Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection▿ †
Identifieur interne : 002188 ( Ncbi/Merge ); précédent : 002187; suivant : 002189Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection▿ †
Auteurs : Gregory A. Zornetzer ; Matthew B. Frieman ; Elizabeth Rosenzweig ; Marcus J. Korth ; Carly Page ; Ralph S. Baric ; Michael G. KatzeSource :
- Journal of Virology [ 0022-538X ] ; 2010.
Descripteurs français
- KwdFr :
- ARN messager (analyse), Analyse de profil d'expression de gènes, Animaux, Facteur de transcription STAT-1 (déficit), Fibrose (génétique), Fibrose (étiologie), Lymphocytes auxiliaires Th2 (immunologie), Macrophages (anatomopathologie), Maladies pulmonaires (génétique), Maladies pulmonaires (étiologie), Phénotype, Récepteur à l'interféron alpha-bêta (déficit), Souris, Souris knockout, Syndrome respiratoire aigu sévère (anatomopathologie), Syndrome respiratoire aigu sévère (immunologie), Virus du SRAS.
- MESH :
- analyse : ARN messager.
- anatomopathologie : Macrophages, Syndrome respiratoire aigu sévère.
- déficit : Facteur de transcription STAT-1, Récepteur à l'interféron alpha-bêta.
- génétique : Fibrose, Maladies pulmonaires.
- immunologie : Lymphocytes auxiliaires Th2, Syndrome respiratoire aigu sévère.
- étiologie : Fibrose, Maladies pulmonaires.
- Analyse de profil d'expression de gènes, Animaux, Phénotype, Souris, Souris knockout, Virus du SRAS.
English descriptors
- KwdEn :
- Animals, Fibrosis (etiology), Fibrosis (genetics), Gene Expression Profiling, Lung Diseases (etiology), Lung Diseases (genetics), Macrophages (pathology), Mice, Mice, Knockout, Phenotype, RNA, Messenger (analysis), Receptor, Interferon alpha-beta (deficiency), SARS Virus, STAT1 Transcription Factor (deficiency), Severe Acute Respiratory Syndrome (immunology), Severe Acute Respiratory Syndrome (pathology), Th2 Cells (immunology).
- MESH :
- chemical , analysis : RNA, Messenger.
- chemical , deficiency : Receptor, Interferon alpha-beta, STAT1 Transcription Factor.
- etiology : Fibrosis, Lung Diseases.
- genetics : Fibrosis, Lung Diseases.
- immunology : Severe Acute Respiratory Syndrome, Th2 Cells.
- pathology : Macrophages, Severe Acute Respiratory Syndrome.
- Animals, Gene Expression Profiling, Mice, Mice, Knockout, Phenotype, SARS Virus.
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1−/−), and STAT1 knockout (STAT1−/−) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1−/− mice, contributing to clearance of the virus. In contrast, STAT1−/− mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1−/− mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a TH2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1−/− mice.
