Increased Pathogenicity and Virulence of Middle East Respiratory Syndrome Coronavirus Clade B In Vitro and In Vivo

Yanqun Wang; Jing Sun; Xiaobo Li; Airu Zhu; Wenda Guan; De-Qiang Sun; Mian Gan; Xuefeng Niu; Jun Dai; Lu Zhang; Zhaoyong Zhang; Yongxia Shi; Shuxiang Huang; Chris Ka Pun Mok; Zifeng Yang; Zhongfang Wang; Wenjie Tan; Yimin Li; Ling Chen; Rongchang Chen; Malik Peiris; Nanshan Zhong; Jingxian Zhao; Jicheng Huang; Jincun Zhao

doi:10.1128/JVI.00861-20

Increased Pathogenicity and Virulence of Middle East Respiratory Syndrome Coronavirus Clade B In Vitro and In Vivo

J Virol. 2020 Jul 16;94(15):e00861-20. doi: 10.1128/JVI.00861-20. Print 2020 Jul 16.

Authors

Yanqun Wang^#¹, Jing Sun^#¹, Xiaobo Li^#², Airu Zhu^#¹, Wenda Guan^#¹, De-Qiang Sun^#³, Mian Gan¹, Xuefeng Niu¹, Jun Dai², Lu Zhang⁴, Zhaoyong Zhang¹, Yongxia Shi², Shuxiang Huang², Chris Ka Pun Mok^{1

5}, Zifeng Yang¹, Zhongfang Wang¹, Wenjie Tan⁶, Yimin Li¹, Ling Chen^{1

7}, Rongchang Chen⁸, Malik Peiris^{1

5}, Nanshan Zhong¹, Jingxian Zhao^#¹, Jicheng Huang^#⁹, Jincun Zhao^#^{10

4}

Affiliations

¹ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
² Technology Center, Guangzhou Custom, Guangzhou, China.
³ State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital of Guangzhou Medical University, China.
⁴ Institute of Infectious Disease, Guangzhou Eighth People's Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Hong Kong HKU-Pasteur Research Pole, School of Public Health, HKU Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
⁶ Key Laboratory of Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
⁷ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
⁸ Shenzhen Institute of Respiratory Disease, First Affiliated Hospital of South University of Science and Technology of China (Shenzhen People's Hospital), Shenzhen, China.
⁹ Technology Center, Guangzhou Custom, Guangzhou, China [email protected] [email protected].
¹⁰ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China [email protected] [email protected].

^# Contributed equally.

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory disease in humans. MERS-CoV strains from early epidemic clade A and contemporary epidemic clade B have not been phenotypically characterized to compare their abilities to infect cells and mice. We isolated the clade B MERS-CoV ChinaGD01 strain from a patient infected during the South Korean MERS outbreak in 2015 and compared the phylogenetics and pathogenicity of MERS-CoV EMC/2012 (clade A) and ChinaGD01 (clade B) in vitro and in vivo Genome alignment analysis showed that most clade-specific mutations occurred in the orf1ab gene, including mutations that were predicted to be potential glycosylation sites. Minor differences in viral growth but no significant differences in plaque size or sensitivity to beta interferon (IFN-β) were detected between these two viruses in vitro ChinaGD01 virus infection induced more weight loss and inflammatory cytokine production in human DPP4-transduced mice. Viral titers were higher in the lungs of ChinaGD01-infected mice than with EMC/2012 infection. Decreased virus-specific CD4⁺ and CD8⁺ T cell numbers were detected in the lungs of ChinaGD01-infected mice. In conclusion, MERS-CoV evolution induced changes to reshape its pathogenicity and virulence in vitro and in vivo and to evade adaptive immune response to hinder viral clearance.IMPORTANCE MERS-CoV is an important emerging pathogen and causes severe respiratory infection in humans. MERS-CoV strains from early epidemic clade A and contemporary epidemic clade B have not been phenotypically characterized to compare their abilities to infect cells and mice. In this study, we showed that a clade B virus ChinaGD01 strain caused more severe disease in mice, with delayed viral clearance, increased inflammatory cytokines, and decreased antiviral T cell responses, than the early clade A virus EMC/2012. Given the differences in pathogenicity of different clades of MERS-CoV, periodic assessment of currently circulating MERS-CoV is needed to monitor potential severity of zoonotic disease.

Keywords: MERS-CoV; T cell response; pathogenicity; phylogenetics; virulence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Coronavirus Infections / virology*
Disease Models, Animal
Genome, Viral
Genotype*
Host-Pathogen Interactions* / immunology
Humans
Interferon Type I / pharmacology
Male
Mice
Middle East Respiratory Syndrome Coronavirus / classification
Middle East Respiratory Syndrome Coronavirus / isolation & purification
Middle East Respiratory Syndrome Coronavirus / pathogenicity
Middle East Respiratory Syndrome Coronavirus / physiology*
Phylogeny
RNA, Viral
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Virulence
Virus Replication / drug effects
Virus Replication / genetics
Whole Genome Sequencing

Substances

Interferon Type I
RNA, Viral