Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques.
Angiotensin converting enzyme 2 (ACE2) is the receptor that severe acute respiratory syndrome coronavirus (SARS-CoV) utilizes for target cell entry and, therefore, plays an important role in SARS pathogenesis. Since Chinese rhesus (rh) macaques do not usually develop SARS after SARS-CoV infection, it has been suggested that rh-ACE2 probably does not support viral entry efficiently. To determine the role of rh-ACE2 in early lung pathogenesis in vivo, we studied eleven Chinese rhesus monkeys experimentally infected with a pathogenic SARS-CoV(PUMC01) strain. Rh-ACE2 genes were amplified from all animals by reverse transcription polymerase chain reaction, and their function was studied in vitro using a pseudovirus entry assay. Many natural non-synonymous (NS) changes were found in rh-ACE2 genes. Compared to human (hu) ACE2, thirty-eight consensus NS changes were found in rh-ACE2. Since these changes do not interact with the receptor binding domain of SARS-CoV, rh-ACE2 in general is as effective as human homolog in supporting viral entry. Rh-ACE2, however, is more polymorphic than hu-ACE2. Additional sporadic NS substitutions in clone Rh11-7 reduced the level of rh-ACE2 protein expression and did not support viral entry effectively. Further mutagenesis analysis showed that a natural mutation Y217N dramatically alters ACE2 expression and entry efficiency. Moreover, introduction of the Y217N mutation into hu-ACE2 caused the down-regulation of expression and reduced viral entry efficiency. These results indicate that the Y217N mutation plays a role in modulating SARS-CoV infection. Our results provide insights for understanding the role of rh-ACE2 in SARS lung pathogenesis in a non-human primate model.
Chen
Yunxin
Y
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, No.5, Panjiayuan, Nanli, Chaoyang District, Beijing, China.
Liu
Li
L
Wei
Qiang
Q
Zhu
Hua
H
Jiang
Hong
H
Tu
Xinming
X
Qin
Chuan
C
Chen
Zhiwei
Z
D000595:Amino Acid Sequence; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D045169:Severe Acute Respiratory Syndrome / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D053586:Virus Internalization
D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2
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