期刊
JOURNAL OF VIROLOGY
卷 84, 期 21, 页码 11297-11309出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01130-10
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资金
- Public Health Service [AI66542, AI075297, AI059443, HL080621]
- U.S. Public Health Service [U54 AI081680]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800060C]
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 T(H)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(-/-) mice.
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