TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection.
Identifieur interne : 000359 ( PubMed/Checkpoint ); précédent : 000358; suivant : 000360TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection.
Auteurs : Naoko Iwata-Yoshikawa [Japon] ; Tadashi Okamura [Japon] ; Yukiko Shimizu [Japon] ; Hideki Hasegawa [Japon] ; Makoto Takeda [Japon] ; Noriyo Nagata [Japon]Source :
- Journal of virology [ 1098-5514 ] ; 2019.
Descripteurs français
- KwdFr :
- Animaux, Cellules Vero, Coronavirus du syndrome respiratoire du Moyen-Orient (immunologie), Femelle, Glycoprotéine de spicule des coronavirus (métabolisme), Humains, Infections à coronavirus (immunologie), Infections à coronavirus (métabolisme), Infections à coronavirus (virologie), Lignée cellulaire, Modèles animaux de maladie humaine, Mâle, Poly I-C (métabolisme), Poumon (immunologie), Poumon (métabolisme), Poumon (virologie), Récepteur de type Toll-3 (métabolisme), Serine endopeptidases (métabolisme), Souris, Souris de lignée C57BL, Souris knockout, Souris transgéniques, Syndrome respiratoire aigu sévère (immunologie), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (virologie), Virus du SRAS.
- MESH :
- immunologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Infections à coronavirus, Poumon, Syndrome respiratoire aigu sévère.
- métabolisme : Glycoprotéine de spicule des coronavirus, Infections à coronavirus, Poly I-C, Poumon, Récepteur de type Toll-3, Serine endopeptidases, Syndrome respiratoire aigu sévère.
- virologie : Infections à coronavirus, Poumon, Syndrome respiratoire aigu sévère.
- Animaux, Cellules Vero, Femelle, Humains, Lignée cellulaire, Modèles animaux de maladie humaine, Mâle, Souris, Souris de lignée C57BL, Souris knockout, Souris transgéniques, Virus du SRAS.
English descriptors
- KwdEn :
- Animals, Cell Line, Chlorocebus aethiops, Coronavirus Infections (immunology), Coronavirus Infections (metabolism), Coronavirus Infections (virology), Disease Models, Animal, Female, Humans, Lung (immunology), Lung (metabolism), Lung (virology), Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle East Respiratory Syndrome Coronavirus (immunology), Poly I-C (metabolism), SARS Virus, Serine Endopeptidases (metabolism), Severe Acute Respiratory Syndrome (immunology), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (virology), Spike Glycoprotein, Coronavirus (metabolism), Toll-Like Receptor 3 (metabolism), Vero Cells.
- MESH :
- chemical , metabolism : Poly I-C, Serine Endopeptidases, Spike Glycoprotein, Coronavirus, Toll-Like Receptor 3.
- immunology : Coronavirus Infections, Lung, Middle East Respiratory Syndrome Coronavirus, Severe Acute Respiratory Syndrome.
- metabolism : Coronavirus Infections, Lung, Severe Acute Respiratory Syndrome.
- virology : Coronavirus Infections, Lung, Severe Acute Respiratory Syndrome.
- Animals, Cell Line, Chlorocebus aethiops, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, SARS Virus, Vero Cells.
Abstract
Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology.IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.
