Breaking down the microbiology world one bite at a time
How a Few Mutations Could Reignite a Deadly Virus
The mosquito-borne Western Equine Encephalitis Virus (WEEV), once a widespread cause of brain inflammation in humans and horses across the Americas, has quietly faded from the spotlight over the past few decades. But a new study reveals that this virus may be gearing up for a comeback.
For decades, the virus caused outbreaks in North and South America, but then it went off the radar. Although WEEV can still be detected in mosquitoes, the last documented human case in North America was in 1999. But in 2023, the virus resurged —an outbreak in South America caused over 2,500 equine infections and more than 200 human cases.
So what changed?
According to the study, the virus could have been evolving— specifically, changing receptors it can use to infect host cells. Viruses need these receptors to get into cells, and WEEV has been really good at targeting a human brain receptor called PCDH10, among other receptors that are important in regulating cholesterol. These receptors are especially abundant in brain tissue, which is why, in the past, the virus was good at causing neurological diseases, like brain swelling.
But over time, many WEEV strains lost their ability to bind to mammalian receptors, partly explaining why human cases diminished. Instead, the virus maintained strong binding capability for avian receptors, keeping its life cycle going in birds and mosquitoes without spilling over into humans.
However, scientists have now found that it doesn’t take many mutations in the virus to change receptors good at binding. With just three mutations in the virus’s surface protein (called E2), the virus can switch which receptor it binds to.
In older, highly virulent strains of WEEV, the E2 protein is shaped just right to interact with some human receptors. But more recent strains have mutations that disrupt these interactions. Changing a single amino acid breaks an important interaction with the PCDH10 receptor, essentially keeping the virus out of human brain cells, and preventing the virus from causing brain swelling.
But when researchers reversed that mutation in the lab, the virus regained its ability to bind human PCDH10—and could once again infect neurons in mice which have PCDH10 receptors closely related to humans. When they added a couple of other mutations in the E2 protein, it helped the virus enter through other receptors, making it better at infecting cells. Which means just a couple of mutations in WEEV can make it more dangerous.
The researchers then tested whether they could block the virus using a protein called RAP, which normally shuts down the receptors the mutated virus had regained access to—brain receptors called VLDLR and ApoER2. While RAP did block those entry routes, it didn’t stop the virus. That’s because, thanks to the other mutation, the virus could still get in through PCDH10.
The researchers also explored how we could fight back against this potentially deadly version of WEEV. The team tested a kind of molecular decoy, treating mice with a piece of the VLDR receptor. Since this piece of VLDR wasn’t attached to cells, it should only bind WEEV but not facilitate any kind of infection. And when the mice were pre-treated with this molecular decoy, more mice survived after being infected with the mutated WEEV.
This study reminds us that we don’t need to wait for viruses to cause outbreaks before we can find out what makes them dangerous and what we can do to stop them—just by looking at their genetic sequence.
Featured image: Made by author using Biorender.com
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