• The Institute of Integrative Systems Biology (CSIC-UV) is co-leading a study that uncovers the infection mechanism of a swine virus related to those that cause common colds in humans
• The results, published in Nature Microbiology, offer insights into the evolution of coronaviruses and their mechanisms of cell entry—crucial data for anticipating and preventing pandemics

An international team led by the Institute of Integrative Systems Biology (I²SysBio), a joint centre of the Spanish National Research Council (CSIC) and the University of Valencia (UV), together with the Institut Pasteur in Paris, has, for the first time, identified a functional receptor for the porcine haemagglutinating encephalomyelitis virus (PHEV), also known as porcine coronavirus. This virus is related to others that cause common colds in humans. The findings, published in Nature Microbiology, represent a major advance in understanding the entry mechanisms of these pathogens, as well as 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 includes SARS-CoV-2, the virus responsible for the recent global pandemic. It is closely related to two human viruses that cause common colds: OC43 and HKU1. Although these viruses were thought to rely on sugars such as sialic acid to enter target cells and infect the host, the new study shows that the PHEV coronavirus can enter cells without them. It uses a protein called DPEP1, located in the cell membrane, as a receptor to facilitate entry.

Using advanced electron microscopy and X-ray crystallography techniques, researchers have visualised how the virus’s spike protein—the “key” that coronaviruses such as SARS-CoV-2 use to enter our 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 Transmission to Humans

“The area 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 coronavirus OC43,” explains Jérémy Dufloo, a researcher at I²SysBio and lead author of the article. “This suggests that the use of DPEP1 as a receptor is specific to the porcine coronavirus PHEV, and that other viruses in the same family use different receptors that have not yet been identified,” he adds.

The study also demonstrates 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 to enter cells, raising questions about the potential for this swine virus to transmit from animals to humans.

Preventing Future Pandemics

This work not only identifies a new viral receptor but also provides key information on the evolution of coronaviruses and their entry mechanisms—fundamental aspects for anticipating and preventing future pandemics.

From a scientific perspective, the finding opens up new lines of research. As Rafael Sanjuán, principal investigator at I²SysBio 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.”

Furthermore, the researcher at the Valencian centre believes that this discovery poses a new challenge: “to identify the receptors used by other coronaviruses related to PHEV, which remain unknown,” he concludes.

Reference:
Dufloo, J., Fernández, I., Arbabian, A., Haouz, A., Temperton, N., Gimenez-Lirola, L.G., Rey, F.A., Sanjuán, R. Dipeptidase 1 is a functional receptor for a porcine coronavirus. Nature Microbiology (2025). https://doi.org/10.1038/s41564-025-02111-7