Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection

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  • Zornetzer, Gregory A.
    • Other Affiliation: University of Washington
  • Frieman, Matthew B.
    • Other Affiliation: University of Maryland
  • Rosenzweig, Elizabeth
    • Other Affiliation: University of Washington
  • Korth, Marcus J.
    • Other Affiliation: University of Washington
  • Page, Carly
    • Other Affiliation: University of Maryland
  • Baric, Ralph
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Katze, Michael G.
    • Other Affiliation: University of Washington
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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  • Article
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  • In Copyright
Journal title
  • Journal of Virology
Journal volume
  • 84
Journal issue
  • 21
Page start
  • 11297
Page end
  • 11309
Language
  • English
ISSN
  • 0022-538X

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