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

Advanced age is a risk factor of severe acute respiratory syndrome(SARS) in humans. To understand its pathogenesis, we developedan animal model using BALB/c mice and the mouse-passaged Frankfurt1 isolate of SARS coronavirus (SARS-CoV). We examined the immuneresponses to SARS-CoV in both young and adult mice. SARS-CoVinduced severe respiratory illness in all adult, but not young,mice on day 2 after inoculation with a mortality rate of 30to 50%. Moribund adult mice showed severe pulmonary edema anddiffuse alveolar damage accompanied by virus replication. Adultmurine lungs, which had significantly higher interleukin (IL)-4and lower IL-10 and IL-13 levels before infection than youngmurine lungs, rapidly produced high levels of proinflammatorychemokines and cytokines known to induce macrophage and neutrophilinfiltration and activation (eg, tumor necrosis factor- ${alpha}$ ). Onday 2 after inoculation, young murine lungs produced not onlyproinflammatory cytokines but also IL-2, interferon- ${gamma}$ , IL-10,and IL-13. Adult mice showed early and acute excessive proinflammatoryresponses (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- ${alpha}$ antibody3 hours after infection had no effect on SARS-CoV infection.However, intraperitoneal interferon- ${gamma}$ injection protected adultmice from the lethal respiratory illness. The experimental modeldescribed here may be useful for elucidating the pathophysiologyof SARS and for evaluating therapies to treat SARS-CoV infection.