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J. Virol. doi:10.1128/JVI.00505-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

SYNTHETIC RECONSTRUCTION OF ZOONOTIC AND EARLY HUMAN SARS-COV ISOLATES THAT PRODUCE FATAL DISEASE IN AGED MICE

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America, Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, University Health Network, University of Toronto, Toronto, Ontario, Canada

^* To whom correspondence should be addressed. Email: rbaric{at}email.unc.edu.

	Abstract

The SARS-CoV epidemic was characterized by high mortality rates in the eldery. 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 age. Using synthetic biology and reverse genetics, we describe the construction of a panel of isogenic 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 HC/SZ/61/03 palm civet 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.

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