Literature detail

Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus.

Yang Yang¹ Lanying Du² Chang Liu¹ Lili Wang² Cuiqing Ma² Jian Tang² Ralph S Baric^3,4 Shibo Jiang^2,5 Fang Li^1,6

Affiliations 6 institutions

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27559
and.
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China [email protected] [email protected].
[email protected] [email protected].

PMID 25114257 2014 Proc Natl Acad Sci U S A eng ppublish

Article

Publication summary

Middle East respiratory syndrome coronavirus (MERS-CoV) currently spreads in humans and causes ∼ 36% fatality in infected patients. Believed to have originated from bats, MERS-CoV is genetically related to bat coronaviruses HKU4 and HKU5. To understand how bat coronaviruses transmit to humans, we investigated the receptor usage and cell entry activity of the virus-surface spike proteins of HKU4 and HKU5. We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5. Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences. First, whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend. Second, in the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells. Thus, MERS-CoV, but not HKU4, has adapted to use human DPP4 and human cellular proteases for efficient human cell entry, contributing to the enhanced pathogenesis of MERS-CoV in humans. These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4. They also suggest that DPP4-recognizing bat coronaviruses threaten human health because of their spikes' capability to adapt to human cells for cross-species transmissions.

Animals Chiroptera Coronavirus Coronavirus Infections Dipeptidyl Peptidase 4 Disease Reservoirs Host Specificity Host-Pathogen Interactions Humans Middle East Receptors, Virus Respiratory Tract Infections Spike Glycoprotein, Coronavirus Virulence Virus Internalization DPP4 protein, human

Structured evidence records

Evidence records

8 total

Receptor Usage 4 records

Receptor Usage Extraction confidence 1.00

Key finding

Dipeptidyl peptidase 4 (DPP4) functions as the receptor for MERS-CoV and bat coronavirus HKU4, but not for HKU5.

Virus

Host

Location

Supporting text

We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5.

Receptors: dipeptidyl peptidase 4 (DPP4)

Receptor Usage Extraction confidence 1.00

Key finding

MERS-CoV spike protein preferentially binds human DPP4 whereas HKU4 spike prefers bat DPP4.

Virus

Host

Location

Supporting text

Whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend.

Receptors: DPP4

Receptor Usage Extraction confidence 1.00

Key finding

MERS-CoV spike enables pseudovirus entry into both bat and human cells, while HKU4 spike enables entry only into bat cells.

Virus

Host

Location

Supporting text

In the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells.

Method: pseudovirus entry assay
Receptors: DPP4
Host factors: host cellular proteases

Receptor Usage Extraction confidence 1.00

Key finding

DPP4 is a functional receptor for HKU4, and host cellular proteases influence its host range.

Virus

Host

Location

Supporting text

These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4.

Receptors: DPP4
Host factors: host cellular proteases

Host Range Experiment 2 records

Host Range Experiment Extraction confidence 0.90

Key finding

MERS-CoV spike enables pseudovirus entry into human cells while HKU4 spike does not, indicating adaptation of MERS-CoV for human cell entry.

Virus

Host

Location

Supporting text

In the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediated pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediated pseudovirus entry into human cells.

Method: pseudovirus entry assay
Experimental system: pseudovirus assay

Host Range Experiment Extraction confidence 0.90

Key finding

Both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, confirming bat cell susceptibility to these spike proteins.

Virus

Host

Location

Supporting text

In the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediated pseudovirus entry into bat cells.

Method: pseudovirus entry assay
Experimental system: pseudovirus assay

Molecular Adaptation 2 records

Molecular Adaptation Extraction confidence 0.90

Key finding

MERS-CoV spike has adapted to human DPP4 and human proteases, enabling efficient entry into human cells.

Virus

Host

Location

Supporting text

MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, whereas HKU4 shows the opposite trend. In the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike mediates pseudovirus entry into human cells. Thus, MERS-CoV has adapted to use human DPP4 and human cellular proteases for efficient human cell entry.

Genes or proteins: spike
Receptors: DPP4
Host factors: cellular proteases
Mechanism types: receptor_binding; cell_entry; host_factor_interaction

Molecular Adaptation Extraction confidence 0.90

Key finding

Bat coronavirus HKU4 uses DPP4 as its receptor and shows adaptation to bat DPP4, with host cellular proteases determining its host range.

Virus

Host

Location

Supporting text

We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5. Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences. HKU4 shows the opposite trend preferring bat DPP4, and host cellular proteases are a host range determinant for HKU4.

Genes or proteins: spike
Receptors: DPP4
Host factors: cellular proteases
Mechanism types: receptor_binding; cell_entry; host_factor_interaction

Citation context

References

40 references

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Evidence overview

Evidence 8

Types 3

Virus 2

Host 4

Evidence types

Receptor Usage 4 Host Range Experiment 2 Molecular Adaptation 2

Linked entities

Viruses

Hosts

Locations

Publication metadata

Journal: Proceedings of the National Academy of Sciences of the United States of America
Volume / Issue / Pages: 111 / 34 / 12516-21
ISSN: 1091-6490
Journal country: United States
DOI: 10.1073/pnas.1405889111