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J Virol. 2009 Jan 21. [Epub ahead of print]
Proteolytic activation of the 1918 influenza virus hemagglutinin.
Chaipan C, Kobasa D, Bertram S, Glowacka I, Steffen I, Solomon Tsegaye T, Takeda M, Bugge T, Kim S, Park Y, Marzi A, P?hlmann S. - Nikolaus-Fiebiger-Center for Molecular Medicine; Institute for Clinical and Molecular Virology, University Hospital Erlangen, 91054 Erlangen, Germany; Respiratory Viruses, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 3R2, Canada; Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA; Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea; Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Proteolytic activation of the hemagglutinin (HA) is indispensable for influenza virus infectivity, and the tissue expression of the responsible cellular proteases impacts viral tropism and pathogenicity.
The HA critically contributes to the exceptionally high pathogenicity of the 1918 influenza virus but the mechanisms underlying cleavage-activation of 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 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 1918 HA.
We provide evidence that NA-dependent, trypsin-independent cleavage-activation of 1918 HA is cell line-dependent and most likely plasminogen-independent, since 1918 NA failed to recruit plasminogen and neither exogenous plasminogen nor the presence of WSN/33 NA promoted efficient 1918 HA cleavage.
The transmembrane serine protease TMPRSS4 was found to be expressed in lung tissue and was shown to cleave 1918 HA.
Accordingly, coexpression of 1918 HA with TMPRSS4 or the previously identified HA-processing protease TMPRSS2 allowed trypsin-independent infection by 1918 HA-bearing pseudotypes, 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 1918 NA.
Moreover, we provide evidence that TMPRSS2 and TMPRSS4 cleavage-activate 1918 HA and therefore may promote viral spread in lung tissue.
PMID: 19158246 [PubMed - as supplied by publisher]
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Proteolytic activation of the 1918 influenza virus hemagglutinin.
Chaipan C, Kobasa D, Bertram S, Glowacka I, Steffen I, Solomon Tsegaye T, Takeda M, Bugge T, Kim S, Park Y, Marzi A, P?hlmann S. - Nikolaus-Fiebiger-Center for Molecular Medicine; Institute for Clinical and Molecular Virology, University Hospital Erlangen, 91054 Erlangen, Germany; Respiratory Viruses, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, R3E 3R2, Canada; Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA; Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea; Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Proteolytic activation of the hemagglutinin (HA) is indispensable for influenza virus infectivity, and the tissue expression of the responsible cellular proteases impacts viral tropism and pathogenicity.
The HA critically contributes to the exceptionally high pathogenicity of the 1918 influenza virus but the mechanisms underlying cleavage-activation of 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 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 1918 HA.
We provide evidence that NA-dependent, trypsin-independent cleavage-activation of 1918 HA is cell line-dependent and most likely plasminogen-independent, since 1918 NA failed to recruit plasminogen and neither exogenous plasminogen nor the presence of WSN/33 NA promoted efficient 1918 HA cleavage.
The transmembrane serine protease TMPRSS4 was found to be expressed in lung tissue and was shown to cleave 1918 HA.
Accordingly, coexpression of 1918 HA with TMPRSS4 or the previously identified HA-processing protease TMPRSS2 allowed trypsin-independent infection by 1918 HA-bearing pseudotypes, 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 1918 NA.
Moreover, we provide evidence that TMPRSS2 and TMPRSS4 cleavage-activate 1918 HA and therefore may promote viral spread in lung tissue.
PMID: 19158246 [PubMed - as supplied by publisher]
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