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Article: Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques

TitleRhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques
Authors
KeywordsACE2
Chinese rhesus monkey
Lung pathogenesis
SARS
SARS-CoV
Issue Date2008
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yviro
Citation
Virology, 2008, v. 381 n. 1, p. 89-97 How to Cite?
AbstractAngiotensin 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. © 2008 Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/60146
ISSN
2015 Impact Factor: 3.2
2015 SCImago Journal Rankings: 1.805
ISI Accession Number ID
Funding AgencyGrant Number
NIH1R01 HL080211-01
Development Fund of the University of Hong Kong (UDF)
Funding Information:

We thank Lian Huang, Zhe Cong, Yali Liu, Wei Tong, Yanfeng Xu, Chunmei Ma, Wei Deng, Xiaowei Dai, Xiuhong Yang, Jiamei Li and Chunshi Jia for technical assistance. We also thank the NIH (1R01 HL080211-01 to Z.C.) and the Development Fund of the University of Hong Kong (UDF) to its AIDS Institute for financial support.

References

 

DC FieldValueLanguage
dc.contributor.authorChen, Yen_HK
dc.contributor.authorLiu, Len_HK
dc.contributor.authorWei, Qen_HK
dc.contributor.authorZhu, Hen_HK
dc.contributor.authorJiang, Hen_HK
dc.contributor.authorTu, Xen_HK
dc.contributor.authorQin, Cen_HK
dc.contributor.authorChen, Zen_HK
dc.date.accessioned2010-05-31T04:04:40Z-
dc.date.available2010-05-31T04:04:40Z-
dc.date.issued2008en_HK
dc.identifier.citationVirology, 2008, v. 381 n. 1, p. 89-97en_HK
dc.identifier.issn0042-6822en_HK
dc.identifier.urihttp://hdl.handle.net/10722/60146-
dc.description.abstractAngiotensin 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. © 2008 Elsevier Inc. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yviroen_HK
dc.relation.ispartofVirologyen_HK
dc.subjectACE2en_HK
dc.subjectChinese rhesus monkeyen_HK
dc.subjectLung pathogenesisen_HK
dc.subjectSARSen_HK
dc.subjectSARS-CoVen_HK
dc.subject.meshMacaca mulatta - virology-
dc.subject.meshPeptidyl-Dipeptidase A - chemistry - genetics - metabolism-
dc.subject.meshSARS Virus - physiology-
dc.subject.meshSevere Acute Respiratory Syndrome - enzymology - pathology - virology-
dc.subject.meshVirus Internalization-
dc.titleRhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaquesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0042-6822&volume=381 &issue=1&spage=89&epage=97&date=2008&atitle=Rhesus+angiotensin+converting+enzyme+2+supports+entry+of+severe+acute+respiratory+syndrome+coronavirus+in+Chinese+macaques.en_HK
dc.identifier.emailLiu, L: liuli71@hkucc.hku.hken_HK
dc.identifier.emailChen, Z: zchenai@hku.hken_HK
dc.identifier.authorityLiu, L=rp00268en_HK
dc.identifier.authorityChen, Z=rp00243en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.virol.2008.08.016en_HK
dc.identifier.pmid18801550en_HK
dc.identifier.scopuseid_2-s2.0-54149102984en_HK
dc.identifier.hkuros163884en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-54149102984&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume381en_HK
dc.identifier.issue1en_HK
dc.identifier.spage89en_HK
dc.identifier.epage97en_HK
dc.identifier.isiWOS:000260595200013-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridChen, Y=8397000000en_HK
dc.identifier.scopusauthoridLiu, L=35784425200en_HK
dc.identifier.scopusauthoridWei, Q=7201692917en_HK
dc.identifier.scopusauthoridZhu, H=35070757700en_HK
dc.identifier.scopusauthoridJiang, H=36077295400en_HK
dc.identifier.scopusauthoridTu, X=8789266900en_HK
dc.identifier.scopusauthoridQin, C=7102688076en_HK
dc.identifier.scopusauthoridChen, Z=35271180800en_HK

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