title: Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice.
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-alpha). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-gamma, 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-alpha antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-gamma 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.
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011, Japan. nnagata@nih.go.jp
authors.forename: Noriyo
authors.initials: N
authors.lastname: Nagata
authors.forename: Naoko
authors.initials: N
authors.lastname: Iwata
authors.forename: Hideki
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Shuetsu
authors.initials: S
authors.lastname: Fukushi
authors.forename: Ayako
authors.initials: A
authors.lastname: Harashima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saijo
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Taguchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morikawa
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Sata
mesh_terms: D000375:Aging / Q000276:immunology* / Q000473:pathology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011650:Pulmonary Alveoli / Q000473:pathology* / Q000821:virology; D011654:Pulmonary Edema / Q000276:immunology / Q000473:pathology / Q000821:virology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology / Q000502:physiology*; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014779:Virus Replication
chemical_list: D016207:Cytokines