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An international team led by the Institute for Integrative Systems Biology (I²SysBio) — a joint centre of the University of Valencia (UV) and the Spanish National Research Council (CSIC) — together with the Institut Pasteur in Paris, has identified, for the first time, a functional receptor for the porcine haemagglutinating encephalomyelitis virus, also known as porcine coronavirus PHEV. This virus is closely related to others that cause common colds in humans. The findings, published in Nature Microbiology, represent a key advance in understanding the mechanisms that these pathogens use to enter cells and how coronaviruses such as the one that caused COVID-19 evolve.
The porcine coronavirus PHEV belongs to the embecoviruses, a subgroup that includes human, bovine and porcine viruses within the large coronavirus family, which also contains SARS-CoV-2, the agent responsible for the recent global pandemic. It is closely related to two human common cold viruses: OC43 and HKU1. Although it was thought that these viruses relied on sugars such as sialic acid to enter their target cells and infect the host organism, the new study shows that the porcine coronavirus PHEV can enter cells without them. Instead, it uses a membrane protein called DPEP1 as a receptor to facilitate its entry.
Using advanced electron microscopy and X-ray crystallography techniques, the researchers have visualised how the virus’s spike protein — the ‘key’ used by coronaviruses such as SARS-CoV-2 to enter cells and initiate infection — binds to the DPEP1 protein. This analysis has provided a precise understanding of the molecular fit between the two proteins, revealing that the virus’s binding region is highly variable, suggesting a strong capacity for evolutionary adaptation.
Antivirals and potential for human transmission
“The region of the spike protein that allows the porcine coronavirus PHEV to bind to the DPEP1 receptor is highly variable and does not appear in the spikes of other similar coronaviruses, such as the human OC43 coronavirus”, explains Jérémy Dufloo, researcher at I²SysBio and lead author of the article. “This suggests that the use of DPEP1 as a receptor is unique to the porcine coronavirus PHEV, and that other viruses in the same family use different receptors that have yet to be identified”, he adds.
The study also shows that the interaction between the porcine coronavirus PHEV and the DPEP1 protein can be blocked by applying this protein in soluble form, opening the door to the development of viral entry inhibitors as an antiviral strategy. Furthermore, experiments confirm that the human version of DPEP1 also enables PHEV coronavirus to enter cells, raising questions about the potential for this porcine virus to transmit from animals to humans.
Preventing future pandemics
This work not only identifies a new viral receptor, but also offers crucial insights into the evolution of coronaviruses and their mechanisms of entry — aspects that are essential for anticipating and preventing future pandemics.
From a scientific standpoint, the discovery opens new lines of research. As Rafael Sanjuán, principal investigator at I²SysBio, professor in the Department of Genetics at the University of Valencia and author of the article, explains: “On the one hand, it will allow us to study the role of DPEP1 in PHEV infection in vivo in greater detail. In addition, it provides a basis for developing drugs or antibodies capable of blocking the interaction between the virus and this receptor, which could lead to new antiviral treatments”. The researcher also believes that the discovery poses a new challenge: “identifying the receptors used by other coronaviruses related to PHEV, which remain unknown”, he concludes.
Reference:
Dufloo, J., Fernández, I., Arbabian, A. et al. Dipeptidase 1 is a functional receptor for a porcine coronavirus. Nat Microbiol 10, 2981–2996 (2025). https://doi.org/10.1038/s41564-025-02111-7
