How Realistic Is The Last of Us’s Fungus Outbreak?


Who’s hungry for mushrooms?
Photo: Liane Hentscher/HBO

Spoilers follow for The Last of Us TV show and video games. 

Thanks to the sprawling IP universe of The Walking Dead, post-apocalyptic narratives about social collapse, hungry hordes, and desperate communities clinging to the last vestiges of civilization are familiar on TV by this point. All that stuff is in The Last of Us, too — just not any zombies.

The HBO series based on the popular video-game franchise from writer Neil Druckmann (seemingly not a fan of the “zombie” descriptor) focuses on a different kind of infection: a fungal one. Unlike The Walking Dead or Resident Evil, in which the dead come back to life, or 28 Days Later, in which a virus turns its hosts extremely violent, the Cordyceps fungus in The Last of Us takes over people’s brains, grows sponge-y masses inside bodies and tendrils out of mouths, and eventually bursts from eyes and foreheads. Humans stay alive as all this happens and spread the infection through bites, and in the course of a weekend, the global warming-enabled fungi mutation has seemingly traveled around the entire world.

In The Last of Us premiere episode, 20 years have passed with no progress made against the fungal threat — which is because of the real-life similarities between fungi and humans as eukaryotes, or organisms with nucleated cells, explains Dr. Ilan Schwartz, an instructor with the Duke University School of Medicine who specializes in immunocompromised hosts and invasive fungal infections.

“Our cells are a lot more complex than, for example, bacteria, and fungi are more related to people than they are to bacteria that cause infections,” says Dr. Schwartz of why there are only three antifungal agents compared with “way more classes of antibacterials.” “We have this problem with our adversary being closely related, and what that means is that the cell machinery is the same as ours. There are far fewer targets for antifungals to work with, to selectively cause damage to fungal cells without causing damage to human cells.”

Those commonalities, plus that uncomfortably true-to-life climate-change framing and the grotesquerie of the infected in The Last of Us, got us thinking: How scared should we be of Cordyceps or any other wide-scale fungal infection, anyway? An investigation!

SPORES VERSUS BITES 
The inciting plot point in The Last of Us was inspired by Druckmann’s viewing of a 2008 Planet Earth segment about how the fungal parasite Ophiocordyceps unilateralis takes over a bullet ant’s body and then grows out of the ant’s head to further spread. Narrator David Attenborough explains in the Planet Earth clip how there are thousands of different types of parasitic fungi, each of which focuses on a specific species — with textured spores, neon-orange poufs, and long gray tendrils emerging from dead moths and beetles. (Although Ophiocordyceps and Cordyceps are different genus, because The Last of Us was influenced by the latter and refers to the former in its narrative, we’re discussing both.)

In The Last of Us video game, the Cordyceps infection spreads partially via spores that travel through the air, necessitating that uninfected characters wear gas masks. As explained by Penn State University’s Dr. David P. Hughes, a Cordyceps specialist who was a scientific advisor on the 2013 video game, the fungus attaches as a spore to a host ant’s body, tunnels inside over the course of a day, and then creates an interior network so that nearly 50 percent of the ant’s body is fungal. (New research Hughes has published since Planet Earth aired clarifies that the fungi doesn’t infect the brain, but preserves it while invading and controlling musculature.) In the TV show, though, spores are abandoned — probably so the cast didn’t have to hide behind masks the whole time — in favor of mouth-tendrils, and a bite from an infected person can turn someone in as few as five minutes.

The infected’s tendency to chomp at whomever is around certainly doesn’t dissuade zombie comparisons, but fungus spreading through bites isn’t uncommon in nature, Dr. Schwartz says. As an example, this scenario isn’t dissimilar from how the fungus Sporothrix brasiliensis is transferred and causes the infection sporotrichosis. A dimorphic fungus that can exist as both a mold and a yeast, Sporothrix brasiliensis can be breathed in as spores from contaminated plant matter or spread through scratches and bites from cats, and is increasingly prevalent in Brazil. “It causes thousands of infections every year. If one of those cats were to be imported somewhere else, and scratch other cats, there is the potential for this fungus to spread throughout the world,” Dr. Schwartz theorizes.

