How a small number of mutations can fuel outbreaks of western equine encephalitis virus

This is the latest finding in a series of studies led by Jonathan Abraham, associate professor of microbiology in the Blavatnik Institute at Harvard Medical School, and his team that aim to understand the risk of western equine encephalitis virus and related viruses. The work, which was supported by federal funding, is published in Cell on April 4.

The findings, the research team said, offer important insights that could help researchers and public health experts better anticipate the likelihood of future outbreaks.

Historically, WEEV has caused large and dangerous outbreaks of encephalitis (a serious type of brain inflammation) among humans and horses throughout the Americas.

The virus circulates mainly between mosquitoes and birds. Since the turn of the century, WEEV has disappeared as a pathogen in North America. In South America, the virus occasionally spilled over to sicken small numbers of humans and mammals. However, in 2023, WEEV caused the first major human outbreak in four decades in South America, involving thousands of horses and over a hundred confirmed human cases.

How did the virus lose its ability to infect humans in North America? Why did the virus persist as a pathogen in South America and re-emerge to cause a major outbreak? The secret lies in alterations in its molecular makeup, the new study found.

Using an advanced imaging technique, the researchers determined how the spike proteins on the surface of 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 one of its spike proteins to a receptor on the surface of the host cell. In order to cause infection, the spike protein and receptor need to fit each other, like matching pieces of a jigsaw puzzle.

In a strain from 1958, when deadly WEEV outbreaks happened regularly, 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.

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

Strains isolated in South America over the past century, including the 2023-2024 outbreak strains, had never acquired the single mutation that would prevent them from attaching to the human and horse 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, found on mammalian brain cells. This same receptor is shared by WEEV's cousin, eastern equine encephalitis virus (EEEV), which is the most virulent alphavirus and has continued to cause outbreaks in North America. 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 dangerous WEEV strain were protected against the deadly brain inflammation caused by these virulent strains.

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

Additionally, the virus's rapid ability to 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," Abraham said.