Illustrations by Brit Weatherbee
Since its debut in January 2023, HBO’s The Last of Us has captivated audiences with its hauntingly beautiful post-apocalyptic American landscapes, deep human drama, and a chilling portrayal of fungified zombies. But how much of the Cordyceps Brain Infection (CBI) at the heart of the story is rooted in real fungal biology? Let’s dive into the fascinating intersection of fact and fiction, and explore what real-world fungal pathogens might mean for humanity’s future. Spoiler alert: it’s both terrifying and fascinating.
What is the Cordyceps Brain Infection in The Last of Us?
In The Last of Us, the fictional affliction is not a virus like in so many zombie films, but rather a fungal disease they call the Cordyceps Brain Infection or CBI. After quickly colonizing their hosts’ brain, the fungal invader directs their host to spread themselves to non-infected people through bites or direct contact with mycelial fibers emanating from the skin and mouth. We know that the infected progress through four stages: Runner, Stalker, Clicker and Bloater, each possessing an increase in physical strength and a multiplication of mushrooms sprouting from their head and body, giving them added protection from human firepower. There is no cure for CBI but one of the show’s main characters, Ellie, has a natural immunity against it.
How real is the Zombie Fungus in The Last of Us?
As bizarre as the show's fictional infection may seem, it's rooted in a very real organism: Ophiocordyceps unilateralis, often called the “zombie-ant fungus.” This parasitic fungus doesn’t invade the brain, as the show suggests, but instead infiltrates the insect’s body and hijacks its muscles. Once environmental conditions are favorable, it compels the infected ant to leave its colony, climb vegetation, and clamp down in a death grip—typically on the underside of a leaf or twig. The fungus then kills the host, sprouts a fruiting body from the cadaver, and releases spores to begin the cycle anew. Though unsettling, Ophiocordyceps is just one of many entomopathogenic fungi—others infect everything from flies to cicadas—that have evolved to manipulate their hosts in eerily precise ways.
What is mushroom fact vs. fiction in the show?
The portrayal of the infected in The Last of Us diverges significantly from the real-life fungi that inspired them. Jon Carver, Lead Mycologist at North Spore, highlights the show’s “visually pleasing but scientifically inaccurate” representation of fungal anatomy. According to Carver, the creators appear to have amalgamated features from slime molds, Ganoderma lucidum (Reishi), and Cordyceps into a single fictional organism—an artistic, rather than realistic, creation. North Spore’s Creative Director, Matt McInnis, also weighed in, pointing out that the dramatic fungal growths responsible for the “Clicker” stage’s signature blindness closely resemble Laetiporus sulphureus, commonly known as Chicken of the Woods.
While the show vividly depicts fungi erupting from human heads and torsos, it glosses over key elements of fungal biology—most notably, spores. “Where are the spores?” asks Rachael Martin, North Spore’s Laboratory Manager. The absence is intentional. In adapting the story for television, the creators chose to remove airborne spores, which were present in the original video game, and instead emphasize direct transmission via mycelial networks. As co-creator Neil Druckmann explained in an interview with Polygon, “If we wanted to treat it realistically… characters would wear gas masks all the time,” limiting the show’s ability to portray nuanced, emotional performances.
Instead, the shift to a sprawling fungal network made the infection more tangible and ominous. As Druckmann noted in Collider, “it became very scary to think that they’re all working against us in this unified way.” Though the choice departs from strict scientific accuracy, it serves the narrative well—trading microscopic realism for a terrifyingly connective, touch-based mechanism of spread that feels more immediate on screen.
The "Clicker" stage of infection resembles Chicken of the Woods mushrooms
Can Cordyceps fungus actually infect humans?
A central premise of The Last of Us hinges on the idea that a Cordyceps-like fungus could suddenly leap from infecting insects to humans. But according to João Araújo, Assistant Curator and Mycologist at the New York Botanical Garden, this scenario is, in reality, “very unlikely.” Speaking to Forbes, Araújo explained that the physical and physiological differences between insects and humans are simply too vast. Insects are small, cold-blooded, and possess radically different internal systems—including open circulatory systems and exoskeletons. “These fungi are not prepared to invade, establish within, and transmit spores from a human body,” Araújo said. In fact, Cordyceps fungi have been coevolving with insects for over 130 million years and have never adapted to infect mammals—or any non-insect animals. The odds of such a drastic host jump happening suddenly are vanishingly small. So, while chilling, a real-life zombie apocalypse brought on by mushrooms remains firmly in the realm of fiction.