DOI: 10.1128/JVI.01815-18
PubMed: 30626688
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
pubmed:30626688Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection.</title>
<author><name sortKey="Iwata Yoshikawa, Naoko" sort="Iwata Yoshikawa, Naoko" uniqKey="Iwata Yoshikawa N" first="Naoko" last="Iwata-Yoshikawa">Naoko Iwata-Yoshikawa</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Okamura, Tadashi" sort="Okamura, Tadashi" uniqKey="Okamura T" first="Tadashi" last="Okamura">Tadashi Okamura</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shimizu, Yukiko" sort="Shimizu, Yukiko" uniqKey="Shimizu Y" first="Yukiko" last="Shimizu">Yukiko Shimizu</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Takeda, Makoto" sort="Takeda, Makoto" uniqKey="Takeda M" first="Makoto" last="Takeda">Makoto Takeda</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Virology III, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nagata, Noriyo" sort="Nagata, Noriyo" uniqKey="Nagata N" first="Noriyo" last="Nagata">Noriyo Nagata</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.</nlm:affiliation>
<country wicri:rule="url">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2019">2019</date>
<idno type="RBID">pubmed:30626688</idno>
<idno type="pmid">30626688</idno>
<idno type="doi">10.1128/JVI.01815-18</idno>
<idno type="wicri:Area/PubMed/Corpus">000681</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000681</idno>
<idno type="wicri:Area/PubMed/Curation">000681</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000681</idno>
<idno type="wicri:Area/PubMed/Checkpoint">000359</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000359</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection.</title>
<author><name sortKey="Iwata Yoshikawa, Naoko" sort="Iwata Yoshikawa, Naoko" uniqKey="Iwata Yoshikawa N" first="Naoko" last="Iwata-Yoshikawa">Naoko Iwata-Yoshikawa</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Okamura, Tadashi" sort="Okamura, Tadashi" uniqKey="Okamura T" first="Tadashi" last="Okamura">Tadashi Okamura</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shimizu, Yukiko" sort="Shimizu, Yukiko" uniqKey="Shimizu Y" first="Yukiko" last="Shimizu">Yukiko Shimizu</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Takeda, Makoto" sort="Takeda, Makoto" uniqKey="Takeda M" first="Makoto" last="Takeda">Makoto Takeda</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.</nlm:affiliation>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Virology III, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nagata, Noriyo" sort="Nagata, Noriyo" uniqKey="Nagata N" first="Noriyo" last="Nagata">Noriyo Nagata</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.</nlm:affiliation>
<country wicri:rule="url">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of virology</title>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Chlorocebus aethiops</term>
<term>Coronavirus Infections (immunology)</term>
<term>Coronavirus Infections (metabolism)</term>
<term>Coronavirus Infections (virology)</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>Humans</term>
<term>Lung (immunology)</term>
<term>Lung (metabolism)</term>
<term>Lung (virology)</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
<term>Mice, Transgenic</term>
<term>Middle East Respiratory Syndrome Coronavirus (immunology)</term>
<term>Poly I-C (metabolism)</term>
<term>SARS Virus</term>
<term>Serine Endopeptidases (metabolism)</term>
<term>Severe Acute Respiratory Syndrome (immunology)</term>
<term>Severe Acute Respiratory Syndrome (metabolism)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Spike Glycoprotein, Coronavirus (metabolism)</term>
<term>Toll-Like Receptor 3 (metabolism)</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Cellules Vero</term>
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (immunologie)</term>
<term>Femelle</term>
<term>Glycoprotéine de spicule des coronavirus (métabolisme)</term>
<term>Humains</term>
<term>Infections à coronavirus (immunologie)</term>
<term>Infections à coronavirus (métabolisme)</term>
<term>Infections à coronavirus (virologie)</term>
<term>Lignée cellulaire</term>
<term>Modèles animaux de maladie humaine</term>
<term>Mâle</term>
<term>Poly I-C (métabolisme)</term>
<term>Poumon (immunologie)</term>
<term>Poumon (métabolisme)</term>
<term>Poumon (virologie)</term>
<term>Récepteur de type Toll-3 (métabolisme)</term>
<term>Serine endopeptidases (métabolisme)</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
<term>Souris transgéniques</term>
<term>Syndrome respiratoire aigu sévère (immunologie)</term>
<term>Syndrome respiratoire aigu sévère (métabolisme)</term>
<term>Syndrome respiratoire aigu sévère (virologie)</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Poly I-C</term>
<term>Serine Endopeptidases</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Toll-Like Receptor 3</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Infections à coronavirus</term>
