Published online before print May 8, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.071060

Accepted for publication February 22, 2008.

Article

Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice

Noriyo Nagata^*@, Naoko Iwata^*, Hideki Hasegawa^*, Shuetsu Fukushi, Ayako Harashima^*, Yuko Sato^*, Masayuki Saijo, Fumihiro Taguchi, Shigeru Morikawa, and Tetsutaro Sata^*

From the Departments of Pathology,* Virology I, and Virology III, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: nnagata{at}nih.go.jp.

	Abstract

Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor- antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon- injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.