Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2.
Identifieur interne : 002548 ( Main/Exploration ); précédent : 002547; suivant : 002549Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2.
Auteurs : Shutoku Matsuyama [Japon] ; Noriyo Nagata ; Kazuya Shirato ; Miyuki Kawase ; Makoto Takeda ; Fumihiro TaguchiSource :
- Journal of virology [ 1098-5514 ] ; 2010.
Descripteurs français
- KwdFr :
- Animaux, Cellules Vero, Cellules géantes (anatomopathologie), Cellules géantes (métabolisme), Cellules géantes (virologie), Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (métabolisme), Humains, Macaca fascicularis, Mâle, Peptidyl-Dipeptidase A (métabolisme), Poumon (cytologie), Poumon (métabolisme), Poumon (virologie), Protéines de l'enveloppe virale (métabolisme), Pénétration virale, Réplication virale, Serine endopeptidases (métabolisme), Syndrome respiratoire aigu sévère (anatomopathologie), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (virologie), Technique d'immunofluorescence, Technique de Western, Virion (physiologie), Virus du SRAS (pathogénicité).
- MESH :
- anatomopathologie : Cellules géantes, Syndrome respiratoire aigu sévère.
- cytologie : Poumon.
- métabolisme : Cellules géantes, Glycoprotéines membranaires, Peptidyl-Dipeptidase A, Poumon, Protéines de l'enveloppe virale, Serine endopeptidases, Syndrome respiratoire aigu sévère.
- pathogénicité : Virus du SRAS.
- physiologie : Virion.
- virologie : Cellules géantes, Poumon, Syndrome respiratoire aigu sévère.
- Animaux, Cellules Vero, Glycoprotéine de spicule des coronavirus, Humains, Macaca fascicularis, Mâle, Pénétration virale, Réplication virale, Technique d'immunofluorescence, Technique de Western.
English descriptors
- KwdEn :
- Animals, Blotting, Western, Chlorocebus aethiops, Fluorescent Antibody Technique, Giant Cells (metabolism), Giant Cells (pathology), Giant Cells (virology), Humans, Lung (cytology), Lung (metabolism), Lung (virology), Macaca fascicularis, Male, Membrane Glycoproteins (metabolism), Peptidyl-Dipeptidase A (metabolism), SARS Virus (pathogenicity), Serine Endopeptidases (metabolism), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (pathology), Severe Acute Respiratory Syndrome (virology), Spike Glycoprotein, Coronavirus, Vero Cells, Viral Envelope Proteins (metabolism), Virion (physiology), Virus Internalization, Virus Replication.
- MESH :
- chemical , metabolism : Membrane Glycoproteins, Peptidyl-Dipeptidase A, Serine Endopeptidases, Viral Envelope Proteins.
- cytology : Lung.
- metabolism : Giant Cells, Lung, Severe Acute Respiratory Syndrome.
- pathogenicity : SARS Virus.
- pathology : Giant Cells, Severe Acute Respiratory Syndrome.
- physiology : Virion.
- virology : Giant Cells, Lung, Severe Acute Respiratory Syndrome.
- Animals, Blotting, Western, Chlorocebus aethiops, Fluorescent Antibody Technique, Humans, Macaca fascicularis, Male, Spike Glycoprotein, Coronavirus, Vero Cells, Virus Internalization, Virus Replication.
