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

作者：Gregory A. Zornetzer, Matthew B. Frieman, Elizabeth Rosenzweig, Marcus J. Korth, Carly Page, Ralph S. Baric, Michael G. Katze · 发表于：Journal of Virology · 年份：2010 · DOI：10.1128/jvi.01130-10 · 被引用次数：49 · 研究领域：SARS-CoV-2 and COVID-19 Research、Respiratory viral infections research、COVID-19 Clinical Research Studies

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.