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Literature detail

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].
PMID 36803605 2023 Cell eng ppublish
PubMed DOI Browse context

Article

Publication summary

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.

bat MERS-like coronavirus dipeptidyl peptidase-4 furin cleavage site pangolin Coronavirus Coronavirus Infections Dipeptidyl Peptidase 4 Pangolins Animals Chiroptera Endopeptidases Humans Mice Middle East Respiratory Syndrome Coronavirus Peptide Hydrolases Receptors, Virus Virus Internalization DPP4 protein, human

Structured evidence records

Evidence records

9 total
Host Range Experiment 2 records
Host Range Experiment Extraction confidence 0.95
Key finding

MjHKU4r-CoV-1 can infect human organoids and hDPP4-transgenic mice via hDPP4-mediated entry, showing an expanded host range beyond bats and pangolins.

Virus
BatCoV-HKU4
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... MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice.

Method
virus isolation; infection assay
Sample type
airways; intestinal organs
Experimental system
organoid
Host Range Experiment Extraction confidence 0.95
Key finding

MjHKU4r-CoV-1 caused infection and pathogenicity in hDPP4-transgenic mice, confirming cross-species susceptibility in vivo.

Virus
BatCoV-HKU4
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
Experimental system
in vivo animal experiment
Cross Species Transmission 1 records
Cross Species Transmission Extraction confidence 0.80
Key finding

A bat MERS-like coronavirus has been detected circulating in pangolins, consistent with transmission between bat and pangolin hosts.

Virus
MERS-CoV
Location
Not specified
Supporting text

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).

Method
pan-CoV PCR; serological survey; virus isolation; genome sequencing
Study design
field surveillance
Transmission direction
animal-to-animal
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.80
Key finding

Genome sequencing and comparative analysis showed that pangolin MjHKU4r-CoV-1 possesses a furin cleavage site absent in bat HKU4r-CoVs, indicating viral genomic evolution associated with expanded host range and adaptation to human DPP4 usage.

Virus
MjHKU4r-CoV
Location
Not specified
Supporting text

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.

Genes or proteins
spike
Analysis methods
genome sequencing; comparative genomics
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.95
Key finding

MjHKU4r-CoV-1 from pangolins has a furin cleavage site absent in bat HKU4r-CoVs and enhanced spike binding to human DPP4, conferring increased host range and infectivity.

Virus
BatCoV-HKU4
Host
Not specified
Location
Not specified
Supporting text

The 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 has a wider host range than bat HKU4-CoV.

Genes or proteins
spike
Receptors
human DPP4
Host factors
host proteases
Mutations
furin cleavage site
Mechanism types
receptor_binding; cell_entry; host_range_expansion; pathogenicity
Receptor Usage 1 records
Receptor Usage Extraction confidence 1.00
Key finding

MjHKU4r-CoV-1 uses human DPP4 as a receptor and host proteases, including furin, to mediate cell entry.

Virus
BatCoV-HKU4
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.

Receptors
human dipeptidyl peptidase-4 (hDPP4)
Host factors
furin; host proteases
Reservoir Ecology 1 records
Reservoir Ecology Extraction confidence 0.85
Key finding

MjHKU4r-CoV, a bat MERS-like coronavirus, was found circulating in Malayan pangolins, identifying pangolins as potential reservoir hosts.

Virus
MjHKU4r-CoV
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)... Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.

Method
pan-CoV PCR; serology; virus isolation
Sample type
pangolin specimens
Serological Evidence 1 records
Serological Evidence Extraction confidence 0.95
Key finding

Seven of 86 Malayan pangolins were seropositive for a MERS-like coronavirus, indicating prior viral exposure.

Virus
MjHKU4r-CoV
Location
Not specified
Supporting text

Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%).

Sample type
serum
Zoonotic Surveillance 1 records
Zoonotic Surveillance Extraction confidence 0.95
Key finding

Surveillance of Malayan pangolins revealed infection and circulation of a novel MERS-like coronavirus (MjHKU4r-CoV) detected by PCR and serology.

Virus
MjHKU4r-CoV
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%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1).

Method
PCR; serology; genome sequencing