Is ‘The Last of Us’ a cautionary tale? The truth about the fungus among us

It’s a terrifying scene.

A staggering mess of something that used to be a person, clothes tattered and falling off its body, leans forward, close to its cringing victim’s face.

It opens its mouth and tendrils — an infectious fungus — seek out its victim’s mouth, each moving individually, sinuously. It’s unnerving, shocking and disconcertingly beautiful.

This done, the victim is infected, like its attacker; it joins the horde of its kin, while the monster moves on in search of more prey.

It’s fiction, a moment from the new hit series “The Last of Us,” in which the fungus turns humans into zombies. The fungus is, however, based on a real one, cordyceps.

The show and the seminal video game on which it is based toy with a frightening conceit: that a change of circumstances — global warming, perhaps — might, under the right conditions, bring down upon us a catastrophic pandemic we are ill-prepared to handle.

And there are indications that that day might be closer than we think.

To be clear, a fungus-spawned zombie apocalypse is highly unlikely. But in the real world, drug-resistant fungal outbreaks are already spreading across the globe, and scientists and governments are only just becoming cognizant of how little we know about the planet’s fungi population, and changes in our environment do in fact raise the spectre that something fungal and sinister may rise from the depths of our incomprehension.

Hostile takeover

In “The Last of Us,” cordyceps is at the root of a worldwide pandemic. People are infected by the millions, by the spores of the fungus, through bites from infected people, or from the aforementioned fungal French kissing.

Fungi — yeasts, mushrooms and more among them — can often be found rooted in the soil in nature, but they differ from plants in that they don’t photosynthesize. Cordyceps is a fungus family containing more than 600 species, many of which are highly adapted to infecting insects. Each of those has a specialty — specific species of ants, grasshoppers, dragonflies, beetles.

In those species — Ophiocordyceps unilateralis is one such — spores from the fungus infect a host (the carpenter ant, in this case) and grow a network of tendrils through the insect’s body, commandeering its muscles.

Recent studies have shown that the fungus doesn’t invade the ant’s brain, merely bypasses it — the insect becomes a captive in its own body, alive but not in control.

That doesn’t last.

Cordyceps, now at the wheel, compels the ant to move upwards on a plant and to clamp its jaws into a leaf stem. The fungus feeds on the ant’s innards until there’s nothing left, then, using the energy it has siphoned from its victim, sends a long tendril through the ant’s head.

Ultimately, the bulb on the end of that tendril bursts, releasing spores into the air to infect other ants. Entire colonies can be wiped out this way.

But while there’s a lot we don’t know about fungi, experts are pretty certain that if and when the zombie apocalypse comes, cordyceps won’t be at the root of it.

“Cordyceps is a fungus that has evolved to interact with insects, and it’s spent millions of years just making this perfect evolutionary concurrence with insects. It is specific for insects and not humans,” says Shawn Lockhart, director of the Centers for Disease Control’s (CDC) Fungal Reference Library.

“Part of the reason that that it can’t infect humans is, number one, it just hasn’t evolved to interact with the type of neural machinery that we have in us. But there’s an even simpler reason: The majority of them just don’t grow above 30 degrees (Celsius). And because our human temperature is 37 and above, they just can’t live in us.”

In fact, cordyceps is benign enough to humans that for years some species have been used in supplements, allegedly to improve energy and immunity, though the scientific jury is still out on that. In all that time, to the best of anyone’s knowledge, it has never sparked a zombie apocalypse.

Thriving in a changing world

Of the 150,000 known species of fungus — and scientists estimate a few million are yet to be discovered — only about 200 are known to infect humans. Of those, the majority cause minor ailments — athlete’s foot, nail infections, skin and hair infections.

There are those that cause more serious infections, though the vast majority occur in people who already have underlying health problems, and those whose immune systems are compromised.

But that doesn’t mean that fungal infections of humans are all trivial.

Fungal diseases are responsible for more than 1.6 million deaths annually, as many as tuberculosis and three times as many as malaria. And some species can cause diseases — invasive aspergillosis is one — that, in immunocompromised patients, can kill half of their victims.

And those numbers are on the rise, especially as strains of fungi that are resistant to current antifungal treatments are spreading across the globe in epidemic fashion.

Candida auris is the poster child for this. First identified in 2009 in Japan, it has now spread to all six inhabited continents and is categorized as a serious global health threat, because it’s not only difficult to identify and the cause of outbreaks in health-care settings across the globe, but it is also resistant to most — and in some strains, all — antifungal drugs.

A large reason for that global spread has been the changing nature of the landscape of human disease.

We’ve seen, over the past few decades, a dramatic increase in the number of vulnerable patients. Populations are aging and medical advances mean there’s been an increase in the number of immunocompromised patients — those who’ve been through chemotherapy, for example. And there has been the advent of new diseases that compromise the immune system, like AIDS.

And fungal infections can be opportunistic. A healthy person can carry with them a colony of fungi with no ill effects until something else — COVID, for example — weakens their immune system. Then a fungal infection can take hold.

The World Health Organization in 2022, for the first time, published its Fungal Priority Pathogens list — a guide to research, development and public health action on fungal infections.

Here’s what it had to say about fungal infections during the COVID pandemic: “Three groups of COVID-19 associated fungal infections; aspergillosis; mucormycosis; and candidaemia, were frequently reported, often with devastating consequences.”

The report also adds: “There is evidence to suggest that both the incidence and geographic range of fungal infections are expanding globally due to climate change.”

