The Last of Us 2: The real science that inspired the zombie fungus

A fungus that slowly moves through the body with the goal of subjugating the brain sounds like something you might see in a video game. That’s because it is: Cordyceps Brain Infection (CBI) has overtaken the planet in The Last of Us (and The Last of Us Part 2). But the fungus that inspired the game really exists — and it’s just as gnarly in real life.

In real life, Cordyceps is a genus of fungus that contains hundreds of species. The fungi are not bent on infecting humans, but they can really do some damage on insects.

In China, a variety called Ophiocordyceps sinensis, or caterpillar fungus, infects the body of ghost moth larvae and is considered a rare prize linked with sexual stamina. But the version of cordyceps most of us are familiar with (perhaps thanks to Planet Earth fame) is Ophiocordyceps unilateralis, which specifically infects carpenter ants.

In carpenter ants, the fungus snakes its way through the body, taking control of their muscles. Then, shortly before its demise, the ant will leave the colony at sunset, find a high-hanging leaf or branch, and clutch it in its jaws. There, the ant hangs motionless until it dies and the fungus emits spores that rain down upon unsuspecting victims. That process has earned it the nickname “zombie fungus."

It’s clear that The Last of Us was influenced by this real-life fungus. For one, it actually shares the genus name.

The other reason is that David Hughes, a professor of entomology and biology at Penn State's College of Agricultural Sciences, consulted with the game developers on the first Last of Us game. Hughes studies cordyceps fungus.

"The developers really did a phenomenal job all by themselves," Hughes tells Inverse.

The Last of Us Part 2 doesn’t update the science of the disease very much from the original. But we’ve actually learned a lot more about how Ophiocordyceps unilateralis works in the interim, Hughes explains. Now we know that cordyceps doesn’t target the ant’s brain to turn it into a zombie: It actually preserves the brain while wreaking havoc everywhere else.

"We can't expect too much from them on this," says Hughes. "We ourselves thought it would be in the brain and we were surprised to find that it wasn't."

Mind control without the brain — In the game, the cordyceps fungus moves through four stages. It slowly strips the infected person of rational thought, vision, their face, and ultimately their humanity. In the game, this whole process takes place within the brain and expands outwards.

In real life, Hughes 2017 research demonstrated that the fungus stops short of the brain.

Instead, it attaches to the body as a spore. Then it tunnels its way from the outside of the ant’s body to the inside over the course of 24 hours (Hughes likens it to a ping-pong ball going through a brick wall). Once there, it develops a fungal network. At the peak of infection, Hughes says that about 40 to 50 percent of the ant’s body is made up of fungus on the inside.

That environment is highly toxic because cells are rupturing as the fungus moves through the ant, says Hughes. Yet, the brain remains ultimately undamaged, even though the fungus could cause damage if it wanted to.

"This is an active decision by the fungal colony as it is growing and replicating inside the body," he says.

Instead, the fungus releases neuromodulators – specifically oxidative reductive chemicals. Those, Hughes explains, keep things healthy in the brain as the rest of the body is under assault. That's all set up for the ant's final act: the death grip.

"What we think is happening in the brain is critically important for behavior manipulation, in order than it can literally walk the ant out of the nest to get it where it needs to go," he says.

The death grip — During the final stage of O. unilateralis infection, which happens about three weeks in, the ant hangs from a leaf as spores are rained downward from its body. It's not terribly different from the stage four infection of Cordyceps Brain Infection in The Last of Us: the stage when the body is covered in fungal plates and the body grows stalk-like projections.

In a 2019 study, scientists performed an analysis of ants infected with the fungus and came up with two explanations for the death grip.

Firstly, they found that the fungus densely crowds muscle cells, which means they could be excreting some type of molecule that causes those muscles to contract. That could produce that final chomp motion that signals the end of the ant’s life.

But they also found that the fungus specifically preserved neuromuscular junctions — places where muscle cells and the brain’s motor neurons come together to exchange information. That suggests that the fungus may cause the brain to send the final “chomp” signal to the jaw muscles which initiates the death grip.

That fits with Hughes' work suggesting that the brain is spared for this reason. Though, it’s a bit of a far cry from the Cordyceps Brain Infection in The Last of Us.

Maybe the cordyceps fungus doesn’t control the brain in real-life the way that the fictional CBI does. But at its heart, they’re both examples of zombification that's as fun as it is scary. In fiction and in reality, it triggers a macabre fascination, says Hughes.

"We're sort of horrified at something coming in and taking over our brain. If I chop off your leg or your arm, you're still you. But if you lose your mind, you stop being you."