Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection.
To establish a small animal model of severe acute respiratory syndrome (SARS), we developed a mouse model of human severe acute respiratory syndrome coronavirus (SARS-CoV) infection by introducing the human gene for angiotensin-converting enzyme 2 (hACE2) (the cellular receptor of SARS-CoV), driven by the mouse ACE2 promoter, into the mouse genome. The hACE2 gene was expressed in lung, heart, kidney, and intestine. We also evaluated the responses of wild-type and transgenic mice to SARS-CoV inoculation. At days 3 and 7 postinoculation, SARS-CoV replicated more efficiently in the lungs of transgenic mice than in those of wild-type mice. In addition, transgenic mice had more severe pulmonary lesions, including interstitial hyperemia and hemorrhage, monocytic and lymphocytic infiltration, protein exudation, and alveolar epithelial cell proliferation and desquamation. Other pathologic changes, including vasculitis, degeneration, and necrosis, were found in the extrapulmonary organs of transgenic mice, and viral antigen was found in brain. Therefore, transgenic mice were more susceptible to SARS-CoV than were wild-type mice, and susceptibility was associated with severe pathologic changes that resembled human SARS infection. These mice will be valuable for testing potential vaccine and antiviral drug therapies and for furthering our understanding of SARS pathogenesis.
Yang
Xiu-Hong
XH
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, PR China.
Deng
Wei
W
Tong
Zan
Z
Liu
Yan-Xia
YX
Zhang
Lian-Feng
LF
Zhu
Hua
H
Gao
Hong
H
Huang
Lan
L
Liu
Ya-Li
YL
Ma
Chun-Mei
CM
Xu
Yan-Feng
YF
Ding
Ming-Xiao
MX
Deng
Hong-Kui
HK
Qin
Chuan
C
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005818:Genetic Engineering; D020022:Genetic Predisposition to Disease; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics / Q000473:pathology / Q000821:virology*
D012333:RNA, Messenger; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2