The beloved video game franchise The Last of Us received a television adaptation that premiered recently on HBO. The story follows a hardened survivor and smuggler named Joel, and a mysterious young teen named Ellie. Together they must traverse a post-apocalyptic United States wasteland carrying with them humanity's greatest hope. What begins as a job between two strangers gradually evolves into a close kinship as the pair rely on each other to overcome all the dangers.

The fall of modern society in The Last of Us world is caused by a fungal pandemic. Humans that are infected are transformed into highly aggressive cannibal-like hosts. It provides a different spin on your classic zombie narrative.

The very first episode of The Last of Us begins by setting up the plausibility of a human fungal outbreak. A TV talk show host from the '60s interviews two epidemiologists who discuss the sources of the next great public health threat. There are examples of fungi altering the behavior of their animal hosts in nature, but could a situation depicted in The Last of Us really occur? We'll explore that very possibility.

The Last of Us Inspiration: Cordyceps

Cordyceps are a genus of fungi known to affect insects and other arthropods. Spores adhere to the surface of its host and they use a specialized tubelike cell to penetrate the body cavity. Once inside, the filaments convert into yeast shaped cells that begin to bud internally to increase propagation and spread. These cordyceps can infect a number of different species or have a specificity for one in particular.

Through a combination of physical and chemical stimuli, the cordyceps can manipulate the central nervous system altering behavior. Infected ants begin to isolate from their nest and act erratically as if in a zombie-like state. Diseased insects also climb to higher elevations and sometimes clamp themselves to structures to immobilize themselves. Spores then erupt from the head and the advanced elevation allows a greater area of spread. Shang et al. have a good summary related to fungi that infect insects in PLOS Pathogens.

Current Human Fungal Infections

We already deal with fungal diseases, or mycosis, currently and their severity can vary. The most common are superficial affecting the skin, nails, and mucous membranes since they are easily exposed areas. I'm sure you have heard of athlete's foot, jock itch, and yeast infections. These usually lead to minor inconveniences such as irritation, itchiness, pain, and discoloration.

Rarer conditions involve infection of deeper tissue including the lungs, blood, and yes, the central nervous system. They can enter the body through open wounds or inhalation, and can be life-threatening depending on the site. For example, cryptococcal meningitis can be fatal if left untreated. Usually, healthy people are not at risk, and can be infected without exhibiting symptoms. However, like with any disease, the immunocompromised are more susceptible. The Center for Disease Control and Prevention has an informative guide on the types of fungal diseases.

The Last of Us: Could the Fungal Pandemic happen?

First and foremost, an exploration of the literature has not uncovered any instances of a cordyceps infection in humans. One reason why is because of our immune and central nervous system. Compared to arthropods, our systems are much more complex. The fungi would first have to develop a means to bypass our sophisticated immune system, and then would need a higher degree of manipulation to control our behavior. It took millions of years for cordyceps to evolve and be able to affect specific insects. That's not to say it couldn't eventually happen, but the needed adaptations would require a significant amount of time. Mutations could explain the jump to our species, but again, because of the differences in physiology, it would require a drastic genetic change.

Another hindrance to any fungal pandemic is our high body temperature. In the journal mBio, Bergman and Casadevall found that 36.7°C is the optimal temperature for mammalian metabolic rates and to protect against environmental microorganisms. The Last of Us predicts the environmental increases due to global warming will allow the fungi to adapt and thrive at higher temperatures. Once again, the theory isn't completely untrue, but the short amount of time between the fictional telecast and pandemic of ~35 years, and the temperature increase of ~0.2°C per decade according to Hansen et al. in the Proceedings of the National Academy of Sciences (PNAS) wouldn't cause such a change in the fungi. The concept is somewhat based on science, but has a much more accelerated path.

Even if a cordyceps infection could occur in humans, the current observations don't include violent behavior. In insects, those afflicted exhibit a daze-induced meandering, hence the zombie comparisons; nothing that is outwardly threatening. However, there are microbes that can induce behavioral changes in mammals. The protozoa Toxoplasma gondii can only reproduce within the intestine of a cat. In a separate PNAS manuscript, Vyas et al. proved that the parasite infected caused infected rodents to be attracted to feline urine increasing the chances they would be eaten.

How to Battle a Last of Us Style Pandemic

We can first look to nature for possible methods to combat cordyceps. Ants mutually groom each other to clean away any adhered spores. They also use chemicals such as formic acid to disinfect areas. Some infected garden ants choose to separate themselves further away and die alone to reduce exposure. Termites coat their colonies with pattern recognition receptors to identify pathogens early on. Also, there are certain locusts that can raise their body temperature either individually or as a swarm to fight off infection.

Currently, there are several treatments for mycosis. Antifungal eye drops, shampoos, lotions, creams, powders, mouthwashes, and lozenges are used for the superficial and subcutaneous ailments. There are oral and IV medications to treat the more serious infections. In all cases, it can be difficult to completely eradicate the fungi resulting in long usages.

The Last of Us does hope a cure or vaccine can be developed to fight off the pandemic. A review found in npj Vaccines by Oliveira et al. showed there are presently no FDA approved vaccines for fungal diseases. In fact, there are only three to have reached human clinical trials, and all of them have mixed results. Though there has been progress in the area, there is still plenty of work to be done.

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