Abstract
The distribution of the severe acute respiratory syndrome coronavirus (SARS-CoV) receptor, an angiotensin-converting enzyme 2 (ACE2), does not strictly correlate with SARS-CoV cell tropism in lungs; therefore, other cellular factors have been predicted to be required for activation of virus infection. In the present study, we identified transmembrane protease serine 2 (TMPRSS2), whose expression does correlate with SARS-CoV infection in the upper lobe of the lung. In Vero cells expressing TMPRSS2, large syncytia were induced by SARS-CoV infection. Further, the lysosome-tropic reagents failed to inhibit, whereas the heptad repeat peptide efficiently inhibited viral entry into cells, suggesting that TMPRSS2 affects the S protein at the cell surface and induces virus-plasma membrane fusion. On the other hand, production of virus in TMPRSS2-expressing cells did not result in S-protein cleavage or increased infectivity of the resulting virus. Thus, TMPRSS2 affects the entry of virus but not other phases of virus replication. We hypothesized that the spatial orientation of TMPRSS2 vis-a-vis S protein is a key mechanism underling this phenomenon. To test this, the TMPRSS2 and S proteins were expressed in cells labeled with fluorescent probes of different colors, and the cell-cell fusion between these cells was tested. Results indicate that TMPRSS2 needs to be expressed in the opposing (target) cell membrane to activate S protein rather than in the producer cell, as found for influenza A virus and metapneumoviruses. This is the first report of TMPRSS2 being required in the target cell for activation of a viral fusion protein but not for the S protein synthesized in and transported to the surface of cells. Our findings suggest that the TMPRSS2 expressed in lung tissues may be a determinant of viral tropism and pathogenicity at the initial site of SARS-CoV infection.
DOI: 10.1128/JVI.01542-10
PubMed: 20926566
Affiliations:
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Le document en format XML
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last="Nagata">Noriyo Nagata</name></author><author><name sortKey="Shirato, Kazuya" sort="Shirato, Kazuya" uniqKey="Shirato K" first="Kazuya" last="Shirato">Kazuya Shirato</name></author><author><name sortKey="Kawase, Miyuki" sort="Kawase, Miyuki" uniqKey="Kawase M" first="Miyuki" last="Kawase">Miyuki Kawase</name></author><author><name sortKey="Takeda, Makoto" sort="Takeda, Makoto" uniqKey="Takeda M" first="Makoto" last="Takeda">Makoto Takeda</name></author><author><name sortKey="Taguchi, Fumihiro" sort="Taguchi, Fumihiro" uniqKey="Taguchi F" first="Fumihiro" last="Taguchi">Fumihiro Taguchi</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2010">2010</date><idno type="RBID">pubmed:20926566</idno><idno type="pmid">20926566</idno><idno type="doi">10.1128/JVI.01542-10</idno><idno type="wicri:Area/PubMed/Corpus">001614</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001614</idno><idno 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first="Makoto" last="Takeda">Makoto Takeda</name></author><author><name sortKey="Taguchi, Fumihiro" sort="Taguchi, Fumihiro" uniqKey="Taguchi F" first="Fumihiro" last="Taguchi">Fumihiro Taguchi</name></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Blotting, Western</term><term>Chlorocebus aethiops</term><term>Fluorescent Antibody Technique</term><term>Giant Cells (metabolism)</term><term>Giant Cells (pathology)</term><term>Giant Cells (virology)</term><term>Humans</term><term>Lung (cytology)</term><term>Lung (metabolism)</term><term>Lung (virology)</term><term>Macaca fascicularis</term><term>Male</term><term>Membrane Glycoproteins (metabolism)</term><term>Peptidyl-Dipeptidase A (metabolism)</term><term>SARS Virus (pathogenicity)</term><term>Serine Endopeptidases (metabolism)</term><term>Severe Acute Respiratory Syndrome (metabolism)</term><term>Severe Acute Respiratory Syndrome (pathology)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Spike Glycoprotein, Coronavirus</term><term>Vero Cells</term><term>Viral Envelope Proteins (metabolism)</term><term>Virion (physiology)</term><term>Virus Internalization</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules Vero</term><term>Cellules géantes (anatomopathologie)</term><term>Cellules géantes (métabolisme)</term><term>Cellules géantes (virologie)</term><term>Glycoprotéine de spicule des coronavirus</term><term>Glycoprotéines membranaires (métabolisme)</term><term>Humains</term><term>Macaca fascicularis</term><term>Mâle</term><term>Peptidyl-Dipeptidase A (métabolisme)</term><term>Poumon (cytologie)</term><term>Poumon (métabolisme)</term><term>Poumon (virologie)</term><term>Protéines de l'enveloppe virale (métabolisme)</term><term>Pénétration virale</term><term>Réplication virale</term><term>Serine endopeptidases (métabolisme)</term><term>Syndrome respiratoire aigu sévère (anatomopathologie)</term><term>Syndrome respiratoire aigu sévère (métabolisme)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Technique d'immunofluorescence</term><term>Technique de Western</term><term>Virion (physiologie)</term><term>Virus du SRAS (pathogénicité)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Membrane Glycoproteins</term><term>Peptidyl-Dipeptidase A</term><term>Serine Endopeptidases</term><term>Viral Envelope Proteins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Cellules géantes</term><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="cytologie" 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fascicularis</term><term>Mâle</term><term>Pénétration virale</term><term>Réplication virale</term><term>Technique d'immunofluorescence</term><term>Technique de Western</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The distribution of the severe acute respiratory syndrome coronavirus (SARS-CoV) receptor, an angiotensin-converting enzyme 2 (ACE2), does not strictly correlate with SARS-CoV cell tropism in lungs; therefore, other cellular factors have been predicted to be required for activation of virus infection. In the present study, we identified transmembrane protease serine 2 (TMPRSS2), whose expression does correlate with SARS-CoV infection in the upper lobe of the lung. In Vero cells expressing TMPRSS2, large syncytia were induced by SARS-CoV infection. Further, the lysosome-tropic reagents failed to inhibit, whereas the heptad repeat peptide efficiently inhibited viral entry into cells, suggesting that TMPRSS2 affects the S protein at the cell surface and induces virus-plasma membrane fusion. On the other hand, production of virus in TMPRSS2-expressing cells did not result in S-protein cleavage or increased infectivity of the resulting virus. Thus, TMPRSS2 affects the entry of virus but not other phases of virus replication. We hypothesized that the spatial orientation of TMPRSS2 vis-a-vis S protein is a key mechanism underling this phenomenon. To test this, the TMPRSS2 and S proteins were expressed in cells labeled with fluorescent probes of different colors, and the cell-cell fusion between these cells was tested. Results indicate that TMPRSS2 needs to be expressed in the opposing (target) cell membrane to activate S protein rather than in the producer cell, as found for influenza A virus and metapneumoviruses. This is the first report of TMPRSS2 being required in the target cell for activation of a viral fusion protein but not for the S protein synthesized in and transported to the surface of cells. Our findings suggest that the TMPRSS2 expressed in lung tissues may be a determinant of viral tropism and pathogenicity at the initial site of SARS-CoV infection.</div></front></TEI><affiliations><list><country><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement></list><tree><noCountry><name sortKey="Kawase, Miyuki" sort="Kawase, Miyuki" uniqKey="Kawase M" first="Miyuki" last="Kawase">Miyuki Kawase</name><name sortKey="Nagata, Noriyo" sort="Nagata, Noriyo" uniqKey="Nagata N" first="Noriyo" last="Nagata">Noriyo Nagata</name><name sortKey="Shirato, Kazuya" sort="Shirato, Kazuya" uniqKey="Shirato K" first="Kazuya" last="Shirato">Kazuya Shirato</name><name sortKey="Taguchi, Fumihiro" sort="Taguchi, Fumihiro" uniqKey="Taguchi F" first="Fumihiro" last="Taguchi">Fumihiro Taguchi</name><name sortKey="Takeda, Makoto" sort="Takeda, Makoto" uniqKey="Takeda M" first="Makoto" last="Takeda">Makoto Takeda</name></noCountry><country name="Japon"><region name="Région de Kantō"><name sortKey="Matsuyama, Shutoku" sort="Matsuyama, Shutoku" uniqKey="Matsuyama S" first="Shutoku" last="Matsuyama">Shutoku Matsuyama</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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