How A Small Number of Mutations Can Fuel Outbreaks of Western Equine Encephalitis Virus

Study shows how spike protein changes determine the risk of viral outbreaks

A watercolor painting of spiky blue circles, an evocative artist’s interpretation of viruses.
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New research shows how small shifts in the molecular makeup of a virus can profoundly alter its fate. These shifts could turn a deadly pathogen into a harmless bug or supercharge a relatively benign virus, influencing its ability to infect humans and cause dangerous outbreaks.

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.

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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.

Authorship, funding, disclosures

Additional authors include Xiaoyi Fan, Wanyu Li, Jessica Oros, Jessica A. Plante, Brooke M. Mitchell, Jesse S. Plung, Himanish Basu, Sivapratha Nagappan-Chettiar, Joshua M. Boeckers, Laurentia V. Tjang, Colin J. Mann, Vesna Brusic, Tierra K. Buck, Haley Varnum, Pan Yang, Linzy M. Malcolm, So Yoen Choi, William M. de Souza, Isaac M. Chiu, Hisashi Umemori, Scott C. Weaver, and Kenneth S. Plante.

This work was supported by NIH awards R01 AI182377, T32AI700245, T32GM144273, T32GM008313, T32AG000222-33, R24 AI120942, T32AG000222-32, and R01 MH125162; the Jackson-Wijaya Fund; Wellcome Trust grant 226075/Z/22/Z; a Burroughs Wellcome award; a Vallee Scholar award; a Smith Family Foundation Odyssey award; a Charles E.W. Grinnell Trust award; and a G. Harold and Leila Y. Mathers Foundation award. Cryo-EM data were collected at the Harvard Cryo-EM Center for Structural Biology at Harvard Medical School.