Why are fungal infections so hard to treat?
The show does get one major detail right: the absence of a vaccine, even decades after the fictional Cordyceps Brain Infection (CBI) first emerged. Fungal infections are notoriously difficult to treat, in large part because fungi—like humans—are eukaryotic. This means they share many cellular structures with us, including nuclei and membrane-bound organelles, making it hard to target fungal cells without also harming human ones. To complicate matters further, fungi, like bacteria and viruses, can evolve resistance to treatments, especially under selective pressure from overuse or incomplete courses of antifungal medication.
Some fungal infections, especially those affecting the skin and nails, are particularly stubborn. They can be difficult to reach with oral or topical medications, and symptoms often mimic other types of infections. In some cases, infections may not even be visible on the skin, making diagnosis challenging. Accurate identification is critical—without it, healthcare providers may struggle to prescribe effective treatments. While The Last of Us dramatizes a worst-case scenario, the underlying message holds true: fungal pathogens, though often overlooked, pose a real and growing challenge in modern medicine.
What are the most dangerous fungal pathogens affecting humans today?
Although mammals—including humans—are generally well-defended against invasive fungal infections, we’re not immune. Most harmful fungi are opportunistic, taking hold when the immune system is compromised. But even in healthy individuals, certain fungal pathogens can cause serious illness, especially when infections go undetected or untreated.
The Centers for Disease Control and Prevention (CDC) estimates that fungal infections are responsible for over 1.5 million deaths globally each year. In the U.S. alone, around 75,000 people are hospitalized annually due to fungal infections—an often underestimated public health burden.
Here are nine fungal pathogens currently recognized as significant threats to human health around the world:
Common Fungal Infections in Humans
| Fungal Pathogen | Description |
| Candida species | Candida is a type of yeast that can cause infections in the mouth, throat, esophagus, and genital area. In severe cases, it can also spread to the bloodstream and cause systemic infections. |
| Sporothrix brasiliensis | An emerging fungal pathogen first appearing in Brazil in 1998, spreading between people and cats throughout South America, leading to facial lesions and sores. Between 1998–2016, over 4,500 human cases spread by cats were identified. |
| Coccidiomycosis | A debilitating disease called Valley Fever. It used to be thought it could exist only in the arid Southwest and California, but now it's appearing as far north as Washington state. This fungus usually infects the lungs and can cause respiratory symptoms including cough, fever, chest pain, and tiredness. |
| Blastomycosis | Found in moist soils throughout the northeast United States, including Minnesota, Wisconsin and Indiana, and can be a serious progressive illness involving multiple organ systems. It has been hypothesized that drier summers and wetter winters, associated with climate change, may create optimal conditions for its dispersal. |
| Aspergillus | Aspergillus is a type of mold that can cause lung infections in people with weakened immune systems or lung diseases such as asthma or cystic fibrosis. It can also cause invasive infections in other parts of the body |
| Cryptococcus neoformans | Cryptococcus is a type of fungus that can cause lung infections and meningitis in people with weakened immune systems, such as those with HIV/AIDS. It was found that increased temperatures drive increases in genetic changes, some of which might presumably lead to higher heat resistance, and others perhaps toward greater disease-causing potential. |
| Histoplasma capsulatum | Histoplasma is a type of fungus that can cause lung infections in people who breathe in its spores. It is found in soil contaminated with bird or bat droppings. |
| Pneumocystis jirovecii | Pneumocystis is a type of fungus that can cause severe pneumonia in people with weakened immune systems, such as those with HIV/AIDS. |
| Dermatophyte fungi | Dermatophytes are a group of fungi that can cause skin, hair, and nail infections, such as athlete's foot, jock itch, and ringworm. |
Candida species
Candida is a type of yeast that can cause infections in the mouth, throat, esophagus, and genital area. In severe cases, it can also spread to the bloodstream and cause systemic infections.
An emerging fungal pathogen first appearing in Brazil in 1998, spreading between people and cats throughout South America, leading to facial lesions and sores. Between 1998–2016, over 4,500 human cases spread by cats were identified.
A debilitating disease called Valley Fever. It used to be thought it could exist only in the arid Southwest and California, but now it's appearing as far north as Washington state. This fungus usually infects the lungs and can cause respiratory symptoms including cough, fever, chest pain, and tiredness.
