Infectious Disease

Spike Protein Mutations Can Fuel Outbreaks of Western Equine Encephalitis

By Jake Miller

Small shifts in the molecular makeup of a virus can profoundly alter its ability to infect animals and humans, according to a series of studies led by Jonathan Abraham, MD, PhD, an associate professor of microbiology in the Blavatnik Institute at Harvard Medical School. The goal of Dr. Abraham and his colleagues was to better understand the risk for western equine encephalitis (WEE) and related viruses. The work, which was supported by federal funding, was published in Cell.

WEE virus circulates mainly between mosquitoes and birds. Since the turn of the century, it has disappeared as a pathogen in North America, and it occasionally spills over to infect small numbers of mammals in South America. However, in 2023, WEEV caused the first major human outbreak in 4 decades in South America, involving thousands of horses and more than 100 confirmed human cases.

How did the virus lose its ability to infect humans in North America, and why did it persist in South America and re-emerge to cause a major outbreak? According to the new study, the secret lies in alterations in the virus’ molecular makeup.

Using an advanced imaging technique, the researchers determined how the spike proteins on the surface of WEEV strains interact with the PCDH10 cell receptor, which is shared by humans and birds.

The virus causes infection by attaching one of its spike proteins to a receptor on the surface of a host cell. The spike protein and receptor need to fit together for an infection to occur.

In a strain from 1958, when deadly WEEV outbreaks occurred regularly, the virus was a good fit for both human and bird cell receptors. In a North American WEEV strain isolated from mosquitoes in California in 2005, the virus was a good fit for bird cell receptors, but not for mammals.

The researchers found that a single mutation in the virus’s spike protein was enough to prevent it from attaching to horse and human cells. The mutation, however, still allowed the virus to enter and infect cells using the bird receptor.

Strains isolated in South America during the past century, including the 2023-2024 outbreak strains, had never acquired the single mutation that would prevent them from attaching to the horse and human cell receptors.

The researchers also observed that a single change in the viral spike protein enabled WEEV strains to attach to a different receptor called VLDLR, which is found on mammalian brain cells. This same receptor is shared by WEEV’s cousin, eastern equine encephalitis virus, the most virulent alphavirus and one that has continued to cause outbreaks in North America. In the past, the highly virulent ancestral forms of WEEV were capable of invading host cells through VLDLR.

When researchers blocked this key receptor using a decoy VLDLR protein, animals infected with the older, more dangerous WEEV strain were protected against the deadly brain inflammation caused by these virulent strains.

The virus’s ability to rapidly shift from a harmless reservoir in insects and wild birds to a dangerous human pathogen highlights the importance of surveillance efforts to monitor for potential outbreaks and emerging diseases.

“The more we understand about this important group of emerging viruses before a serious threat emerges, the better,” Dr. Abraham said.

For More Information

This article was originally published on the Harvard Medical School website. It has been edited for style and length. https://hms.harvard.edu/news/how-small-number-mutations-can-fuel-outbreaks-western-equine-encephalitis-virus

Fan X, Li W, Oros J, et al. Molecular basis for shifted receptor recognition by an encephalitic arbovirus. Cell. 2025;S0092-8674(25)00347-2. doi: 10.1016/j.cell.2025.03.029 https://www.cell.com/cell/fulltext/S0092-8674(25)00347-2