<term>Poumon</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Coronavirus Infections</term>
<term>Lung</term>
<term>Middle East Respiratory Syndrome Coronavirus</term>
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus Infections</term>
<term>Lung</term>
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycoprotéine de spicule des coronavirus</term>
<term>Infections à coronavirus</term>
<term>Poly I-C</term>
<term>Poumon</term>
<term>Récepteur de type Toll-3</term>
<term>Serine endopeptidases</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term>
<term>Poumon</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term>
<term>Lung</term>
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Chlorocebus aethiops</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
<term>Mice, Transgenic</term>
<term>SARS Virus</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules Vero</term>
<term>Femelle</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Modèles animaux de maladie humaine</term>
<term>Mâle</term>
<term>Souris</term>
<term>Souris de lignée C57BL</term>
<term>Souris knockout</term>
<term>Souris transgéniques</term>
<term>Virus du SRAS</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). <i>In vitro</i>
, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection <i>in vivo</i>
are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology.<b>IMPORTANCE</b>
Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30626688</PMID>
<DateCompleted><Year>2019</Year>
<Month>11</Month>
<Day>19</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>09</Day>
</DateRevised>
<Article PubModel="Electronic-Print"><Journal><ISSN IssnType="Electronic">1098-5514</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>93</Volume>
<Issue>6</Issue>
<PubDate><Year>2019</Year>
<Month>03</Month>
<Day>15</Day>
</PubDate>
</JournalIssue>
<Title>Journal of virology</Title>
<ISOAbbreviation>J. Virol.</ISOAbbreviation>
</Journal>
<ArticleTitle>TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection.</ArticleTitle>
<ELocationID EIdType="pii" ValidYN="Y">e01815-18</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.1128/JVI.01815-18</ELocationID>
<Abstract><AbstractText>Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). <i>In vitro</i>
, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection <i>in vivo</i>
are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology.<b>IMPORTANCE</b>
Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.</AbstractText>
<CopyrightInformation>Copyright © 2019 American Society for Microbiology.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y" EqualContrib="Y"><LastName>Iwata-Yoshikawa</LastName>
<ForeName>Naoko</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y" EqualContrib="Y"><LastName>Okamura</LastName>
<ForeName>Tadashi</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Section of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shimizu</LastName>
<ForeName>Yukiko</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hasegawa</LastName>
<ForeName>Hideki</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Takeda</LastName>
<ForeName>Makoto</ForeName>
<Initials>M</Initials>
<Identifier Source="ORCID">0000-0002-8194-7727</Identifier>
<AffiliationInfo><Affiliation>Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nagata</LastName>
<ForeName>Noriyo</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2019</Year>
<Month>03</Month>
<Day>05</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>J Virol</MedlineTA>
<NlmUniqueID>0113724</NlmUniqueID>
<ISSNLinking>0022-538X</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D064370">Spike Glycoprotein, Coronavirus</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D051196">Toll-Like Receptor 3</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.4.21.-</RegistryNumber>
<NameOfSubstance UI="D012697">Serine Endopeptidases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.4.21.-</RegistryNumber>
<NameOfSubstance UI="C000588699">TMPRSS2 protein, mouse</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>O84C90HH2L</RegistryNumber>
<NameOfSubstance UI="D011070">Poly I-C</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008168" MajorTopicYN="N">Lung</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018345" MajorTopicYN="N">Mice, Knockout</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008822" MajorTopicYN="N">Mice, Transgenic</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011070" MajorTopicYN="N">Poly I-C</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012697" MajorTopicYN="N">Serine Endopeptidases</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045169" MajorTopicYN="N">Severe Acute Respiratory Syndrome</DescriptorName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D064370" MajorTopicYN="N">Spike Glycoprotein, Coronavirus</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051196" MajorTopicYN="N">Toll-Like Receptor 3</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D014709" MajorTopicYN="N">Vero Cells</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">MERS-CoV</Keyword>
