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Journal of Virology, November 2006, p. 10382-10394, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00747-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Murine Hepatitis Virus Strain 1 Produces a Clinically Relevant Model of Severe Acute Respiratory Syndrome in A/J Mice

Nadine De Albuquerque,1,4 Ehtesham Baig,5 Xuezhong Ma,1,4 Jianhua Zhang,1,4 William He,1,4 Andrea Rowe,1,4 Marlena Habal,1,4 Mingfeng Liu,1,4 Itay Shalev,1,4 Gregory P. Downey,1,4 Reginald Gorczynski,2,4 Jagdish Butany,3 Julian Leibowitz,7 Susan R. Weiss,6 Ian D. McGilvray,2,4,5 M. James Phillips,3,4 Eleanor N. Fish,5 and Gary A. Levy1,4,5*

Departments of Medicine,1 Surgery,2 Pathology,3 the Multi Organ Transplant Program,4 University Health Network, University of Toronto, Toronto, Ontario, Canada,5 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania,6 Department of Microbial and Molecular Pathogenesis, Texas A&M University System-HSC, College Station, Texas7

Received 12 April 2006/ Accepted 5 August 2006

Severe acute respiratory syndrome (SARS) is a life-threatening infectious disease which has been difficult to study and treat because of the lack of a readily available animal model. Intranasal infection of A/J mice with the coronavirus murine hepatitis virus strain 1 (MHV-1) produced pulmonary pathological features of SARS. All MHV-1-infected A/J mice developed progressive interstitial pneumonitis, including dense macrophage infiltrates, giant cells, and hyaline membranes, resulting in death of all animals. In contrast, other mouse strains developed only mild transitory disease. Infected A/J mice had significantly higher cytokine levels, particularly macrophage chemoattractant protein 1 (MCP-1/CCL-2), gamma interferon, and tumor necrosis factor alpha. Furthermore, FGL2/fibroleukin mRNA transcripts and protein and fibrin deposits were markedly increased in the lungs of infected A/J mice. These animals developed a less robust type I interferon response to MHV-1 infection than resistant C57BL/6J mice, and treatment with recombinant beta interferon improved survival. This study describes a potentially useful small animal model of human SARS, defines its pathogenesis, and suggests treatment strategies.

* Corresponding author. Mailing address: Toronto General Hospital, 585 University Ave., NCSB-11-1236, Toronto, Ontario M5G 2N2, Canada. Phone: (416) 340-5166. Fax: (416) 340-3378. E-mail: glfgl2{at}attglobal.net.

Journal of Virology, November 2006, p. 10382-10394, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00747-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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