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Genetic Diversity and Evolution

Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium

Timothy Sheahan, Barry Rockx, Eric Donaldson, Amy Sims, Raymond Pickles, Davide Corti, Ralph Baric
Timothy Sheahan
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Barry Rockx
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Eric Donaldson
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Amy Sims
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Raymond Pickles
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
3Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Davide Corti
4Institute for Research in Biomedicine, Bellinzona, Switzerland
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Ralph Baric
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
2Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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  • For correspondence: rbaric@email.unc.edu
DOI: 10.1128/JVI.02041-07
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ABSTRACT

In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) emerged and caused over 8,000 human cases of infection and more than 700 deaths worldwide. Zoonotic SARS-CoV likely evolved to infect humans by a series of transmission events between humans and animals for sale in China. Using synthetic biology, we engineered the spike protein (S) from a civet strain, SZ16, into our epidemic strain infectious clone, creating the chimeric virus icSZ16-S, which was infectious but yielded progeny viruses incapable of propagating in vitro. After introducing a K479N mutation within the S receptor binding domain (RBD) of SZ16, the recombinant virus (icSZ16-S K479N) replicated in Vero cells but was severely debilitated in growth. The in vitro evolution of icSZ16-S K479N on human airway epithelial (HAE) cells produced two viruses (icSZ16-S K479N D8 and D22) with enhanced growth on HAE cells and on delayed brain tumor cells expressing the SARS-CoV receptor, human angiotensin I converting enzyme 2 (hACE2). The icSZ16-S K479N D8 and D22 virus RBDs contained mutations in ACE2 contact residues, Y442F and L472F, that remodeled S interactions with hACE2. Further, these viruses were neutralized by a human monoclonal antibody (MAb), S230.15, but the parent icSZ16-S K479N strain was eight times more resistant than the mutants. These data suggest that the human adaptation of zoonotic SARS-CoV strains may select for some variants that are highly susceptible to select MAbs that bind to RBDs. The epidemic, icSZ16-S K479N, and icSZ16-S K479N D22 viruses replicate similarly in the BALB/c mouse lung, highlighting the potential use of these zoonotic spike SARS-CoVs to assess vaccine or serotherapy efficacy in vivo.

  • Copyright © 2008 American Society for Microbiology
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Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium
Timothy Sheahan, Barry Rockx, Eric Donaldson, Amy Sims, Raymond Pickles, Davide Corti, Ralph Baric
Journal of Virology Feb 2008, 82 (5) 2274-2285; DOI: 10.1128/JVI.02041-07

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Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium
Timothy Sheahan, Barry Rockx, Eric Donaldson, Amy Sims, Raymond Pickles, Davide Corti, Ralph Baric
Journal of Virology Feb 2008, 82 (5) 2274-2285; DOI: 10.1128/JVI.02041-07
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KEYWORDS

SARS Virus
Trachea
zoonoses

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