Receptor Usage of a Novel Bat Lineage C Betacoronavirus Reveals Evolution of Middle East Respiratory Syndrome-Related Coronavirus Spike Proteins for Human Dipeptidyl Peptidase 4 Binding.

Susanna K P Lau^1,2,3,4 Libiao Zhang⁵ Hayes K H Luk² Lifeng Xiong² Xingwen Peng⁵ Kenneth S M Li² Xiangyang He⁵ Pyrear Su-Hui Zhao² Rachel Y Y Fan² Antonio C P Wong² Syed Shakeel Ahmed² Jian-Piao Cai² Jasper F W Chan^1,2,3,4 Yinyan Sun⁶ Dongyan Jin⁷ Honglin Chen^1,2,3,4 Terrence C K Lau⁸ Raven K H Kok^1,2,3,4 Wenhui Li⁶ Kwok-Yung Yuen^1,2,3,4 Patrick C Y Woo^1,2,3,4

Affiliations 8 institutions

State Key Laboratory of Emerging Infectious Diseases The University of Hong Kong, China.
Department of Microbiology The University of Hong Kong, China.
Carol Yu Centre for Infection The University of Hong Kong, China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, China.
Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, and Guangdong Institute of Applied Biological Resources, Guangzhou, Guangdong Province, China.
National Institute of Biological Sciences, Zhongguancun Life Science Park, Changping, Beijing, China.
School of Biomedical Sciences, The University of Hong Kong, China.
Department of Biomedical Sciences, City University of Hong Kong, China.

PMID29346682 DOI10.1093/infdis/jiy018 Year2018 Journal The Journal of infectious diseases J Infect Dis Languageeng Statusppublish

Abstract

Although bats are known to harbor Middle East Respiratory Syndrome coronavirus (MERS-CoV)-related viruses, the role of bats in the evolutionary origin and pathway remains obscure. We identified a novel MERS-CoV-related betacoronavirus, Hp-BatCoV HKU25, from Chinese pipistrelle bats. Although it is closely related to MERS-CoV in most genome regions, its spike protein occupies a phylogenetic position between that of Ty-BatCoV HKU4 and Pi-BatCoV HKU5. Because Ty-BatCoV HKU4 but not Pi-BatCoV HKU5 can use the MERS-CoV receptor human dipeptidyl peptidase 4 (hDPP4) for cell entry, we tested the ability of Hp-BatCoV HKU25 to bind and use hDPP4. The HKU25-receptor binding domain (RBD) can bind to hDPP4 protein and hDPP4-expressing cells, but it does so with lower efficiency than that of MERS-RBD. Pseudovirus assays showed that HKU25-spike can use hDPP4 for entry to hDPP4-expressing cells, although with lower efficiency than that of MERS-spike and HKU4-spike. Our findings support a bat origin of MERS-CoV and suggest that bat CoV spike proteins may have evolved in a stepwise manner for binding to hDPP4.

Supporting text Virus Host Location

Chiroptera 371 Evolution, Molecular 176 Virus Internalization 100 Animals 1948 Betacoronavirus 78 Dipeptidyl Peptidase 4 32 HEK293 Cells 61 Humans 1440 Phylogeny 805 Protein Binding 193 Receptors, Virus 204 Sequence Analysis, DNA 113 Spike Glycoprotein, Coronavirus 274 DPP4 protein, human 16

Evidence records

4 total

Zoonotic Surveillance

1 records · 1 evidence types

Evidence type Viral Detection

1 records

OVE2837 Viral Detection

Key finding

A novel MERS-CoV-related betacoronavirus, Hp-BatCoV HKU25, was detected in Chinese pipistrelle bats.

Virus

Host

Location

Supporting text

We identified a novel MERS-CoV-related betacoronavirus, Hp-BatCoV HKU25, from Chinese pipistrelle bats.

Method: viral genome identification | molecular detection

Experimental Infection

1 records · 1 evidence types

Evidence type Host Range Experiment

1 records

OVE2841 Host Range Experiment

Key finding

MERS-CoV spike used hDPP4 for efficient entry into hDPP4-expressing human cells in pseudovirus experiments, serving as a positive control for susceptibility.

Virus

Host

Location

Supporting text

Pseudovirus assays showed that HKU25-spike can use hDPP4 for entry to hDPP4-expressing cells, although with lower efficiency than that of MERS-spike and HKU4-spike.

Method: pseudovirus assay | spike-mediated cell entry testing
Sample type: hDPP4-expressing cells
Experimental system: pseudovirus cell entry assay

Functional Mechanism

1 records · 1 evidence types

Evidence type Receptor Usage

1 records

OVE2838 Receptor Usage

Key finding

Hp-BatCoV HKU25 spike protein binds to human dipeptidyl peptidase 4 (hDPP4) and mediates cell entry with lower efficiency than MERS-CoV.

Virus

Host

Location

Supporting text

The HKU25-receptor binding domain (RBD) can bind to hDPP4 protein and hDPP4-expressing cells, but it does so with lower efficiency than that of MERS-RBD.

Method: receptor-binding assays | pseudovirus entry assays
Receptors: human dipeptidyl peptidase 4 | hDPP4

Genomic Evolution

1 records · 1 evidence types

Evidence type Phylogenetic Evolution

1 records

OVE2842 Phylogenetic Evolution

Key finding

Comparative phylogenetic analysis showed that the spike protein of Hp-BatCoV HKU25 occupies an evolutionary position between Ty-BatCoV HKU4 and Pi-BatCoV HKU5.

Virus

Host

Location

Supporting text

Its spike protein occupies a phylogenetic position between that of Ty-BatCoV HKU4 and Pi-BatCoV HKU5.

Genes or proteins: spike protein
Analysis methods: comparative genomics | phylogenetic analysis

References

47 references

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