title: Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection.
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.
authors: Department of Microbiology, School of Medicine, University of Washington, Box 358070, Seattle, WA 98195-8070, USA.
authors: Gregory A
authors: GA
authors: Zornetzer
authors: Matthew B
authors: MB
authors: Frieman
authors: Elizabeth
authors: E
authors: Rosenzweig
authors: Marcus J
authors: MJ
authors: Korth
authors: Carly
authors: C
authors: Page
authors: Ralph S
authors: RS
authors: Baric
authors: Michael G
authors: MG
authors: Katze
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000209:etiology* / Q000235:genetics; D020869:Gene Expression Profiling; D008171:Lung Diseases / Q000209:etiology / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency; D045473:Severe acute respiratory syndrome-related coronavirus; D050794:STAT1 Transcription Factor / Q000172:deficiency*; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D053633:Receptor, Interferon alpha-beta