Unraveling the Role of Mutations in Western Equine Encephalitis Virus Outbreaks

Recent research highlights the significant impact that minor mutations in viruses can have on their ability to cause outbreaks, particularly focusing on the Western Equine Encephalitis Virus (WEEV). This study, conducted by a team at Harvard Medical School, provides crucial insights into how changes at the molecular level can transform a virus from being harmless to highly infectious.

The findings, published in the journal Cell, were spearheaded by a microbiology team aiming to assess the risks associated with WEEV and similar viruses. Historically, WEEV has been responsible for severe encephalitis outbreaks affecting both humans and horses across the Americas.

WEEV primarily circulates between mosquitoes and birds. Notably, the virus has largely vanished as a significant health threat in North America but continues to appear sporadically in South America. In 2023, WEEV re-emerged in South America, leading to an extensive outbreak affecting thousands of horses and over a hundred confirmed human cases.

This resurgence raises critical questions: What caused WEEV to lose its infectivity in North America, and why did it persist in South America to trigger this latest outbreak? The research indicates that subtle mutations in the virus's structure may hold the answers.

Utilizing advanced imaging techniques, the research team analyzed how the spike proteins of different WEEV strains interact with specific cell receptors, namely PCDH10, which are common to both humans and birds. The virus attaches to these receptors to initiate infection, akin to fitting pieces of a jigsaw puzzle.

For instance, a strain from 1958, during a period of frequent and severe WEEV outbreaks, exhibited a strong compatibility with both human and avian cell receptors. In contrast, a strain collected in 2005 from California mosquitoes showed a preference for avian receptors, lacking the ability to effectively bind to mammalian cells due to a single mutation in its spike protein.

This mutation effectively barred the virus from attaching to the receptors found on human and equine cells while allowing it to infect through avian receptors. Conversely, strains from South America, including those responsible for the recent outbreak, have retained their capacity to bind to both human and horse cell receptors.

Furthermore, the study highlighted a specific alteration in the viral spike protein that permits WEEV strains to attach to another receptor, VLDLR, located on mammalian brain cells. This receptor is also utilized by Eastern Equine Encephalitis Virus (EEEV), a highly virulent relative of WEEV that continues to trigger outbreaks in North America. Historical strains of WEEV have also demonstrated the ability to invade host cells through VLDLR.

Importantly, when researchers inhibited the VLDLR receptor using a decoy protein, subjects infected with older, more virulent WEEV strains displayed a protective response against the severe brain inflammation these strains typically induce.

These findings are pivotal for improving pandemic preparedness. They shed light on the factors contributing to the first significant human outbreak of WEEV in four decades in South America and may inform surveillance strategies for North American WEEV strains, monitoring their potential to trigger large outbreaks.

The rapid transition of the virus from a benign presence in birds and insects to a dangerous pathogen for humans underscores the urgency of ongoing surveillance to detect and address emerging health threats.