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Cited by 162SARS-CoV-2 and COVID-19 Researchinterferon and immune responsesCytokine Signaling Pathways and Interactions

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

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Frieman, Matthew B., Chen, Jun, Morrison, Thomas E., Whitmore, Alan, Funkhouser, William, Ward, Jerrold M., Lamirande, Elaine W., Roberts, Anjeanette +3 more·2010·PLoS Pathogens
DOI 10.1371/journal.ppat.1000849PMC PMC2851658
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Abstract

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.

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  • Characterization of a recombinant mouse-adapted SARS-CoV strain rMA15 in STAT1 knockout mice revealed increased pathology in the absence of STAT1 signaling, including evidence of pulmonary fibrotic lesions.

    “Characterization of a recombinant mouse-adapted SARS-CoV strain (rMA15) in STAT1 knockout mice revealed increased pathology in the absence of STAT1 signaling, including evidence of pulmonary fibrotic lesions (52).”

    From Into the Eye of the Cytokine Storm (2012) · cites this paper as [52]

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  1. [23]Rockx B Baas T Zornetzer GA Haagmans B Sheahan T 2009 Early Upregulation of ARDS Associated Cytokines Promote Lethal Disease in an Aged Mouse Model of SARS-CoV Infection. J Virol PMC2704758 19420084

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Authors
Frieman, M. B., Chen, J., Morrison, T. E., Whitmore, A., Funkhouser, W., Ward, J. M., Lamirande, E. W., Roberts, A., Heise, M., Subbarao, K., & Baric, R. S.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • National Institutes of Health (US)
Corresponding author
Baric, Ralph S.
ORCID
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2010-04-08
Volume
6
Issue
4
Pages
e1000849
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1000849
PMC
PMC2851658
OpenAlex
W2049537492
Cited by
158
References
55
Citations by year
2026: 1 · 2024: 10 · 2023: 8 · 2022: 14 · 2021: 14 · 2020: 51 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 11 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 13
FWCI
5.99
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (AI075297, AI059443, R01AI075297, AI66542, F32AI066542, P01AI059443)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
SARS-CoV, STAT1, interferon signaling, type I interferon, interferon-gamma, interferon lambda, viral pathogenesis, innate immunity, STAT1 knockout mice, lung lesions, disseminated viral infection, cell proliferation regulation
MeSH terms
Animals, Female, Flow Cytometry, Interferon Type I, Interferon-gamma, Gene Expression, Cytokines, In Situ Hybridization, Receptors, Interferon, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome-related coronavirus, STAT1 Transcription Factor, Mice

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