<Keyword MajorTopicYN="Y">SARS-CoV</Keyword>
<Keyword MajorTopicYN="Y">TMPRSS2</Keyword>
<Keyword MajorTopicYN="Y">animal model</Keyword>
<Keyword MajorTopicYN="Y">immunopathology</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year>
<Month>10</Month>
<Day>11</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2018</Year>
<Month>12</Month>
<Day>28</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2019</Year>
<Month>1</Month>
<Day>11</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2019</Year>
<Month>11</Month>
<Day>20</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2019</Year>
<Month>1</Month>
<Day>11</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>epublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">30626688</ArticleId>
<ArticleId IdType="pii">JVI.01815-18</ArticleId>
<ArticleId IdType="doi">10.1128/JVI.01815-18</ArticleId>
<ArticleId IdType="pmc">PMC6401451</ArticleId>
</ArticleIdList>
<ReferenceList><Reference><Citation>J Virol. 2019 Mar 5;93(6):</Citation>
<ArticleIdList><ArticleId IdType="pubmed">30626685</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Curr Opin Virol. 2017 Jun;24:16-24</Citation>
<ArticleIdList><ArticleId IdType="pubmed">28414992</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Am J Pathol. 2016 Mar;186(3):652-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">26857507</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>East Mediterr Health J. 2013;19 Suppl 1:S12-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23888790</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Nature. 2005 Feb 24;433(7028):887-92</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15711573</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Pathol. 2001 Jan;193(1):134-40</Citation>
<ArticleIdList><ArticleId IdType="pubmed">11169526</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Lancet. 2003 Apr 19;361(9366):1319-25</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12711465</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2013 May;87(10):5502-11</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23468491</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Hum Immunol. 2002 Sep;63(9):719-30</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12175726</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Pulm Pharmacol Ther. 2015 Aug;33:66-74</Citation>
<ArticleIdList><ArticleId IdType="pubmed">26166259</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Mol Genet Med. 2008 Nov 29;3(1):167-75</Citation>
<ArticleIdList><ArticleId IdType="pubmed">19565019</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>N Engl J Med. 2003 May 15;348(20):1953-66</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12690092</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2014 Jan;88(2):1293-307</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24227843</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2014 May;88(9):4744-51</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24522916</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Antiviral Res. 2013 Dec;100(3):605-14</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24121034</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Pathol. 2002 Feb;196(2):220-7</Citation>
<ArticleIdList><ArticleId IdType="pubmed">11793374</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16714379</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>N Engl J Med. 2003 May 15;348(20):1986-94</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12682352</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>N Engl J Med. 2012 Nov 8;367(19):1814-20</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23075143</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2006 Oct;80(19):9896-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16973594</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Pathol. 2015 Jan;235(2):175-84</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25294366</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>N Engl J Med. 2003 May 15;348(20):1967-76</Citation>
<ArticleIdList><ArticleId IdType="pubmed">12690091</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Lancet. 2004 Jan 10;363(9403):99-104</Citation>
<ArticleIdList><ArticleId IdType="pubmed">14726162</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Biol Chem. 2009 Aug 28;284(35):23177-81</Citation>
<ArticleIdList><ArticleId IdType="pubmed">19487698</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2013 Jun;87(11):6150-60</Citation>
<ArticleIdList><ArticleId IdType="pubmed">23536651</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Osong Public Health Res Perspect. 2015 Aug;6(4):269-78</Citation>
<ArticleIdList><ArticleId IdType="pubmed">26473095</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Immunity. 2010 Mar 26;32(3):305-15</Citation>
