title: Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus.
abstract: The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA. Paul-McCray@uiowa.edu
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.forename: Lecia
authors.initials: L
authors.lastname: Pewe
authors.forename: Christine
authors.initials: C
authors.lastname: Wohlford-Lenane
authors.forename: Melissa
authors.initials: M
authors.lastname: Hickey
authors.forename: Lori
authors.initials: L
authors.lastname: Manzel
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Jason
authors.initials: J
authors.lastname: Netland
authors.forename: Hong Peng
authors.initials: HP
authors.lastname: Jia
authors.forename: Carmen
authors.initials: C
authors.lastname: Halabi
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Patricia
authors.initials: P
authors.lastname: Kirby
authors.forename: Dwight C
authors.initials: DC
authors.lastname: Look
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D006801:Humans; D053538:Keratin-18 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000472:pathogenicity*; D045169:Severe Acute Respiratory Syndrome / Q000401:mortality / Q000473:pathology / Q000821:virology
chemical_list: D053538:Keratin-18; D007703:Peptidyl-Dipeptidase A