-type virus in cell culture. By contrast, in the presence of plasminogen, the mutant viruses failed to undergo multiple cycles of replication while the wild-type virus grew normally. The mutant viruses showed attenuated growth in mice and failed to grow at all in the brain. Furthermore, another mutant WSN virus, possessing an NA with a glycosylation site at position 130 (146 in N2 numbering), leading to the loss of neurovirulence, failed to grow in cell culture in the presence of plasminogen. We conclude that the plasminogen-binding activity of the WSN NA determines its pathogenicity in mice.

* Corresponding author. Mailing address: Department of Pathobiological Sciences, University of Wisconsin---Madison, 2015 Linden Dr., Madison, WI 53706. Phone: (608) 265-4925. Fax: (608) 265-5622. E-mail: kawaokay{at}svm.vetmed.wisc.edu.

Journal of Virology, October 2001, p. 9297-9301, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9297-9301.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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