SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism

被引:130
作者
Frieman, Matthew B. [1 ]
Chen, Jun [2 ]
Morrison, Thomas E. [3 ]
Whitmore, Alan [3 ]
Funkhouser, William [4 ]
Ward, Jerrold M. [5 ,6 ]
Lamirande, Elaine W. [2 ]
Roberts, Anjeanette [2 ]
Heise, Mark
Subbarao, Kanta [2 ]
Baric, Ralph S. [1 ,3 ]
机构
[1] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA
[2] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA
[3] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA
[4] Univ N Carolina, Dept Anat Pathol & Surg Pathol, Chapel Hill, NC USA
[5] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA
[6] NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA
关键词
ACUTE RESPIRATORY SYNDROME; CORONAVIRUS CAUSES DISEASE; INNATE IMMUNITY; HOST-DEFENSE; INFECTION; MICE; IFN; REPLICATION; RESPONSES; PROTEIN;
D O I
10.1371/journal.ppat.1000849
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Severe acute respiratory syndrome coronavirus (SARS-CoV) infection often caused severe end stage lung disease and organizing phase diffuse alveolar damage, especially in the elderly. The virus-host interactions that governed development of these acute end stage lung diseases and death are unknown. To address this question, we evaluated the role of innate immune signaling in protection from human (Urbani) and a recombinant mouse adapted SARS-CoV, designated rMA15. In contrast to most models of viral pathogenesis, infection of type I, type II or type III interferon knockout mice (129 background) with either Urbani or MA15 viruses resulted in clinical disease outcomes, including transient weight loss, denuding bronchiolitis and alveolar inflammation and recovery, identical to that seen in infection of wildtype mice. This suggests that type I, II and III interferon signaling play minor roles in regulating SARS pathogenesis in mouse models. In contrast, infection of STAT1(-/-) mice resulted in severe disease, high virus titer, extensive pulmonary lesions and 100% mortality by day 9 and 30 post-infection with rMA15 or Urbani viruses, respectively. Non-lethal in BALB/c mice, Urbani SARS CoV infection in STAT1(-/-) mice caused disseminated infection involving the liver, spleen and other tissues after day 9. These findings demonstrated that SARS-CoV pathogenesis is regulated by a STAT1 dependent but type I, II and III interferon receptor independent, mechanism. In contrast to a well documented role in innate immunity, we propose that STAT1 also protects mice via its role as an antagonist of unrestrained cell proliferation.
引用
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页码:1 / 14
页数:14
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