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Journal of Virology, February 2007, p. 1848-1857, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01967-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Participation of both Host and Virus Factors in Induction of Severe Acute Respiratory Syndrome (SARS) in F344 Rats Infected with SARS Coronavirus{triangledown}

Noriyo Nagata,1* Naoko Iwata,1 Hideki Hasegawa,1 Shuetsu Fukushi,2 Masaru Yokoyama,3 Ayako Harashima,1 Yuko Sato,1 Masayuki Saijo,2 Shigeru Morikawa,2 and Tetsutaro Sata1

Departments of Pathology,1 Virology I,2 Center for Pathogen Genomics, National Institute of Infectious Diseases, Tokyo, Japan3

Received 9 September 2006/ Accepted 20 November 2006

To understand the pathogenesis and develop an animal model of severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV), the Frankfurt 1 SARS-CoV isolate was passaged serially in young F344 rats. Young rats were susceptible to SARS-CoV but cleared the virus rapidly within 3 to 5 days of intranasal inoculation. After 10 serial passages, replication and virulence of SARS-CoV were increased in the respiratory tract of young rats without clinical signs. By contrast, adult rats infected with the passaged virus showed respiratory symptoms and severe pathological lesions in the lung. Levels of inflammatory cytokines in sera and lung tissues were significantly higher in adult F344 rats than in young rats. During in vivo passage of SARS-CoV, a single amino acid substitution was introduced within the binding domain of the viral spike protein recognizing angiotensin-converting enzyme 2 (ACE2), which is known as a SARS-CoV receptor. The rat-passaged virus more efficiently infected CHO cells expressing rat ACE2 than did the original isolate. These results strongly indicate that host and virus factors such as advanced age and virus adaptation are critical for the development of SARS in rats.

* Corresponding author. Mailing address: Department of Pathology, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011, Japan. Phone: 81-42-561-0771. Fax: 81-42-561-6572. E-mail: nnagata{at}nih.go.jp.

{triangledown} Published ahead of print on 6 December 2006.

Journal of Virology, February 2007, p. 1848-1857, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01967-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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