News Notes

Small Mutations Can Fuel Viral Outbreaks

Small shifts in the molecular makeup of a virus can alter its ability to cause outbreaks.

Using an advanced imaging technique, researchers at Harvard Medical School determined how the spike proteins on the surface of Western equine encephalitis virus (WEEV) strains isolated over the past century interact with a type of cell receptor known as PCDH10 that is shared by humans and birds. The virus enters its host and causes infection by attaching 1 of its spike proteins to a receptor on the surface of the host cell. To cause infection, the spike protein and receptor need to fit each other like 2 puzzle pieces.

In a strain from 1958, when deadly WEEV outbreaks happened regularly in North and South America, the virus was a good fit for both human and bird cell receptors. However, a North American WEEV strain isolated from mosquitoes in California in 2005 was a good fit for bird cell receptors but not for mammals. A single mutation in the virus’s spike protein was enough to prevent it from attaching to human and horse cells.

Strains isolated in South America over the past century, including 2023-2024 outbreak strains which affected thousands of horses and more than 100 people in South America, had never acquired the single mutation that would prevent them from attaching to the human and horse cell receptors. A single change in the viral spike protein enabled WEEV strains to attach to a different receptor called VLDLR found on mammalian brain cells. In the past, highly virulent, ancestral forms of WEEV were capable of invading host cells through VLDLR. Notably, when researchers blocked this key receptor using a decoy VLDLR protein, animals infected with the older, more virulent WEEV strain were protected against the encephalitis.

The new findings offer critical clues for pandemic preparedness because they provide insights on the first major human outbreak of WEEV in 4 decades and could help efforts to monitor North American WEEV strains for their potential to cause large outbreaks. MeV

For more information:
Xiaoyi Fan et al. Molecular basis for shifted receptor recognition by an encephalitic arbovirus. Cell. 2025;188(11):2957-2973.E28
https://linkinghub.elsevier.com/retrieve/pii/S0092867425003472