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A Severe Acute Respiratory Syndrome-Associated Coronavirus-Specific Protein Enhances Virulence of an Attenuated Murine Coronavirus

Lecia Pewe,^1, Haixia Zhou,^2, Jason Netland,¹ Chandra Tangudu,³ Heidi Olivares,³ Lei Shi,⁴ Dwight Look,⁴ Thomas Gallagher,³ and Stanley Perlman^1,2*

Departments of Pediatrics,¹ Microbiology,² Internal Medicine, University of Iowa, Iowa City, Iowa 52242,⁴ Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, Illinois 60153³

Received 11 April 2005/ Accepted 8 June 2005

Most animal species that can be infected with the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) do not reproducibly develop clinical disease, hindering studies of pathogenesis. To develop an alternative system for the study of SARS-CoV, we introduced individual SARS-CoV genes (open reading frames [ORFs]) into the genome of an attenuated murine coronavirus. One protein, the product of SARS-CoV ORF6, converted a sublethal infection to a uniformly lethal encephalitis and enhanced virus growth in tissue culture cells, indicating that SARS-CoV proteins function in the context of a heterologous coronavirus infection. Furthermore, these results suggest that the attenuated murine coronavirus lacks a virulence gene residing in SARS-CoV. Recombinant murine coronaviruses cause a reproducible and well-characterized clinical disease, offer virtually no risk to laboratory personnel, and should be useful for elucidating the role of SARS-CoV nonstructural proteins in viral replication and pathogenesis.

L.P. and H.Z. contributed equally to the work.

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