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Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques.
Virology. 2008 Nov 10; 381(1):89-97.V

Abstract

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.

Authors+Show Affiliations

Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, No.5, Panjiayuan, Nanli, Chaoyang District, Beijing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18801550

Citation

Chen, Yunxin, et al. "Rhesus Angiotensin Converting Enzyme 2 Supports Entry of Severe Acute Respiratory Syndrome Coronavirus in Chinese Macaques." Virology, vol. 381, no. 1, 2008, pp. 89-97.
Chen Y, Liu L, Wei Q, et al. Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques. Virology. 2008;381(1):89-97.
Chen, Y., Liu, L., Wei, Q., Zhu, H., Jiang, H., Tu, X., Qin, C., & Chen, Z. (2008). Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques. Virology, 381(1), 89-97. https://doi.org/10.1016/j.virol.2008.08.016
Chen Y, et al. Rhesus Angiotensin Converting Enzyme 2 Supports Entry of Severe Acute Respiratory Syndrome Coronavirus in Chinese Macaques. Virology. 2008 Nov 10;381(1):89-97. PubMed PMID: 18801550.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques. AU - Chen,Yunxin, AU - Liu,Li, AU - Wei,Qiang, AU - Zhu,Hua, AU - Jiang,Hong, AU - Tu,Xinming, AU - Qin,Chuan, AU - Chen,Zhiwei, Y1 - 2008/09/17/ PY - 2008/06/04/received PY - 2008/08/04/revised PY - 2008/08/06/accepted PY - 2008/9/20/pubmed PY - 2008/12/24/medline PY - 2008/9/20/entrez SP - 89 EP - 97 JF - Virology JO - Virology VL - 381 IS - 1 N2 - 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. SN - 1096-0341 UR - https://www.unboundmedicine.com/medline/citation/18801550/Rhesus_angiotensin_converting_enzyme_2_supports_entry_of_severe_acute_respiratory_syndrome_coronavirus_in_Chinese_macaques_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0042-6822(08)00523-0 DB - PRIME DP - Unbound Medicine ER -