<ArticleIdList><ArticleId IdType="pubmed">20346772</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2011 May;85(9):4122-34</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21325420</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2016 Apr 14;90(9):4298-4307</Citation>
<ArticleIdList><ArticleId IdType="pubmed">26889029</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2005 Mar;79(5):2910-9</Citation>
<ArticleIdList><ArticleId IdType="pubmed">15709010</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2015 May;89(9):5154-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25673722</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Semin Cell Dev Biol. 2016 May;53:85-93</Citation>
<ArticleIdList><ArticleId IdType="pubmed">26428296</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2010 Dec;84(24):12658-64</Citation>
<ArticleIdList><ArticleId IdType="pubmed">20926566</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Infect Dis. 2015 Oct 15;212(8):1214-21</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25904605</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Am J Pathol. 2008 Jun;172(6):1625-37</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18467696</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Antiviral Res. 2015 Apr;116:76-84</Citation>
<ArticleIdList><ArticleId IdType="pubmed">25666761</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2014 Aug;88(15):8597-614</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24850731</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Lancet. 2003 Oct 25;362(9393):1353-8</Citation>
<ArticleIdList><ArticleId IdType="pubmed">14585636</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Nat Rev Microbiol. 2009 Jun;7(6):439-50</Citation>
<ArticleIdList><ArticleId IdType="pubmed">19430490</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>PLoS One. 2012;7(4):e35876</Citation>
<ArticleIdList><ArticleId IdType="pubmed">22558251</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2011 Jan;85(2):873-82</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21068237</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2013 Dec;87(23):12552-61</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24027332</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2574-9</Citation>
<ArticleIdList><ArticleId IdType="pubmed">18256187</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Nat Rev Microbiol. 2016 Aug;14(8):523-34</Citation>
<ArticleIdList><ArticleId IdType="pubmed">27344959</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2014 May;88(10):5608-16</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24600012</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Biol Chem. 2002 Mar 8;277(10):8338-45</Citation>
<ArticleIdList><ArticleId IdType="pubmed">11756432</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Mol Cell Biol. 2006 Feb;26(3):965-75</Citation>
<ArticleIdList><ArticleId IdType="pubmed">16428450</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>Virology. 2018 Apr;517:9-15</Citation>
<ArticleIdList><ArticleId IdType="pubmed">29217279</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>J Virol. 2011 Dec;85(24):13363-72</Citation>
<ArticleIdList><ArticleId IdType="pubmed">21994442</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
<ReferenceList><Reference><Citation>PLoS Pathog. 2013;9(12):e1003774</Citation>
<ArticleIdList><ArticleId IdType="pubmed">24348248</ArticleId>
</ArticleIdList>
</Reference>
</ReferenceList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>Japon</li>
</country>
<region><li>Région de Kantō</li>
</region>
<settlement><li>Tokyo</li>
</settlement>
</list>
<tree><country name="Japon"><region name="Région de Kantō"><name sortKey="Iwata Yoshikawa, Naoko" sort="Iwata Yoshikawa, Naoko" uniqKey="Iwata Yoshikawa N" first="Naoko" last="Iwata-Yoshikawa">Naoko Iwata-Yoshikawa</name>
</region>
<name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name>
<name sortKey="Nagata, Noriyo" sort="Nagata, Noriyo" uniqKey="Nagata N" first="Noriyo" last="Nagata">Noriyo Nagata</name>
<name sortKey="Okamura, Tadashi" sort="Okamura, Tadashi" uniqKey="Okamura T" first="Tadashi" last="Okamura">Tadashi Okamura</name>
<name sortKey="Shimizu, Yukiko" sort="Shimizu, Yukiko" uniqKey="Shimizu Y" first="Yukiko" last="Shimizu">Yukiko Shimizu</name>
<name sortKey="Takeda, Makoto" sort="Takeda, Makoto" uniqKey="Takeda M" first="Makoto" last="Takeda">Makoto Takeda</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/PubMed/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000359 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Checkpoint/biblio.hfd -nk 000359 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= MersV1 |flux= PubMed |étape= Checkpoint |type= RBID |clé= pubmed:30626688 |texte= TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Checkpoint/RBID.i -Sk "pubmed:30626688" \ | HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Checkpoint/biblio.hfd \ | NlmPubMed2Wicri -a MersV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |