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Is ‘The Last of Us’ Fungal Outbreak Possible? A Scientific Investigation


HBO’s Chernobyl was a masterful series dramatizing the 1986 nuclear reactor meltdown at the eponymous power plant. The Craig Mazin-directed limited series dominated the cultural conversation in our pre-pandemic world, earning critical praise and a couple of Emmys. At CNET Science we were most interested in how closely Mazin and co. were able to stick to real-world science. Turns out, they did a good job.

Mazin’s next HBO outing is The Last of Us, based on the 2013 survival-horror video game of the same name. CNET’s own Sean Keane has described the show, which debuted on Sunday, as “the greatest video game adaptation ever made.”

The Last of Us imagines a world ravaged by a fungal apocalypse caused by a creepy, mind-controlling fungus known as Cordyceps. That fungus is real, so I’ve naturally been wondering just how likely a fungi apocalypse really is. 

The idea has been investigated in the context of the game many times, but HBO’s version of the Cordyceps brain infection is slightly different to the one game developer Naughty Dog first conjured in 2013. 

What follows is an investigation of the plausibility of a fungal pandemic, caused by a Cordyceps-like pathogen that changes human behavior. I’m going to assume you’re at least somewhat familiar with the story of Joel and Ellie, the two protagonists making their way across the ruins of a post-apocalyptic USA. I’m also going to say at the top that this is an examination of a fictional world, so there’s always wiggle room for the story to develop in unexpected ways. It’s not meant to be a medical document, so keep that in mind and if you’re really not interested in the underlying real world inspiration for a fungal pandemic and just want to see Pedro and Bella cook (I’m looking at you, Andy Greenwald), this might not be for you.  

It also includes some light spoilers from episode 3 of The Last of Us, so if you’re trying to keep your viewing experience spoiler-free, it’s time for you to bail. 

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The real world inspiration for The Last of Us

You can blame David Attenborough and nature documentaries for the shambling, clicking horrors that haunt The Last of Us.

In a must-watch episode on jungles in the 2006 BBC series Planet Earth, Attenborough and his documentary team encounter various behavior-manipulating fungi, including one that parasitizes carpenter ants: Ophiocordyceps. In the clip, which has been viewed on YouTube over 10 million times, the camera lingers on an ant with its jaws wrapped around a tree branch. A ghostly violin plays as Attenborough narrates the scene.

“Like something out of science fiction, the fruiting body of Cordyceps erupts from the ant’s head,” he says. 

The Planet Earth scene inspired Bruce Straley and Neil Druckmann, the director and creative director respectively, on 2013’s The Last of Us. In a GamesBeat interview after the game’s release, Druckmann mentions “ripping off” the documentary and Straley says that zombie ants were the “jumping off point” for the game. And the game does hew closely to its real-world source material.

The life cycle of Ophiocordyceps is gruesome but beautiful. Ants that come into contact with Ophiocordyceps spores on the jungle floor become infected. The fungus slips inside the ant’s body and begins to replicate. It takes up residence in particular regions, like the brain and muscle, releasing chemical compounds to manipulate behavior of the ant. The ant is directed to the underside of a leaf, high above the ground, and bites into it. Its jaw locks around the leaf thanks to some clever fungal compounds and it stays there until the fruiting body erupts from its head. Eventually it bursts open and releases more spores to the ground.

The process is highly specific. One species of Ophiocordyceps typically infects and zombifies just one species of ant. This specificity extends to the way the fungus takes over the mind of its host. A 2014 paper explored the ant-fungus relationship, finding that Ophiocordyceps had evolved a particular set of compounds to influence behavior of one species of ant, but those same compounds did not alter the behavior of different ant species (though the fungus will still often kill those ants).

Our real-world understanding of the fungus has also changed since The Last of Us was released in 2013.

The Planet Earth documentary was released in 2006. At the time, the ant-infecting parasite was, scientifically, known as Cordyceps unilateralis. In 2007, many of the Cordyceps fungi that parasitize insects, including ants but also things like caterpillars and spiders, were reclassified into a different family of fungi — Ophiocordyceps. While The Last of Us uses these two words interchangeably, they are now classed as different genera of fungi and scientists still use Cordyceps as a kind of generic name for all the species.

The Last of Us timeline

The pandemic’s origins are not revealed in the video game beyond a few stray newspaper clippings and notes, which seem to point to a South American origin. HBO’s adaptation dives a little further into the backstory, specifically in episodes 2 and 3. This gives us a little more to work with in terms of real world plausibility.

Here’s the timeline, as we understand it.

On the morning of Sept. 23, 2003, a woman working at a flour and grain factory on the western side of Jakarta was bitten by an unknown human being. She became violent, attacked four coworkers, biting three of them, before being locked in a bathroom and shot in the skull.

The three coworkers who were bitten were executed a few hours later. Fourteen coworkers could not be located.

A day later, on Sept. 24, 2003, two police officers in Jakarta, Indonesia walk into a restaurant and interrupt Ms. Ratna, a professor of mycology at the University of Indonesia, as she’s eating lunch. They take her to a laboratory at the Ministry of Health where she looks down a microscope and identifies a fungus: Ophiocordyceps. 

(Depending on the species Ratna saw, the fungus would have likely been classed as a Cordyceps in 2003… a potential plot hole or pedantry?)

Ratna asks why it’s been stained with chlorazol — which is commonly used to identify fungal elements from human hair, nails or other specimens. “Cordyceps cannot survive in humans,” she tells the police officer. She then examines the corpse of the woman who worked at the flour and grain factory. She cuts open the bite wound on the woman’s leg and rummages around in her mouth, discovering the corpse has been colonized by Ophiocordyceps.

After making her discovery, she makes a recommendation: The officer should bomb the city and everyone in it. 

On Sept. 26, 2003, the outbreak hits the US. This is dubbed Outbreak Day. In Austin, Texas, the first indications of trouble are obvious as ambulances screech through the city at around 3:15 p.m. 

In the early hours of Sept. 27, the outbreak reaches critical mass and the streets become chaotic. Planes are crashing into the ground. Highways out of Austin become blocked by the military. Members of the public have, against the advice of the emergency broadcast system, fled their homes. 

By Monday, Sept. 29, Joel explains to Ellie, “everything was gone.”

Ellie sits in room with grass on the floor as Tess talks to her in The Last of Us.

In The Last of Us, humanity tries to pick itself up two decades after a mutant Cordyceps fungus kickstarts a pandemic.

HBO

So, could it happen?

The short answer is: It’s improbable. The longer answer? Maybe, but with a ton of caveats

There are two key plot devices that underpin the fungal pandemic in the TV version of The Last of Us — climate change and how the fungi reproduce.

The Last of Us sets up its first season with an interview segment that takes place in 1968. Two fictional researchers are discussing pandemics on a talk show. One of them, Dr. Neumann, says he’s not scared of bacteria or viruses kickstarting a pandemic, unlike the other guest. What scares him most is fungi. Mostly because they don’t just kill the host, but take it over. 

The audience laughs (and after the past three years, you might too). Then 35 years later in the fictional world, that’s exactly what happens.

In the real world, scientists have often wondered why insects, plants and amphibians are so susceptible to fungal diseases. Research has shown that regulating body temperature, or homeothermy, is a great barrier against fungal infection. Fungi thrive in cooler environments and that’s why they’re potent enemies of insects, amphibians and plants. It also means they’re not as big a danger to hot-blooded animals, like ourselves. Fungi also have to be able to absorb human tissue, which they mostly struggle to do, and even if they manage to invade us, they still have to contend with a robust human immune system.

Humans can be infected by fungi, though. Candida, a yeast which causes thrush, is a potent species. A multidrug-resistant species, Candida auris, is of major concern in hospitals. There are also molds, which cause athlete’s foot and ringworm. Sometimes, these fungi evade our defenses, especially those of us with compromised immune systems. 

“The one thing you have to remember with fungal infections is that they predominantly infect people with an underlying condition,” Julianne Djordjevic, an associate professor at the University of Sydney who studies fungal infection of humans, tells CNET.

Things are changing, though. The world, ours and the one in The Last of Us, is heating up. “What if, for instance, the world were to get slightly warmer?” the fictional Dr. Neumann asks in the premiere. Higher temperatures could see fungi slowly adapt and evolve to withstand the types of heat they might experience inside a human body. Some scientists believe this is why Candida infections might be on the rise

Another species known as Ophiocordyceps sinensis, found on the Tibetan plateau, provides a potential counter. The species has long been used in Chinese medicine and some of the compounds it creates have been studied for their anti-cancer properties. However, in 2018, mycologists showed climate change — in addition to overharvesting — was leading to a decline in the species. The Himalayas are particularly vulnerable as the world warms and, at least for this species, adaptation and evolution aren’t keeping pace. Perhaps we’re warming the world too quickly for fungi to adapt.

Spores and tendrils

But how does Cordyceps spread? And so fast? As an ascomycetes, or sac fungi, the Ophiocordyceps that inhabit Earth’s temperate jungles propagate and survive via spores. It’s part of their life cycle: infect an ant, take it over, create a fruiting body, release the spores, start again.

HBO’s adaptation makes one huge change from the video game: spores aren’t the way Cordyceps moves between people. Mazin has said this is mostly because spores would mean everybody would have to wear a mask all the time (I’m not sure that’s particularly true but it would be pretty clunky in a TV show). Nevertheless, the adaptation replaces spores with “tendrils” and bites from infected people, two things we haven’t seen as infectious agents in the real world. They’re also affected by proximity. Whereas spores can travel hundreds of miles, tendrils and bites need close contact.

That’s the toughest part of this pandemic to square, but The Last of Us tries to provide a creative solution as to how society collapsed. 

Joel wearing a gas masks punches an Infected in a dimly lit room. Torchlight provides a silhouette of the Infected against a green and white wall.

In the video game, Joel and Ellie sometimes don gas masks in areas of dense Cordyceps spores.

Naughty Dog

Early in the series, as Joel and Ellie are wandering through the wreckage of civilization, Joel briefly touches on the accepted narrative of the pandemic’s origins: Cordyceps mutated. Then the fungi got into the food supply — things like bread, sugar and cereal all carried the mutated strain — and that food supply was shuttled around the globe. 

There is precedent for this kind of thing. The Great Famine, which ravaged Ireland in the 1840s and 1850s, was caused by an organism similar to a fungus, known as Phytophthora infestans, destroying potato crops. Though it didn’t directly infect and kill (or “mind control”) humans, it shows we’re at least susceptible to fungi in ways that aren’t getting much attention.

But the tendrils are still a problem for plausibility, even if their advantages for infected organization are partially explained in an early episode.

“The fungus also grows underground,” Tess, another survivor who partners with Joel, explains to Ellie in an early episode. “Long fibers like wires, some of them stretching over a mile. You step on a patch of Cordyceps in one place and you can wake a dozen infected from somewhere else.” This connection could alert infected to uninfected and make it near impossible to avoid them, but in the early stages of the pandemic it would take some extremely inept government responses to truly take off.

Maybe not so unlikely, given what we know about the most recent pandemics…

However, this change would require a major evolutionary deviation for Ophiocordyceps. Provided the Cordyceps that Ratna sees down her microscope and the Cordyceps in the real world are fundamentally the same, it would mean the fungus has fundamentally changed on a genetic level to something entirely alien. It would also be unusual for those fungi to then be in food crops unless those crops are highly contaminated with ants or spiders or moths. 

Overcoming these challenges we still have to get to a place where the fungus can control the behavior of a human being. While fungal compounds can alter the human mind (think LSD, for instance, which was isolated from a rye fungus), the specific compounds required to make humans more aggressive and help spread the infection would require a miraculous evolutionary leap for Ophiocordyceps.

Regardless, there a lot of challenges for a mutated fungus to overcome. Perhaps these will be explained in later episodes.  

