Rhesus Angiotensin Converting Enzyme 2 Supports Entry of Severe Acute Respiratory Syndrome Coronavirus in Chinese Macaques

Overview

Journal Virology

Specialty Microbiology

Date 2008 Sep 20

PMID 18801550

Citations 22

Authors

Yunxin Chen

Li Liu

Qiang Wei

Hua Zhu

Hong Jiang

Xinming Tu

Chuan Qin

Zhiwei Chen

Affiliations

Soon will be listed here.

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.

Citing Articles

Detached epithelial cell plugs from the upper respiratory tract favour distal lung injury in Golden Syrian hamsters (Mesocricetus auratus) when experimentally infected with the A.2 Brazilian SARS-CoV-2 strain.

Pelajo-Machado M, da Silva A, Rodrigues D, Paiva M, Muller R, da Costa L Mem Inst Oswaldo Cruz. 2024; 119:e240100.

PMID: 39442103 PMC: 11493349. DOI: 10.1590/0074-02760240100.

COVID-19 susceptibility: potential of polymorphisms.

Chaudhary M Egypt J Med Hum Genet. 2024; 21(1):54.

PMID: 38624559 PMC: 7502288. DOI: 10.1186/s43042-020-00099-9.

Experimental and clinical data analysis for identification of COVID-19 resistant ACE2 mutations.

Raghav P, Raghav A, Lathwal A, Saxena A, Mann Z, Sengar M Sci Rep. 2023; 13(1):2351.

PMID: 36759535 PMC: 9910265. DOI: 10.1038/s41598-022-20773-9.

Animal models and SARS-CoV-2-induced pulmonary and neurological injuries.

Pinto M, da Silva A, Rodrigues D, Muller R, de Vasconcelos G, Neves P Mem Inst Oswaldo Cruz. 2023; 117:e220239.

PMID: 36700583 PMC: 9870265. DOI: 10.1590/0074-02760220239.

Mitochondrial regulation of acute extrafollicular B-cell responses to COVID-19 severity.

Cao T, Liu L, To K, Lim C, Zhou R, Ming Y Clin Transl Med. 2022; 12(9):e1025.

PMID: 36103567 PMC: 9473490. DOI: 10.1002/ctm2.1025.

References

Donnelly C, Fisher M, Fraser C, Ghani A, Riley S, Ferguson N . Epidemiological and genetic analysis of severe acute respiratory syndrome. Lancet Infect Dis. 2004; 4(11):672-83. PMC: 7106498. DOI: 10.1016/S1473-3099(04)01173-9. View

Han D, Penn-Nicholson A, Cho M . Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology. 2006; 350(1):15-25. PMC: 7111894. DOI: 10.1016/j.virol.2006.01.029. View

Chen Z, Zhang L, Qin C, Ba L, Yi C, Zhang F . Recombinant modified vaccinia virus Ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region. J Virol. 2005; 79(5):2678-88. PMC: 548443. DOI: 10.1128/JVI.79.5.2678-2688.2005. View

Riley S, Fraser C, Donnelly C, Ghani A, Abu-Raddad L, Hedley A . Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions. Science. 2003; 300(5627):1961-6. DOI: 10.1126/science.1086478. View

Itoyama S, Keicho N, Hijikata M, Quy T, Phi N, Long H . Identification of an alternative 5'-untranslated exon and new polymorphisms of angiotensin-converting enzyme 2 gene: lack of association with SARS in the Vietnamese population. Am J Med Genet A. 2005; 136(1):52-7. PMC: 7138097. DOI: 10.1002/ajmg.a.30779. View

Chen Z, Gettie A, Ho D, Marx P . Primary SIVsm isolates use the CCR5 coreceptor from sooty mangabeys naturally infected in west Africa: a comparison of coreceptor usage of primary SIVsm, HIV-2, and SIVmac. Virology. 1998; 246(1):113-24. DOI: 10.1006/viro.1998.9174. View

Qin C, Wang J, Wei Q, She M, Marasco W, Jiang H . An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus. J Pathol. 2005; 206(3):251-9. PMC: 7167940. DOI: 10.1002/path.1769. View

Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B . A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11(8):875-9. PMC: 7095783. DOI: 10.1038/nm1267. View

Peiris J, Yuen K, Osterhaus A, Stohr K . The severe acute respiratory syndrome. N Engl J Med. 2003; 349(25):2431-41. DOI: 10.1056/NEJMra032498. View

10.

Chen Z, Zhou P, Ho D, Landau N, Marx P . Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J Virol. 1997; 71(4):2705-14. PMC: 191392. DOI: 10.1128/JVI.71.4.2705-2714.1997. View

11.

He L, Ding Y, Zhang Q, Che X, He Y, Shen H . Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol. 2006; 210(3):288-97. PMC: 7167655. DOI: 10.1002/path.2067. View

12.

Sims A, Baric R, Yount B, Burkett S, Collins P, Pickles R . Severe acute respiratory syndrome coronavirus infection of human ciliated airway epithelia: role of ciliated cells in viral spread in the conducting airways of the lungs. J Virol. 2005; 79(24):15511-24. PMC: 1316022. DOI: 10.1128/JVI.79.24.15511-15524.2005. View

13.

Kuiken T, Fouchier R, Schutten M, Rimmelzwaan G, van Amerongen G, van Riel D . Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet. 2003; 362(9380):263-70. PMC: 7112434. DOI: 10.1016/S0140-6736(03)13967-0. View

14.

Liu L, Fang Q, Deng F, Wang H, Yi C, Ba L . Natural mutations in the receptor binding domain of spike glycoprotein determine the reactivity of cross-neutralization between palm civet coronavirus and severe acute respiratory syndrome coronavirus. J Virol. 2007; 81(9):4694-700. PMC: 1900161. DOI: 10.1128/JVI.02389-06. View

15.

Yi C, Ba L, Zhang L, Ho D, Chen Z . Single amino acid substitutions in the severe acute respiratory syndrome coronavirus spike glycoprotein determine viral entry and immunogenicity of a major neutralizing domain. J Virol. 2005; 79(18):11638-46. PMC: 1212612. DOI: 10.1128/JVI.79.18.11638-11646.2005. View

16.

Peiris J, Chu C, Cheng V, Chan K, Hung I, Poon L . Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003; 361(9371):1767-72. PMC: 7112410. DOI: 10.1016/s0140-6736(03)13412-5. View

17.

Mossel E, Huang C, Narayanan K, Makino S, Tesh R, Peters C . Exogenous ACE2 expression allows refractory cell lines to support severe acute respiratory syndrome coronavirus replication. J Virol. 2005; 79(6):3846-50. PMC: 1075706. DOI: 10.1128/JVI.79.6.3846-3850.2005. View

18.

Li W, Moore M, Vasilieva N, Sui J, Wong S, Berne M . Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426(6965):450-4. PMC: 7095016. DOI: 10.1038/nature02145. View

19.

Chen Z, Kwon D, Jin Z, Monard S, Telfer P, Jones M . Natural infection of a homozygous delta24 CCR5 red-capped mangabey with an R2b-tropic simian immunodeficiency virus. J Exp Med. 1998; 188(11):2057-65. PMC: 2212380. DOI: 10.1084/jem.188.11.2057. View

20.

Drosten C, Gunther S, Preiser W, van der Werf S, Brodt H, Becker S . Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003; 348(20):1967-76. DOI: 10.1056/NEJMoa030747. View