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    Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection

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    Author
    Zornetzer, G.A.
    Frieman, M.B.
    Rosenzweig, E.
    Date
    2010
    Journal
    Journal of Virology
    Publisher
    American Society for Microbiology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1128/JVI.01130-10
    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.
    Sponsors
    National Institutes of Health, NIH: R01AI075297; U54AI081680
    Keyword
    severe acute respiratory syndrome coronavirus
    SARS-CoV
    transcriptome analysis
    SARS Virus
    Coronavirus Infections
    STAT1 Transcription Factor
    Gene Expression Profiling
    Mice
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-77957963666&doi=10.1128%2fJVI.01130-10&partnerID=40&md5=8e4a2754eaa1df4fb902fd36218a8677; http://hdl.handle.net/10713/12430
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.01130-10
    Scopus Count
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    UMB Coronavirus Publications

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