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Journal of Virology, July 2007, p. 7410-7423, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00505-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Synthetic Reconstruction of Zoonotic and Early Human Severe Acute Respiratory Syndrome Coronavirus Isolates That Produce Fatal Disease in Aged Mice{triangledown}

Barry Rockx,1 Timothy Sheahan,2 Eric Donaldson,2 Jack Harkema,4 Amy Sims,1 Mark Heise,2,3 Raymond Pickles,2,5 Mark Cameron,6 David Kelvin,6 and Ralph Baric1,2,3*

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,1 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,2 Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,3 Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan,4 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,5 University Health Network, University of Toronto, Toronto, Ontario, Canada6

Received 9 March 2007/ Accepted 3 May 2007

The severe acute respiratory syndrome (SARS) epidemic was characterized by high mortality rates in the elderly. The molecular mechanisms that govern enhanced susceptibility of elderly populations are not known, and robust animal models are needed that recapitulate the increased pathogenic phenotype noted with increasing age. Using synthetic biology and reverse genetics, we describe the construction of a panel of isogenic SARS coronavirus (SARS-CoV) strains bearing variant spike glycoproteins that are representative of zoonotic strains found in palm civets and raccoon dogs, as well as isolates spanning the early, middle, and late phases of the SARS-CoV epidemic. The recombinant viruses replicated efficiently in cell culture and demonstrated variable sensitivities to neutralization with antibodies. The human but not the zoonotic variants replicated efficiently in human airway epithelial cultures, supporting earlier hypotheses that zoonotic isolates are less pathogenic in humans but can evolve into highly pathogenic strains. All viruses replicated efficiently, but none produced clinical disease or death in young animals. In contrast, severe clinical disease, diffuse alveolar damage, hyaline membrane formation, alveolitis, and death were noted in 12-month-old mice inoculated with the palm civet HC/SZ/61/03 strain or early-human-phase GZ02 variants but not with related middle- and late-phase epidemic or raccoon dog strains. This panel of SARS-CoV recombinants bearing zoonotic and human epidemic spike glycoproteins will provide heterologous challenge models for testing vaccine efficacy against zoonotic reintroductions as well as provide the appropriate model system for elucidating the complex virus-host interactions that contribute to more-severe and fatal SARS-CoV disease and acute respiratory distress in the elderly.

* Corresponding author. Mailing address: Department of Epidemiology, 2107 McGavran-Greenberg, CB#7435, University of North Carolina, Chapel Hill, NC 27699-7435. Phone: (919) 966-3895. Fax: (919) 966-0584. E-mail: rbaric{at}email.unc.edu

{triangledown} Published ahead of print on 16 May 2007.

Journal of Virology, July 2007, p. 7410-7423, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00505-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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