Blastomycosis
Found in moist soils throughout the northeast United States, including Minnesota, Wisconsin and Indiana, and can be a serious progressive illness involving multiple organ systems. It has been hypothesized that drier summers and wetter winters, associated with climate change, may create optimal conditions for its dispersal.
Aspergillus
Aspergillus is a type of mold that can cause lung infections in people with weakened immune systems or lung diseases such as asthma or cystic fibrosis. It can also cause invasive infections in other parts of the body.
Cryptococcus neoformans
Cryptococcus is a type of fungus that can cause lung infections and meningitis in people with weakened immune systems, such as those with HIV/AIDS. It was found that increased temperatures drive increases in genetic changes, some of which might presumably lead to higher heat resistance, and others perhaps toward greater disease-causing potential.
Histoplasma capsulatum
Histoplasma is a type of fungus that can cause lung infections in people who breathe in its spores. It is found in soil contaminated with bird or bat droppings.
Pneumocystis jirovecii
Pneumocystis is a type of fungus that can cause severe pneumonia in people with weakened immune systems, such as those with HIV/AIDS.
Dermatophyte fungi
Dermatophytes are a group of fungi that can cause skin, hair, and nail infections, such as athlete's foot, jock itch, and ringworm.
Which fungal diseases are causing global pandemics?
Among the fungal pathogens listed above, Candida auris stands out as a top concern for global health authorities. First identified in Japan in 2006, this yeast has spread rapidly in healthcare settings—especially hospitals and long-term care facilities—where it causes invasive infections in the bloodstream and internal organs, including the kidneys, heart, and brain. C. auris is notoriously difficult to treat due to its frequent resistance to multiple antifungal drugs and its tenacity in clinical environments. Some strains have shown a mortality rate of up to 60%.
Its emergence has sparked speculation that climate change may be playing a role. As global temperatures rise, fungi that adapt to warmer environments may be better poised to breach the thermal defenses of warm-blooded mammals. While Candida auris is a far cry from a real-world CBI scenario, its sudden appearance and adaptability point toward a future where fungal diseases are increasingly relevant to human health.
Nature has already offered sobering previews. Two devastating fungal pandemics are currently reshaping entire ecosystems in the animal kingdom:
Chytrid fungus (Batrachochytrium dendrobatidis) has been described as “perhaps the most devastating disease ever recorded in terms of species scope and death toll.” Since its discovery in 1998, chytrid has been linked to declines in nearly 500 amphibian species—wiping out 90 of them entirely. It targets the skin of amphibians, disrupting their ability to regulate water and electrolytes, ultimately leading to cardiac arrest.
White-nose syndrome, caused by the fungus Pseudogymnoascus destructans, was first detected in 2006 in hibernating bats in New York. Since then, it has decimated populations across North America, killing over 90% of some species, including the northern long-eared, little brown, and tri-colored bats. The fungus thrives in cold, damp environments like caves, eroding the skin of hibernating bats and waking them prematurely—leading to fatal energy depletion.
Both diseases are incurable and continue to spread. However, there is a glimmer of hope: in some populations, individuals have shown natural resistance, hinting at the possibility of future adaptation or even recovery—though likely on an evolutionary timescale.
Candida auris culture in a petri dish
A chytrid-infected frog1
A hibernating bat showing signs of fungal infection
Are all spores dangerous?
While toxic and pathogenic mushrooms are well-known for causing serious health issues—ranging from skin infections to gastrointestinal distress and even multi-organ failure—it's less widely recognized that even “safe” or edible mushrooms can pose health risks under certain conditions.
Repeated exposure to high concentrations of airborne mushroom spores—even from non-toxic species—can trigger a range of inflammatory lung conditions. Often referred to informally as “Spore Lung,” these ailments fall under the umbrella of hypersensitivity pneumonitis or allergic fungal sinusitis, depending on the site and severity of exposure. Symptoms may include chronic coughing, wheezing, shortness of breath, and fatigue.
The risk is particularly relevant for those who work regularly with mushrooms, such as farmers, foragers, cultivators, and lab technicians. During peak sporulation—when mushrooms release their spores into the air—protective measures like face masks or respirators, good ventilation, and limiting exposure time can significantly reduce the risk of respiratory irritation or long-term lung damage.
In short, even friendly fungi deserve a healthy dose of respect.
What new fungal threats are emerging in nature and media?
As The Last of Us enters Season 2, the reintroduction of spore-based transmission isn't just a dramatic device—it reflects real scientific developments in fungal biology. In the show, Ellie enters a quarantined hospital basement thick with airborne Cordyceps spores that infect her adversary, Nora, but leave Ellie unharmed due to her immunity. This moment resonates with 2024 research revealing just how adaptive fungal pathogens are becoming. A study published in Frontiers in Microbiology uncovered high variability in the gene clusters of Ophiocordyceps unilateralis, the "zombie-ant" fungus, including genes that regulate neuroactive compounds linked to host manipulation (Almeyda-Leon et al., 2024).
This aligns disturbingly well with a 2025 paper in the Biochemical Journal, which found that Cordyceps javanica can not only survive at higher temperatures but also shift its sporulation behavior in response to environmental variability—traits that could theoretically support host range expansion under climate stress (Li et al., 2025). Further supporting the plausibility of complex fungal-host interactions, a separate 2024 study demonstrated that infection by O. unilateralis causes measurable neurochemical and immunological changes in its ant hosts, providing further insight into fungal-induced behavioral manipulation (Boaretto et al., 2024).
In a fictional but increasingly credible twist, Season 2's depiction of spores penetrating Jackson’s infrastructure via tendrils mirrors the real-world anxieties scientists now express: fungi are not static threats—they are dynamic, adaptable, and evolving rapidly. With spores now once again a primary transmission vector in the show, the science and storytelling are closer than ever.
Final thoughts
The imagined Cordyceps Brain Infection (CBI) in The Last of Us is a compelling fusion of science and storytelling—an artful chimera of traits drawn from multiple real-world fungi that renders the parasite both mesmerizing and monstrous. While a mind-controlling fungal apocalypse remains firmly in the realm of fiction, the show highlights some very real concerns: namely, how our environmental impact could be giving rise to novel pathogenic fungi, and the challenge of developing antifungal treatments due to the cellular similarity between fungi and humans.
The unsettling truth is that climate change may be chipping away at one of our most fundamental defenses: our warm-bloodedness. As global temperatures rise, more fungal species are being pressured to adapt to higher heat thresholds—potentially closing the temperature gap that once kept them out of our bodies. In this light, the greatest irony may be that The Last of Us isn’t a warning about an implausible future, but a haunting metaphor for a biological arms race already underway.
References
Carpenter, Nicole. Why The Last of Us creators swapped spores for Cordyceps networks. The short answer: An HBO version had to be watchable. 1/22/23. https://www.polygon.com/entertainment/23562421/last-of-us-cordyceps-spores-tv-show-hbo
Parshall, Allison. Could the Zombie Fungus in TV’s The Last of Us Really Infect People? Scientific American: 2/10/23. https://www.scientificamerican.com/article/could-the-zombie-fungus-in-tvs-the-last-of-us-really-infect-people/#:~:text=Now%20clearly%2C%20some%20fungi%20have,for%20Ophiocordyceps%2C%20there's%20no%20chance.
WHO fungal priority pathogens list to guide research, development and public health action. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240060241
Almeyda-Leon, I. H., Calderon, L. C., Sim, N. H., Dos-Santos, A. L., Carazzolle, M. F., & Loreto, R. G. (2024). High variability of secondary metabolite biosynthesis gene clusters in the zombie-ant fungus Ophiocordyceps unilateralis. Frontiers in Microbiology, 15, 1348759. https://doi.org/10.3389/fmicb.2024.1348759
Li, W., Lei, Z., Zeng, Q., Zhao, Z., Lin, T., & Yu, Z. (2025). Temperature adaptability and sporulation of Cordyceps javanica under climate variability: Implications for fungal host range expansion. Biochemical Journal, 482(1), 111–123. https://doi.org/10.1042/BCJ20240350
Boaretto, M., Tose, L. V., Moreira, R. G., & Loreto, R. G. (2024). Neurochemical and immune alterations in ants manipulated by Ophiocordyceps. ResearchGate. https://www.researchgate.net/publication/377108656
Photo Citation
1Brem, Forrest. 2008. This file was published in a Public Library of Science journal. Their website states that the content of all PLOS journals is published under the Creative Commons Attribution 4.0 license (or its previous version depending on the publication date), unless indicated otherwise.