Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection
Identifieur interne : 002951 ( Main/Merge ); précédent : 002950; suivant : 002952Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection
Auteurs : Gregory A. Zornetzer [États-Unis] ; Matthew B. Frieman [États-Unis] ; Elizabeth Rosenzweig [États-Unis] ; Marcus J. Korth [États-Unis] ; Carly Page [États-Unis] ; Ralph S. Baric [États-Unis] ; Michael G. Katze [États-Unis]Source :
- Journal of virology [ 0022-538X ] ; 2010.
Descripteurs français
- Pascal (Inist)
English descriptors
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.
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<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<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.</div>
</front>
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<tree><country name="États-Unis"><region name="Washington (État)"><name sortKey="Zornetzer, Gregory A" sort="Zornetzer, Gregory A" uniqKey="Zornetzer G" first="Gregory A." last="Zornetzer">Gregory A. Zornetzer</name>
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<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Frieman, Matthew B" sort="Frieman, Matthew B" uniqKey="Frieman M" first="Matthew B." last="Frieman">Matthew B. Frieman</name>
<name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name>
<name sortKey="Korth, Marcus J" sort="Korth, Marcus J" uniqKey="Korth M" first="Marcus J." last="Korth">Marcus J. Korth</name>
<name sortKey="Page, Carly" sort="Page, Carly" uniqKey="Page C" first="Carly" last="Page">Carly Page</name>
<name sortKey="Rosenzweig, Elizabeth" sort="Rosenzweig, Elizabeth" uniqKey="Rosenzweig E" first="Elizabeth" last="Rosenzweig">Elizabeth Rosenzweig</name>
</country>
</tree>
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</record>
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