The first three episodes of HBO’s The Last of Us have a lot to say about fungi. The series begins with a warning, as a gray-haired epidemiologist played by actor John Hannah cautions us that some fungi, including Ophiocordyceps, “seek not to kill but to control” the behavior of the animals they infect. Later, a mycologist at the University of Indonesia, played by Christine Hakim, explains that there is no medicine nor vaccine to fight off such a fungus in humans. What she proposes next—that our only solution to an emerging fungal epidemic is to “bomb this city and everyone in it”—is prime cinematic hyperbole. Although we fight these infections with intravenous therapy, not incendiary devices, there’s still real cause for concern when it comes to fungi.
The fungi that colonize our vast planet, though mostly a far cry from the phantasmic organisms that transform people into zombies, can pose serious threats to agriculture, biodiversity, and human health, especially in an increasingly warmer world. These fungi are precisely the ones you should be familiar with and, in some cases, fear.
Common human-associated fungi, which the public perceive as “bad” or “gross,” such as the ones that cause athlete’s foot, dandruff, run-of-the-mill yeast infections, and toenail fungus, are not the ones that keep doctors awake at night. But you can’t sell what you can’t see so Hollywood continues to play up the behavior-modifying properties of a few exceptional fungi at the expense of the truly invasive ones that are responsible for hospital stays and a majority of patient deaths.
“From a clinical perspective, the impact of these fungal diseases is really underappreciated,” says Bridget Barker, an associate professor of mycology at Northern Arizona University. “The patients get really sick before they get intervention.” Because many fungi opportunistically infect already sick patients, it complicates our understanding of their role in patient deaths and probably helps explain their near absence from the public conversation.
Even for physicians, especially those in many parts of the world where some of these fungal infections are most prevalent, “the biggest challenge is making the diagnosis,” says Ilan Schwartz, a physician at Duke University in North Carolina who specializes in fungal diseases.
In some places, clinicians still lack even the most basic tests, which can lead to an incorrect determination. By the time they realize a fungus, not a bacterial infection like tuberculosis, is causing the disease, treatment is generally less effective and can unfortunately lead to death.
But, if caught early enough, therapies can be very effective.
Tried-and-tested fungal treatments
There are three main classes of antifungals, medications that kill or suppress fungi, according to Schwartz. Of these, only one (azoles) can be taken as a pill outside the hospital setting. The negative side effects of the other two, echinocandins and polyenes, require professional medical oversight. “Any resistance to any one of these classes is hugely important and really restricts our ability to treat patients,” Schwartz explains.
And just how far-fetched is the emergence of fungi that resist our best drugs? One soil-dwelling fungus that also causes lung infections, Aspergillus fumigatus, shows resistance in 10 to 15 percent of isolates in some locations, Schwartz says. “The azoles they use in the field [to combat plant pathogenic fungi] are structurally very similar to the one we use in the clinic.” So what Joel told Ellie in the third episode of The Last of Us is right: Fungi are mutating. Though many have mastered the art of invading animals long ago, including people, they are becoming harder to fight once they are inside us.
Killer fungi outside of fiction
Some might argue that the fungi that live rent-free in our bodies are far more alarming than Ophiocordyceps. This includes fungi that cause Valley Fever, a disease in the southwestern US that is expanding northward and westward as the climate warms. Two closely related soil-inhabiting fungi responsible for this disease, Coccidioides posadasii and Coccidioides immitis (simply called “Cocci”), are a major concern. “We’re already seeing increases in areas in California where they hadn’t seen very many cases,” says Barker, who is among the world’s experts on Cocci. The Onygenales, the larger group of fungi that includes Cocci, are “concerning,” she notes, “because they cause disease in otherwise healthy people.” And because this particular group is co-evolving with mammals, “this is probably where the future threats will come from.”
Schwartz has his own concerns about Cocci. “The environment that favors the growth of this fungus is also the environment that favors wildfires,” he explains. The epithelial changes that occur with wildfire exposure dramatically increases the risk of Valley Fever.” When the ash settles in our lungs, so too may these fungi.
Cocci is far from the only fungal infection showing up in the clinic. In fact, outside of specific geographic areas where they are endemic, few cases of Cocci or its Onygenales counterparts are reported nationwide. “What I see as a clinician on a day-to-day basis is primarily invasive candidiasis and aspergillosis,” Schwartz says. These fungal diseases affect people with weakened immune systems, many because of cancer or a viral infection, including HIV/AIDS, COVID-19, or flu. The human immune system can also be weakened by treatment with corticosteroids and immunosuppressant drugs, like ciclosporin (coincidentally, a drug naturally produced by a close relative of Ophiocordyceps). “Viruses themselves cause various forms of immunoparesis [or dampened immune response] that then allow secondary infections to come in and basically run amuck,” Schwartz explains.
Lessons from epidemics in wildlife
Fungi infect animals, too—with their own implications for human health. Some recent large-scale fungal disease outbreaks among wildlife include mass die-offs of amphibians, due to chytridiomycosis, and bats, due to white-nose syndrome. An unchecked fungal animal pandemic can look apocalyptic: a dark backwater bloated with hundreds of frogs floating belly up, for instance, with their fungus-stiffened legs rising out of the water.
Prior to the 1990s, only a handful of mycologists knew anything about these bizarre aquatic fungi we call chytrids. The most famous among them, Batrachochytrium dendrobatidis or Bd, is responsible for the extinction of some 90 amphibian species with another 124 species experiencing global population declines of 90 percent or more.
Why should we care about frog-killing fungi? Well, like with human pathogens, climate change can accelerate spread in areas where the fungus was previously kept in check according to Rabern Simmons, a chytrid expert and curator of fungi at Purdue University Herbaria. More importantly, we are just now beginning to see the “hidden human welfare costs” of biodiversity loss, he says. In Costa Rica and Panama, an area hard hit by chytridiomycosis, Bd-driven collapse of amphibians has led to more mosquitoes and malaria cases in humans, as per a 2022 study. “We are seeing human health implications because of a microscopic aquatic mobile fungus that hardly anybody knew about,” says Simmons.
There is nothing fictional about the threat some fungi pose to us. While Ophiocordyceps fungi will continue to manipulate and kill insects, as it has done over millions of years of co-evolutionary history with their invertebrate hosts, the human fungal epidemic on the horizon likely will not bother to modify our behavior. Our history is more likely to intersect with an unassuming mold lurking quietly in the soil or forming a biofilm in a hospital sink: ever adapting to our dwindling lines of defense. Though a world where we do too little to stop a rising tide of fungal pathogens is a horrific prospect, our collective failure to recognize the interconnectedness between pathogens, people, animals, and plants could be more terrifying.