A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry

Jing Chen; Xinglou Yang; Haorui Si; Qianchun Gong; Tengcheng Que; Jing Li; Yang Li; Chunguang Wu; Wei Zhang; Ying Chen; Yun Luo; Yan Zhu; Bei Li; Dongsheng Luo; Ben Hu; Haofeng Lin; Rendi Jiang; Tingting Jiang; Qian Li; Meiqin Liu; Shizhe Xie; Jia Su; Xiaoshuang Zheng; Ang Li; Yulin Yao; Yong Yang; Panyu Chen; Aiqiong Wu; Meihong He; Xinhua Lin; Yigang Tong; Yanling Hu; Zheng-Li Shi; Peng Zhou

doi:10.1016/j.cell.2023.01.019

A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry

Cell. 2023 Feb 16;186(4):850-863.e16. doi: 10.1016/j.cell.2023.01.019.

Authors

Jing Chen¹, Xinglou Yang¹, Haorui Si², Qianchun Gong³, Tengcheng Que⁴, Jing Li⁵, Yang Li¹, Chunguang Wu², Wei Zhang¹, Ying Chen², Yun Luo², Yan Zhu¹, Bei Li¹, Dongsheng Luo¹, Ben Hu¹, Haofeng Lin², Rendi Jiang⁶, Tingting Jiang¹, Qian Li², Meiqin Liu², Shizhe Xie², Jia Su², Xiaoshuang Zheng², Ang Li², Yulin Yao¹, Yong Yang², Panyu Chen⁷, Aiqiong Wu⁷, Meihong He⁷, Xinhua Lin⁸, Yigang Tong⁹, Yanling Hu¹⁰, Zheng-Li Shi¹¹, Peng Zhou¹²

Affiliations

¹ CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
² CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China.
³ State Key Laboratory of Genetic Engineering, School of Life Sciences, Greater Bay Area Institute of Precision Medicine (Guangzhou), Zhongshan Hospital, Fudan University Shanghai, Shanghai 200438, China; Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Chengdu 610041, China.
⁴ Guangxi Zhuang Autonomous Region Terrestrial Wildlife Medical-aid and Monitoring Epidemic Diseases Research Center, Nanning 530028, Guangxi, China; Faculty of Data Science, City University of Macau, Beijing, China.
⁵ Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
⁶ State Key Laboratory of Genetic Engineering, School of Life Sciences, Greater Bay Area Institute of Precision Medicine (Guangzhou), Zhongshan Hospital, Fudan University Shanghai, Shanghai 200438, China.
⁷ Guangxi Zhuang Autonomous Region Terrestrial Wildlife Medical-aid and Monitoring Epidemic Diseases Research Center, Nanning 530028, Guangxi, China.
⁸ State Key Laboratory of Genetic Engineering, School of Life Sciences, Greater Bay Area Institute of Precision Medicine (Guangzhou), Zhongshan Hospital, Fudan University Shanghai, Shanghai 200438, China; Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Chengdu 610041, China. Electronic address: [email protected].
⁹ Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China. Electronic address: [email protected].
¹⁰ Institute of Life Sciences, Guangxi Medical University, Nanning 530021, Guangxi, China; Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, Guangxi, China. Electronic address: [email protected].
¹¹ CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. Electronic address: [email protected].
¹² CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 51005, Guangdong Province, China. Electronic address: [email protected].

Abstract

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.

Keywords: bat MERS-like coronavirus; dipeptidyl peptidase-4; furin cleavage site; pangolin.

Publication types

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

MeSH terms

Animals
Chiroptera
Coronavirus Infections* / veterinary
Coronavirus Infections* / virology
Coronavirus* / physiology
Dipeptidyl Peptidase 4* / genetics
Dipeptidyl Peptidase 4* / metabolism
Endopeptidases / metabolism
Humans
Mice
Middle East Respiratory Syndrome Coronavirus / genetics
Middle East Respiratory Syndrome Coronavirus / metabolism
Pangolins*
Peptide Hydrolases / metabolism
Receptors, Virus / metabolism
Virus Internalization

Substances

Dipeptidyl Peptidase 4
DPP4 protein, human
Endopeptidases
Peptide Hydrolases
Receptors, Virus