OmniVira

Aminopeptidase N is a receptor for hedgehog merbecoviruses.

Min Jin1 Victoria A Jefferson2 Zhe Zhao3 Nicholas J Catanzaro4 Luca De Sabato5 Emma L Keeler3 Bridget L Menasche3 Cameron Hoffman4 Boyd L Yount4 Anna Castelli6 Ilaria Di Bartolo5 Gabriele Vaccari5 Tyler N Starr7 Stephanie N Seifert2 Adrian A Castellanos8 Barbara A Han8 Leonid Serebryannyy9 Alicen B Spaulding9 Daniel C Douek9 Ana Moreno6 Ralph S Baric4 Craig B Wilen3 James M Rini1,10 Michael Letko11
Affiliations 11 institutions
  1. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
  2. Paul G. Allen School for Global Health, Washington State University, Pullman, WA, USA.
  3. Departments of Laboratory Medicine and Immunobiology, Yale University, New Haven, CT, USA.
  4. Department of Epidemiology, Gillings School of Global Public Heath, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  5. Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy.
  6. Virology Department, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, Brescia, Italy.
  7. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.
  8. Cary Institute of Ecosystem Studies, Millbrook, NY, USA.
  9. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  10. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  11. Paul G. Allen School for Global Health, Washington State University, Pullman, WA, USA. [email protected].
PMID42749891 DOI10.1038/s41564-026-02447-8 Year2026 Journal Nature microbiology Nat Microbiol Languageeng Publication statusActive
Active Last checked 2026-09-18 03:30:37 Source: NCBI PubMed

Abstract

Merbecoviruses, closely related to the Middle East respiratory syndrome coronavirus, circulate in hedgehogs throughout Europe and Asia, raising concerns about zoonotic transmission to humans and domestic animals. However, it is not clear how these viruses enter host cells. Here we tested three coronavirus receptors from European hedgehogs (Erinaceus europaeus) in cell-based assays and identified aminopeptidase N (APN) as a receptor for hedgehog merbecoviruses. We verified it by pseudotype experiments using an in vitro reporter system based on replication competent vesicular stomatitis virus and protein binding assays. Hedgehog coronavirus spike proteins showed enhanced infectivity when produced at 33 °C, approximating the physiological hedgehog body temperature, as compared with 37 °C. A screen of 30 mammalian APN orthologues showed restricted cross-species receptor use, including the inability to use human APN. Electron cryomicroscopy revealed a distinct glycoprotein-receptor interface unlike known coronavirus spike-APN interactions, clarifying species barriers. These findings broaden our understanding of receptor use across merbecoviruses and betacoronaviruses and inform risk assessments for viral emergence.

Supporting text Virus Host Location

Evidence records

5 total
Experimental Infection
2 records · 1 evidence types
Evidence type Host Range Experiment
2 records
OVE12152 Host Range Experiment
Key finding

Hedgehog merbecoviruses could not use human aminopeptidase N (APN) and showed restricted use across 30 mammalian APN orthologues in receptor-entry assays.

Virus
Merbecovirus
Host
30 mammalian APN orthologues Experimental system human APN Experimental system hedgehogs Erinaceidae Context pending
Location
Not specified
Supporting text

A screen of 30 mammalian APN orthologues showed restricted cross-species receptor use, including the inability to use human APN.

Method
receptor-expression assay | pseudotype experiments | protein binding assays
Experimental system
cell-based receptor-entry assays using heterologous expression of mammalian APN orthologues
OVE12153 Host Range Experiment
Key finding

Hedgehog coronavirus spike pseudotypes were more infectious when produced at 33 °C than at 37 °C.

Virus
hedgehog coronavirus 1
Host
cell-based assays Experimental system hedgehogs Erinaceidae Context pending
Location
Not specified
Supporting text

Hedgehog coronavirus spike proteins showed enhanced infectivity when produced at 33 °C, approximating the physiological hedgehog body temperature, as compared with 37 °C.

Method
pseudotype experiments | in vitro reporter system based on replication competent vesicular stomatitis virus
Experimental system
pseudotype infectivity assay using replication-competent VSV reporter system
Functional Mechanism
3 records · 1 evidence types
Evidence type Receptor Usage
3 records
OVE12149 Receptor Usage
Key finding

Aminopeptidase N (APN) functions as a receptor for hedgehog merbecoviruses.

Virus
Merbecovirus
Host
western European hedgehog Erinaceus europaeus Experimental system
Location
Not specified
Supporting text

Here we tested three coronavirus receptors from European hedgehogs (Erinaceus europaeus) in cell-based assays and identified aminopeptidase N (APN) as a receptor for hedgehog merbecoviruses.

Method
cell-based assays
Receptors
aminopeptidase N (APN)
OVE12151 Receptor Usage
Key finding

Electron cryomicroscopy defined a distinct spike–APN interface for hedgehog merbecoviruses, explaining restricted cross-species receptor usage.

Virus
Merbecovirus
Host
Not specified
Location
Not specified
Supporting text

Electron cryomicroscopy revealed a distinct glycoprotein-receptor interface unlike known coronavirus spike-APN interactions, clarifying species barriers.

Method
electron cryomicroscopy
Receptors
APN
OVE12150 Receptor Usage
Key finding

APN receptor usage by hedgehog merbecoviruses was validated using VSV-based pseudotype entry and protein binding assays.

Virus
Merbecovirus
Host
Not specified
Location
Not specified
Supporting text

We verified it by pseudotype experiments using an in vitro reporter system based on replication competent vesicular stomatitis virus and protein binding assays.

Method
pseudotype experiments using replication competent vesicular stomatitis virus | protein binding assays
Receptors
APN