Url:
DOI: 10.1128/JVI.01130-10
PubMed: 20702617
PubMed Central: 2953159
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PMC:2953159Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1<sup>−/−</sup>
), and STAT1 knockout (STAT1<sup>−/−</sup>
) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1<sup>−/−</sup>
mice, contributing to clearance of the virus. In contrast, STAT1<sup>−/−</sup>
mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1<sup>−/−</sup>
mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a T<sub>H</sub>
2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1<sup>−/−</sup>
mice.</p>
</div>
</front>
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<front><div type="abstract" xml:lang="en"><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1<sup>−/−</sup>
), and STAT1 knockout (STAT1<sup>−/−</sup>
) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1<sup>−/−</sup>
mice, contributing to clearance of the virus. In contrast, STAT1<sup>−/−</sup>
mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1<sup>−/−</sup>
mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a T<sub>H</sub>
2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1<sup>−/−</sup>
mice.</p>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection.</title>
<author><name sortKey="Zornetzer, Gregory A" sort="Zornetzer, Gregory A" uniqKey="Zornetzer G" first="Gregory A" last="Zornetzer">Gregory A. Zornetzer</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology, School of Medicine, University of Washington, Box 358070, Seattle, WA 98195-8070, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology, School of Medicine, University of Washington, Box 358070, Seattle, WA 98195-8070</wicri:regionArea>
<placeName><region type="state">Washington (État)</region>
<settlement type="city">Seattle</settlement>
</placeName>
<orgName type="university">Université de Washington</orgName>
</affiliation>
</author>
<author><name sortKey="Frieman, Matthew B" sort="Frieman, Matthew B" uniqKey="Frieman M" first="Matthew B" last="Frieman">Matthew B. Frieman</name>
</author>
<author><name sortKey="Rosenzweig, Elizabeth" sort="Rosenzweig, Elizabeth" uniqKey="Rosenzweig E" first="Elizabeth" last="Rosenzweig">Elizabeth Rosenzweig</name>
</author>
<author><name sortKey="Korth, Marcus J" sort="Korth, Marcus J" uniqKey="Korth M" first="Marcus J" last="Korth">Marcus J. Korth</name>
</author>
<author><name sortKey="Page, Carly" sort="Page, Carly" uniqKey="Page C" first="Carly" last="Page">Carly Page</name>
</author>
<author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name>
</author>
<author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G" last="Katze">Michael G. Katze</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>Fibrosis (etiology)</term>
<term>Fibrosis (genetics)</term>
<term>Gene Expression Profiling</term>
<term>Lung Diseases (etiology)</term>
<term>Lung Diseases (genetics)</term>
<term>Macrophages (pathology)</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Phenotype</term>
<term>RNA, Messenger (analysis)</term>
<term>Receptor, Interferon alpha-beta (deficiency)</term>
<term>SARS Virus</term>
<term>STAT1 Transcription Factor (deficiency)</term>
<term>Severe Acute Respiratory Syndrome (immunology)</term>
<term>Severe Acute Respiratory Syndrome (pathology)</term>
<term>Th2 Cells (immunology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>ARN messager (analyse)</term>
<term>Analyse de profil d'expression de gènes</term>
<term>Animaux</term>
<term>Facteur de transcription STAT-1 (déficit)</term>
<term>Fibrose (génétique)</term>
<term>Fibrose (étiologie)</term>
<term>Lymphocytes auxiliaires Th2 (immunologie)</term>
<term>Macrophages (anatomopathologie)</term>
<term>Maladies pulmonaires (génétique)</term>
<term>Maladies pulmonaires (étiologie)</term>
<term>Phénotype</term>
<term>Récepteur à l'interféron alpha-bêta (déficit)</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Syndrome respiratoire aigu sévère (anatomopathologie)</term>
<term>Syndrome respiratoire aigu sévère (immunologie)</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>RNA, Messenger</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Receptor, Interferon alpha-beta</term>
<term>STAT1 Transcription Factor</term>
</keywords>
<keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>ARN messager</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Macrophages</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Facteur de transcription STAT-1</term>
<term>Récepteur à l'interféron alpha-bêta</term>
</keywords>
<keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Fibrosis</term>
<term>Lung Diseases</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Fibrosis</term>
<term>Lung Diseases</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Fibrose</term>
<term>Maladies pulmonaires</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Lymphocytes auxiliaires Th2</term>
<term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
<term>Th2 Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Macrophages</term>
<term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" qualifier="étiologie" xml:lang="fr"><term>Fibrose</term>
<term>Maladies pulmonaires</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Gene Expression Profiling</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Phenotype</term>
<term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Analyse de profil d'expression de gènes</term>
<term>Animaux</term>
<term>Phénotype</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Virus du SRAS</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1-/-), and STAT1 knockout (STAT1-/-) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1-/- mice, contributing to clearance of the virus. In contrast, STAT1-/- mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1-/- mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a TH2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1-/- mice.</div>
</front>
</TEI>
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