Oh and a final note: It’s not that spores don’t exist in HBO’s The Last of Us reality. In episode 2, Ellie asks “so there aren’t super infected that explode spores on you?” The response comes from Tess: “Shit, I hope not.” If spores aren’t an issue for infection then why are they mentioned in this way? Plot hole or potential unexplored infection pathway?

a cordyceps infected wasp species with two yellow, budding stalks protruding from its back

Whenever I see an insect with Ophiocordyceps stalks protruding from its exoskeleton I think, damn… Nature is metal.

Kevin Schafer/Getty Images

Life and death 

One of the under-examined elements of the Last of Us fungal pandemic is the decades-long survival of certain kinds of Infected. Let’s put the “Clickers,” an infected that first appears in episode 2, under our microscope.

In episode 2, Ellie asks Joel and Tess about infected with “split open heads that stay in the dark like bats” as they’re walking toward their rendezvous point in Boston. Joel and Tess stay silent, giving a knowing glance at each other. They know exactly what Ellie is referring to: the Clickers.

Clickers are typically found in damp, dark places like abandoned buildings, sewers and basements. Places without any light. There’s a good in-game reason for this: Sunlight and airflow don’t create the right conditions for spores to infect someone enough to turn them into Clickers. With the spores being removed in the TV show as an infection mechanism, the pathophysiology of Clicker infection is a little harder to discern.

Clicker’s skulls have completely been overtaken by Ophiocordyceps — to the point where they no longer have eyes — because of the brain infection. The bat analogy Ellie uses is apt because Clickers are named for the blood-curdling sounds they use to navigate the world. Without eyes, they need to echolocate, just like a bat or a dolphin. 

While Clickers offer up the most horrifying example of the Infected in the show so far (perhaps, besides another type of infected Ellie makes reference to in episode 2), they also present the most problems for a scientific eye. For one, Infected take months to years to become Clickers — how is a fungus going to prevent human tissue from breaking down?

Dr. Neuman, the scientist in the opening episode, provides something of an answer, suggesting that certain kinds of fungus do produce compounds that we use medicinally. For instance, penicillin. Bacteria, which are a key component of tissue degradation after death, have been at war with fungi for eons. This is why some fungi have evolved defenses that humans have co-opted. Penicillin is one, Cyclosporin — an immune inhibitor — is another.

So, theoretically, fungus can make chemical compounds that are beneficial for humans but we’re again in Extreme Evolutionary Leap territory. The Clickers and other long-term infected should be falling apart 20 years after the pandemic began. 

Should we worry about fungal pandemics?

Pretty much every major crop that humanity depends on is threatened by a fungal pathogen. Rice, wheat and maize represent the biggest and most important source of calories for the human population. If a fungal pandemic were to rip through the crop supply… well, it might not be as frightening as the bitey, mind controlled “zombies” of The Last of Us, but it could be devastating in a different way.

What’s concerning researchers today is the rise of fungi which are resistant to antifungal drugs. According to a paper published in the journal Science in 2018, crop-destroying fungi accounts for about one fifth of perennial yield losses. They write that “[t]o avoid a global collapse in our ability to control fungal infections,” we need to promote the discovery of new antifungal drugs and ensure our current use of pesticides and chemicals don’t give rise to more worrisome strains. 

Another consideration? A dual pandemic — one that lowers the immunity of humans to such a point that pathogenic fungi can take hold.

Consider COVID-19. During the height of the pandemic, patients with COVID-19 were sometimes presenting with fungal diseases. Researchers investigated cases of “mucormycosis,” which is caused by black fungus, in 18 countries in 2022, writing that it’s an understudied and poorly understood complication of severe COVID-19. It seemed to affect males more than females and was predisposed to those with diabetes, an underlying condition that can affect immunity.

While it’s one of the freakiest apocalypse scenarios and makes good fodder for sci-fi TV, Cordyceps is unlikely to reduce humanity’s numbers by the billion. But the enemy is out there and we should be prepared. Right now, we’re not.

Updated Jan. 18: Closed captions make it clear the doctor at the beginning of the show is Dr. Neuman, not Dr. Newman. We’ve changed the spelling in this piece.   
Updated Jan. 22: Ibu is an honorific for woman in Indonesian, rather than Prof. Ratna’s first name. Added the section “life and death” after Clickers first appearance.

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