Cordyceps can’t infect humans (… yet?), but spores from other fungi that live in soil and animal droppings can, and are a legitimate danger to immunocompromised people. Plus, certain fungi can spew out thousands of spores at a time that travel inches in the air. Masks, then: good for public health! Who’d have thought!


GLOBAL WARMING’S IMPACT 
Fungi love warmth and moistness, but it’s a delicate balance when it comes to how much heat they can handle. Of the possible millions of fungi species around the world, fewer than 500 are known to grow on mammals because “the temperature we think of as normal is the temperature warm enough to kill most fungi without killing us,” according to Rob Dunn in the 2011 New Scientist article “Killer Fungi Made Us Hot-Blooded.”

Still, about a dozen fungal species kill nearly 1.5 million people a year, and more scientists are beginning to seriously look at how much climate change is affecting those numbers. Given that, is the scenario posed in The Last of Us premiere — in which a warming planet helped Cordyceps mutate into a version that could infect humans — actually feasible?

Dr. Schwartz, while not a Cordyceps expert, points to one theory about the fungus Candida auris, a yeast that “sort of came out of nowhere” in 1996 and has since spread around the world, with an outsized effect on those with weakened immune systems. Resistant to multiple antifungal drugs, Candida auris can cause an invasive infection in blood, and could be an example of a mutation able to take advantage of the slimmer gap between the temperature of its environment and the temperature of our bodies, Dr. Schwartz explains.

“It’s not outlandish, the argument that global warming has increased the thermal tolerance of a fungi. It hasn’t been proven. It’s a hypothesis, and it’s happening on a fairly slow scale,” he adds. “But it is possible.”


THE FOOD SUPPLY AND IMMUNITY 
In both The Last of Us video games and the TV series, Cordyceps was initially transmitted through food: infected South American crops in the former, and an infected flour and grain factory in Jakarta, Indonesia, in the latter. There’s real-life history here: In the Middle Ages, the illness St. Anthony’s fire killed tens of thousands of people and was caused by rye infected with the fungus Claviceps purpurea. Ergotism poisoning has continued more recently, too: 200 people sick from rye bread in Manchester in 1928, an entire French town poisoned by a local baker in 1951. Former Rensselaer Polytechnic Institute professor Linnda R. Caporael has even theorized that the same fungal infection played a role in the Salem witch trials.

In The Last of Us TV show’s 2023 storyline, years of Cordyceps infection tracing back to bread, cereal, and pancake mix have turned people into creatures like clickers, who have elaborate mushroom-like growths coming out of their heads and sponge-y masses inside their bodies, and are hungry to spread the fungus. The only hope for a cure is Ellie’s seeming immunity, which Dr. Schwartz says is difficult to fact-check given how little we know about how so many fungi work.

“Presumably, exposure is being experienced by lots of people, but only very few people develop the disease,” Dr. Schwartz says of the connection between fungi and the infections they cause. “Is that related to the amount that they’re exposed to? Or does it have some other host factors? I’m not sure. There’s still a lot that we don’t understand.”

For now, Dr. Schwartz is unfazed. There are fungi species that have become beneficial for humans, like Cordyceps subsessilis, which is used in organ-transplant drugs, and Cordyceps militaris and Ophiocordyceps senensis, which are considered health supplements. Various fungi have potential as insecticides to slow malaria-spreading mosquitoes, and fungal-derived psilocybin has been tested as an anxiety treatment for people with end-stage cancer. There’s good that can come from fungi, too, and the circumstances needed for a destructive outbreak event are beholden to myriad factors that would need to align in the exact right way. 

Until then — if there ever is a then — The Last of Us can remain primarily in the entertainment space, Dr. Schwartz says: “I don’t think we need to worry. There’s lots of serious concerns in the world, but this isn’t one of them.”




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