Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease

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  • Matthew Frieman
    • Other Affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
  • Boyd Yount
    • Other Affiliation: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Sudhakar Agnihothram
    • Other Affiliation: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Carly Page
    • Other Affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
  • Eric Donaldson
    • Other Affiliation: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Anjeanette Roberts
    • Other Affiliation: Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA
  • Leatrice Vogel
    • Other Affiliation: Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA
  • Becky Woodruff
    • Other Affiliation: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  • Diana Scorpio
    • Other Affiliation: Department of Molecular and Comparative Pathology, Johns Hopkins University, Baltimore, Maryland, USA
  • Kanta Subbarao
    • Other Affiliation: Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA
  • Ralph S. Baric
    • Other Affiliation: Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Abstract
  • SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease.
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  • Article
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  • In Copyright
Journal title
  • Journal of Virology
Journal volume
  • 86
Journal issue
  • 2
Page start
  • 884
Page end
  • 897
Language
  • English
ISSN
  • 1098-5514
  • 0022-538X
  • 1070-6321
Publisher
  • American Society for Microbiology

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