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Journal of Virology, September 2008, p. 8721-8732, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00818-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pathways of Cross-Species Transmission of Synthetically Reconstructed Zoonotic Severe Acute Respiratory Syndrome Coronavirus{triangledown}

Timothy Sheahan,1 Barry Rockx,2 Eric Donaldson,1 Davide Corti,3 and Ralph Baric1,2*

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,1 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,2 Institute for Research in Biomedicine, Bellinzona, Switzerland3

Received 16 April 2008/ Accepted 16 June 2008

Zoonotic severe acute respiratory syndrome coronavirus (SARS-CoV) likely evolved to infect humans by a series of transmission events between humans and animals in markets in China. Virus sequence data suggest that the palm civet served as an amplification host in which civet and human interaction fostered the evolution of the epidemic SARS Urbani strain. The prototypic civet strain of SARS-CoV, SZ16, was isolated from a palm civet but has not been successfully cultured in vitro. To propagate a chimeric recombinant SARS-CoV bearing an SZ16 spike (S) glycoprotein (icSZ16-S), we constructed cell lines expressing the civet ortholog (DBT-cACE2) of the SARS-CoV receptor (hACE2). Zoonotic SARS-CoV was completely dependent on ACE2 for entry. Urbani grew with similar kinetics in both the DBT-cACE2 and the DBT-hACE2 cells, while icSZ16-S only grew in DBT-cACE2 cells. The SZ16-S mutant viruses adapted to human airway epithelial cells and displayed enhanced affinity for hACE2 but exhibited severe growth defects in the DBT-cACE2 cells, suggesting that the evolutionary pathway that promoted efficient hACE2 interactions simultaneously abolished efficient cACE2 interactions. Structural modeling predicted two distinct biochemical interaction networks by which zoonotic receptor binding domain architecture can productively engage hACE2, but only the Urbani mutational repertoire promoted efficient usage of both hACE2 and cACE2 binding interfaces. Since dual species tropism was preserved in Urbani, it is likely that the virus evolved a high affinity for cACE2/hACE2 receptors through adaptation via repeated passages between human and civet hosts. Furthermore, zoonotic SARS-CoV was variably neutralized by antibodies that were effective against the epidemic strain, highlighting their utility for evaluating passive immunization efficacy.

* Corresponding author. Mailing address: Department of Epidemiology, 2107 McGavran-Greenberg, CB no. 7435, University of North Carolina, Chapel Hill, NC 27699-7435. Phone: (919) 966-3895. Fax: (919) 966-2089. E-mail: rbaric{at}email.unc.edu

{triangledown} Published ahead of print on 25 June 2008.

Journal of Virology, September 2008, p. 8721-8732, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00818-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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