SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism
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and III Interferon Receptor Independent Mechanism. PLoS Pathog 6(4): e1000849. doi:10.1371/journal.ppat.1000849
SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism
Matthew B. Frieman 0 1
Jun Chen 0 1
Thomas E. Morrison 0 1
Alan Whitmore 0 1
William Funkhouser 0 1
Jerrold M. Ward 0 1
Elaine W. Lamirande 0 1
Anjeanette Roberts 0 1
Mark Heise 0 1
Kanta Subbarao 0 1
Ralph S. 0 1
Michael Gale Jr., University of Washington, United States of America
0 a Current address: Department of Microbiology and Immunology, University of Maryland School of Medicine , Baltimore , Maryland, United States of America b Current address: Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland, United States of America c Current address: Department of Microbiology, University of Colorado Denver , Aurora, Colorado , United States of America
1 1 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 2 Laboratory of Infectious Diseases , NIAID, NIH, Bethesda , Maryland, United States of America, 3 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 4 Department of Anatomic Pathology and Surgical Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America , 5 Comparative Medicine Branch, NIAID, NIH, Bethesda , Maryland, United States of America, 6 Laboratory of Immunopathology, NIAID, NIH , Bethesda, Maryland , United States of America
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 STAT12/2 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 SARSCoV infection in STAT12/2 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.
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Funding: This work was supported by grants AI66542 to Matthew Frieman, AI075297 and AI059443 to Ralph Baric and by the Intramural Research Program of
NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
SARS Coronavirus (SARS-CoV) is a highly pathogenic
respiratory virus that emerged in China during the winter of
2002 and infected about 8,000 people globally and resulted in
,800 deaths, with greatly increased mortality rates in persons over
50 years of age (WHO). On initial isolation of SARS-CoV from
infected patients, it was identified as a novel Group 2 Coronavirus
and the genetic mechanisms governing the increased pathogenicity
of the virus remain undefined [1,2]. In severe cases, SARS-CoV
infection rapidly progressed to acute respiratory distress syndrome
(ARDS) during the acute phase of infection or to an organizing
phase diffuse alveolar damage following virus clearance; two
clinically devastating end stage lung diseases. The molecular
mechanisms governing these severe end stage lung disease
outcomes are unknown, although similar pathologies have been
reported following H5N1 and 1918 influenza virus infection.
The innate immune response is a key first line of defense against
invading pathogens and is dependent on various signaling
pathways and sensors that ultimately induce hundreds of
antiviral proteins to establish a suboptimal environment for replication
and spread of invading pathogens [3,4]. During virus infection the
type I interferon (IFN) induction and signaling ma (...truncated)