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New Insights into Virus Evolution: Implications for Public Health

Recent studies illuminate how minor adjustments in a virus’s molecular structure can significantly impact its behavior, potentially transforming a lethal pathogen into a benign organism or enhancing a relatively mild virus’s virulence, affecting its capacity to infect humans and trigger serious outbreaks.

This significant discovery is part of ongoing research led by Jonathan Abraham, an associate professor of microbiology at Harvard Medical School’s Blavatnik Institute. The team focused on the western equine encephalitis virus (WEEV) and its relatives, aiming to assess the risks they pose. Their findings, which received federal funding support, were published in the journal Cell on April 4.

The researchers emphasize that these findings could assist scientists and public health officials in forecasting the potential for future outbreaks more accurately.

WEEV has a history of causing significant outbreaks of encephalitis—a severe brain inflammation—affecting both humans and equines across the Americas. It primarily circulates between mosquito populations and birds. After largely vanishing as a threat in North America since the early 2000s, WEEV resurfaced in South America in 2023, resulting in its first major human outbreak in forty years, with thousands of horses affected and over a hundred confirmed human cases recorded.

Researchers are investigating why WEEV became less capable of causing infections in North America while continuing to exist as a pathogen in South America, ultimately leading to its recent resurgence. Their research suggests that the changes in the molecular composition of the virus are pivotal.

Utilizing sophisticated imaging techniques, the scientists examined how the spike proteins on the surface of various WEEV strains from the last century interact with the PCDH10 receptor, which is present in both humans and birds.

The virus initiates an infection by attaching one of its spike proteins to a receptor located on a host cell’s surface. This attachment is akin to matching pieces in a jigsaw puzzle, demanding precise compatibility between the spike protein and the receptor.

A strain identified from 1958, during a period marked by frequent and deadly WEEV outbreaks, showcased a strong affinity for receptors in both humans and birds. In contrast, a strain isolated in California in 2005 had evolved to fit bird receptors well but lacked the ability to attach to mammalian receptors.

Crucially, the researchers discovered that a single mutation in the spike protein of the virus was sufficient to hinder its ability to bind with receptors found on human and horse cells. Fortunately, this mutation still permitted the virus to invade cells via the bird receptor.

Strains from South America over the last century, including those responsible for the recent outbreak, did not undergo this critical mutation, maintaining their ability to infect human and equine hosts.

Moreover, the study revealed that even a solitary change in the viral spike protein could enable WEEV strains to bind to a different receptor, VLDLR, which is located on mammalian brain cells. This receptor is also utilized by WEEV’s relative, teh eastern equine encephalitis virus (EEEV), notorious for its high virulence and ongoing outbreaks in North America. Historical strains of WEEV were found capable of infecting host cells via VLDLR as well.

Interestingly, blocking this essential receptor using a decoy VLDLR protein yielded protective benefits for animals infected with older, more virulent WEEV strains, shielding them from severe brain inflammation.

The insights gleaned from this research are invaluable for pandemic preparedness. They enhance understanding of the recent major human outbreak of WEEV in South America and could inform surveillance strategies aimed at monitoring North American WEEV strains for potential risks of large-scale outbreaks.

The virus’s ability to rapidly transition from a seemingly harmless entity in insect and bird populations to a significant human pathogen underscores the critical need for diligent monitoring and preparedness against emerging infectious diseases. Jonathan Abraham emphasizes, “The more we understand about this important group of emerging viruses before a serious threat emerges, the better.”

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