Unknown hazard

The spread of fungal infections that we know about is worrisome enough to scientists — but that could be just the tip of a potentially very large iceberg. There’s also the prospect of what’s below the surface — something arising from the vast chasm of what we don’t know about the world’s fungi, especially all those countless undiscovered species.

“That’s something that that worries all of us in mycology,” says Lockhart. “There are millions of species of fungus and quite a few of them live in tropical areas … And as they adjust over time and evolve to survive at warmer temperatures, there’s always the chance that one fungus who’s not been pathogenic (disease-causing) to humans so far could be able to adapt itself to a newer environment, raise its temperature or its temperature tolerance, and then cause infections in humans. We are very concerned about that.”

In fact, a recent study at Duke University determined that when the pathogenic Cryptococcus deneoformans was exposed to elevated temperatures, the number of genetic changes the fungus made increased, potentially paving the way for adaptations that could increase its risk to humans.

So, not only are fungal diseases dangerous to humans, not only are they spreading across the globe, but there is the potential, with changes to our environment, for new fungal threats to emerge.

And on top of that, the fungal infections we’re already battling are rapidly proving more difficult to treat.

Limits on treatment

More and more, scientists and doctors are finding strains of fungi which are resistant to the drugs they use for patient treatment. Some of that occurs by adaptation through exposure to the limited range of drugs available.

But there’s also concern that the use of antifungals in spraying crops is increasing resistance in certain fungi — the sprays used on crops are closely related to the antifungals doctors have at their disposal.

Candida auris, Aspergillus fumigatus and Cryptococcus neoformans, for example — three of the top four on WHO’s priority list, have all shown resistances to various antifungal treatments, in C. auris’s case, sometimes to all of them.

Doctors face this problem with a limited number of weapons in their arsenal. Unlike bacteriological infections, from which they can draw from nearly a dozen major classes of treatments, there are now only three major classes of treatments for fungal infections. When a fungus is resistant to even one of those classes, options for doctors can shrink pretty rapidly.

“You find out oftentimes when you’re doing antifungal surveillance testing that it’s a fungal pathogen that you’ve isolated from the patient,” says Denice Bay, assistant professor in the Department of Medical Microbiology and Infectious Diseases at the University of Manitoba. “You’re really testing it against whatever arsenal of drugs that you have available to find the best therapy that’s at your disposal. And in some cases, if they’re resistant to all three classes, you really don’t have that many other options.”

There are a couple of reasons for that lack of options, she says. One is the very nature of fungi themselves.

In the dark

Unlike bacteria and viruses, fungi are eukaryotes, as are humans, meaning their cells contain a nucleus and organelles enclosed by a membrane. In fact, fungi are more closely related to animals than they are to plants.

As a result, though we’ve developed a wide of array of antibacterial drugs, it’s much more difficult to develop an antifungal treatment that isn’t also antihuman.

The other reason is that we just don’t know enough about fungi.

They haven’t been studied as intensely, haven’t been the focus of frantic development of vaccines and treatments, haven’t been at the forefront of the public’s mind as have bacteria and, most recently, viruses.

The squeaky wheel, says Bay, gets the grease. And in this case, the grease is funding and incentives for research and monitoring.

Traditionally, after all, fungi did not cause large outbreaks like bacteria the caused the Black Death or the virus that brought us COVID. And until relatively recently, fungal pathogens had low levels of resistance to antifungal drugs.

But that’s all changing now, says Aleeza Gerstein, a fungal biologist and assistant professor of Microbiology & Statistics at the University of Manitoba. Researchers and public health agencies alike are paying more attention to fungi, but there’s a lot of catching up to do.

“What we don’t know about fungi far, far exceeds what we do,” she says, calling the Candida auris emergence from Japan the canary in the proverbial coal mine.

“Before Candida auris, Canada’s National Microbiology Labs, the Public Health Agency, to my knowledge, did not have a fungal research program and it was Candida auris that made them say, ‘OK, now we need to we need to start monitoring for fungal infections as well as bacterial and viral.’”

“We don’t have a really good handle on what is even out there,” she says.

It’s not just Canada. One of the key findings in the WHO report was the global paucity of data on fungi.

“The systematic reviews revealed major knowledge gaps on the global burden of fungal infections and antifungal resistance,” it reported. “All 19 pathogens included in the prioritization lacked comprehensive data on the burden of disease, especially data relating to morbidity.”

With millions of species undiscovered, Gerstein says money spent on fungi research would not only would help stem the rising tide of global fungal infections, it might also turn out to be a treasure trove.

We’re already the beneficiary of “good” fungi: the mushrooms on your steak, the truffles in your mashed potatoes, the yeast that makes your bread rise, and the role fungi play in wine, beer and soy sauce, to name a few.

Even the zombifying cordyceps has a yin to its “The Last of Us” yang; scientists have found that cicadas in Japan have managed to domesticate the zombie fungus and put it to work making essential vitamins and other nutrients.

The roots of various fungi have been used to make packaging, clothes, shoes, sustainable leather and skin-care products. One researcher in Manitoba is even using fungi to make new building materials.

To Gerstein, the possibilities in that untapped well of fungal knowledge are fascinating.

“How cool is it that we’re living amongst things and we have no idea what they are?”

“Life is beautiful. We should understand the species we share the planet with, and not just because we’re afraid it’s going to hurt us.”

SHARE: