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Journal of Virology, April 2009, p. 3200-3211, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02205-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Proteolytic Activation of the 1918 Influenza Virus Hemagglutinin{triangledown}

Chawaree Chaipan,1,2,{dagger} Darwyn Kobasa,3,4,{dagger} Stephanie Bertram,5,{dagger} Ilona Glowacka,5 Imke Steffen,5 Theodros Solomon Tsegaye,5 Makoto Takeda,6 Thomas H. Bugge,7 Semi Kim,8 Youngwoo Park,8 Andrea Marzi,1,2,9* and Stefan Pöhlmann1,2,5*

Nikolaus Fiebiger Center for Molecular Medicine,1 Institute for Clinical and Molecular Virology, University Hospital Erlangen, 91054 Erlangen, Germany,2 Respiratory Viruses, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada,3 Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 3R2 Canada,4 Institute of Virology, Hannover Medical School, 30625 Hannover, Germany,5 Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan,6 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892,7 Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea,8 Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada9

Received 17 October 2008/ Accepted 11 January 2009

Proteolytic activation of the hemagglutinin (HA) protein is indispensable for influenza virus infectivity, and the tissue expression of the responsible cellular proteases impacts viral tropism and pathogenicity. The HA protein critically contributes to the exceptionally high pathogenicity of the 1918 influenza virus, but the mechanisms underlying cleavage activation of the 1918 HA have not been characterized. The neuraminidase (NA) protein of the 1918 influenza virus allows trypsin-independent growth in canine kidney cells (MDCK). However, it is at present unknown if the 1918 NA, like the NA of the closely related strain A/WSN/33, facilitates HA cleavage activation by recruiting the proprotease plasminogen. Moreover, it is not known which pulmonary proteases activate the 1918 HA. We provide evidence that NA-dependent, trypsin-independent cleavage activation of the 1918 HA is cell line dependent and most likely plasminogen independent since the 1918 NA failed to recruit plasminogen and neither exogenous plasminogen nor the presence of the A/WSN/33 NA promoted efficient cleavage of the 1918 HA. The transmembrane serine protease TMPRSS4 was found to be expressed in lung tissue and was shown to cleave the 1918 HA. Accordingly, coexpression of the 1918 HA with TMPRSS4 or the previously identified HA-processing protease TMPRSS2 allowed trypsin-independent infection by pseuodotypes bearing the 1918 HA, indicating that these proteases might support 1918 influenza virus spread in the lung. In summary, we show that the previously reported 1918 NA-dependent spread of the 1918 influenza virus is a cell line-dependent phenomenon and is not due to plasminogen recruitment by the 1918 NA. Moreover, we provide evidence that TMPRSS2 and TMPRSS4 activate the 1918 HA by cleavage and therefore may promote viral spread in lung tissue.

* Corresponding author. Present address for Andrea Marzi: Rocky Mountain Laboratories, Laboratory of Virology, 903 South 4th St., Hamilton, MT 59840. Phone: (406) 375-7421. Fax: (406) 375-9620. E-mail: marzia{at}niaid.nih.gov. Mailing address for Stefan Pöhlmann: Institute of Virology, OE 5230, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany. Phone: 49 511 532 4382. Fax: 49 511 532 8736. E-mail: Poehlmann.Stefan{at}MH-Hannover.DE

{triangledown} Published ahead of print on 21 January 2009.

{dagger} C.C., D.K., and S.B. contributed equally to this work.

Journal of Virology, April 2009, p. 3200-3211, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02205-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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