OmniVira

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

Jing Chen1 Xinglou Yang1 Haorui Si2,3 Qianchun Gong4,5 Tengcheng Que6,7 Jing Li8 Yang Li1 Chunguang Wu2,3 Wei Zhang1 Ying Chen2,3 Yun Luo2,3 Yan Zhu1 Bei Li1 Dongsheng Luo1 Ben Hu1 Haofeng Lin2,3 Rendi Jiang9 Tingting Jiang1 Qian Li2,3 Meiqin Liu2,3 Shizhe Xie2,3 Jia Su2,3 Xiaoshuang Zheng2,3 Ang Li2,3 Yulin Yao1 Yong Yang2,3 Panyu Chen10 Aiqiong Wu10 Meihong He10 Xinhua Lin4,11 Yigang Tong12 Yanling Hu13,14 Zheng-Li Shi15 Peng Zhou2,16
Affiliations 16 institutions
  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
  3. University of Chinese Academy of Sciences, Beijing, China.
  4. 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
  5. 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.
  6. Guangxi Zhuang Autonomous Region Terrestrial Wildlife Medical-aid and Monitoring Epidemic Diseases Research Center, Nanning 530028, Guangxi, China
  7. Faculty of Data Science, City University of Macau, Beijing, China.
  8. Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
  9. 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.
  10. Guangxi Zhuang Autonomous Region Terrestrial Wildlife Medical-aid and Monitoring Epidemic Diseases Research Center, Nanning 530028, Guangxi, China.
  11. 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].
  12. 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].
  13. Institute of Life Sciences, Guangxi Medical University, Nanning 530021, Guangxi, China
  14. 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].
  15. CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. Electronic address: [email protected].
  16. Guangzhou Laboratory, No. 9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou 51005, Guangdong Province, China. Electronic address: [email protected].
PMID36803605 DOI10.1016/j.cell.2023.01.019 Year2023 Journal Cell Languageeng Statusppublish

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.

Supporting text Virus Host Location
bat MERS-like coronavirus 1 dipeptidyl peptidase-4 2 furin cleavage site 5 pangolin 10 Coronavirus 92 Coronavirus Infections 171 Dipeptidyl Peptidase 4 32 Pangolins 29 Animals 1948 Chiroptera 371 Endopeptidases 2 Humans 1440 Mice 253 Middle East Respiratory Syndrome Coronavirus 68 Peptide Hydrolases 4 Receptors, Virus 204 Virus Internalization 100 DPP4 protein, human 16

Evidence records

8 total
Zoonotic Surveillance
4 records · 4 evidence types
Evidence type Virus Isolation
1 records
OVE6734 Virus Isolation
Key finding

An infectious MjHKU4r-CoV-1 virus was successfully isolated from Malayan pangolins.

Virus
bat coronavirus HKU4
Host
Malayan pangolin Manis javanica Natural host
Location
Not specified
Supporting text

We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1).

Sample type
pangolin samples
Evidence type Viral Detection
1 records
OVE6732 Viral Detection
Key finding

MjHKU4r-CoV, a MERS-like coronavirus, was detected in Malayan pangolins with four of 86 animals testing positive by pan-CoV PCR.

Virus
Manis javanica HKU4-related coronavirus Merbecovirus
Host
Malayan pangolin Manis javanica Natural host
Location
Not specified
Supporting text

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%).

Method
pan-CoV PCR
Evidence type Serological Evidence
1 records
OVE6733 Serological Evidence
Key finding

Seven of 86 Malayan pangolins were seropositive for the MERS-like coronavirus MjHKU4r-CoV, indicating prior exposure.

Virus
Manis javanica HKU4-related coronavirus Merbecovirus
Host
Malayan pangolin Manis javanica Natural host
Location
Not specified
Supporting text

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%).

Method
serological test
Sample type
serum
Evidence type Reservoir Ecology
1 records
OVE6739 Reservoir Ecology
Key finding

Pangolins are identified as reservoir hosts of coronaviruses poised for human disease emergence.

Virus
Coronaviridae Manis javanica HKU4-related coronavirus
Host
pangolins Manidae Natural host
Location
Not specified
Supporting text

Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.

Method
ecological interpretation based on viral detection and serology in natural pangolin populations
Experimental Infection
2 records · 2 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE6738 Pathogenicity Experiment
Key finding

MjHKU4r-CoV-1 caused pathogenic infection in human airway and intestinal organoids and in hDPP4-transgenic mice, demonstrating disease phenotype in both systems.

Virus
bat coronavirus HKU4
Host
human Homo sapiens Experimental system house mouse Mus musculus Experimental system
Location
Not specified
Supporting text

MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice.

Method
experimental infection | pathogenicity assessment in organoid model | infection of transgenic mouse model
Experimental system
human airway and intestinal organoids and hDPP4-transgenic mouse model
Evidence type Host Range Experiment
1 records
OVE6737 Host Range Experiment
Key finding

MjHKU4r-CoV-1 demonstrated a broader host range than bat HKU4-CoV, showing infectivity in human airway and intestinal organoids and in hDPP4-transgenic mice.

Virus
bat coronavirus HKU4 Coronaviridae
Host
human Homo sapiens Experimental system house mouse Mus musculus Experimental system Malayan pangolin Manis javanica Natural host bats Chiroptera Context pending
Location
Not specified
Supporting text

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.

Method
virus isolation | cell infection assay | organoid infection | transgenic mouse infection challenge | pathogenicity assessment
Sample type
airway tissue | intestinal organoid | mouse tissue
Experimental system
human organoid infection model and hDPP4-transgenic mouse challenge model
Functional Mechanism
2 records · 2 evidence types
Evidence type Receptor Usage
1 records
OVE6735 Receptor Usage
Key finding

MjHKU4r-CoV-1 uses human dipeptidyl peptidase-4 (hDPP4) as a receptor and relies on host proteases for cell entry.

Virus
bat coronavirus HKU4
Host
human Homo sapiens Experimental system
Location
Not specified
Supporting text

This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection.

Method
receptor binding assay | cell infection assay
Receptors
human dipeptidyl peptidase-4 | hDPP4
Host factors
host proteases
Evidence type Molecular Adaptation
1 records
OVE6736 Molecular Adaptation
Key finding

MjHKU4r-CoV-1 possesses a furin cleavage site in its spike that enhances infection and is absent in all known bat HKU4r-CoVs.

Virus
bat coronavirus HKU4 Coronaviridae
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
spike
Receptors
human dipeptidyl peptidase-4 (hDPP4)
Host factors
host proteases
Mutations
furin cleavage site
Mechanism types
receptor usage | host entry | host-range expansion