Fungal Science behind The Last of Us

The recent popular TV series The Last of Us tells the story of a dystopian world where people are infected by a type of fungus that makes them act zombie-like. The series was introduced with a scene in which two epidemiological experts converse about a possible future pandemic. When asked, one of the experts says that he is not particularly afraid of a pandemic caused by a virus or a bacterium. Although these infections can spread havoc across the globe, humanity has always taken victory in such a fight. There are enough clinical possibilities to treat viral or bacterial threats, and scientists generally know a lot about these infectious agents. The scientist does admit, however, that an infectious disease caused by a fungus can be particularly fearsome. Rightfully, he shares that there is currently a very small therapeutic arsenal against fungal infections. Additionally, the current science on fungi is simply not as extensive as it is on bacteria and viruses.

Although the idea of people being infected by fungus and turning into blood-thirsty zombies is rather far-fetched, it is based on something very real (Benadjaoud & Brownstein 2023). The fungus infecting the patients, Ophiocordyceps unilateralis, does exist and is even known for its strong mind-controlling capabilities. It renders the psychology and the instincts of its host ineffective, thereby creating a physical extension of itself that is completely submissive to its will. Luckily, examples of hosts infecting other biological bodies have not been seen. Another key aspect that is portrayed fictionally in the show is that O. unilateralis does not infect humans in real-life. Rather, it infects ants (Yong, 2017).

Ants generally have a very well-orchestrated society within a nest. Each individual has a role, which together makes for a thriving colony. Some ants are foragers, whereas others are warriors. Because the role an ant takes upon itself depends on its appearance, an ant’s genotype, which dictates its phenotype, correlates to its place within the colony (Schwander et al., 2005). Since ants only thrive in their environment with an amazingly organised division of labour, their individual responsibilities are usually highly specific. However, once O. unilateralis has properly infected the ant, it starts to manipulate its host’s behaviour. First, the ant abandons its typical work and leaves the nest. Then, it climbs up plants and attaches itself to leaves or twigs, hanging upside down. Here it takes its last breath, while the fungus continues to grow inside its body. After the death of its host, the fungus grows out of the cadaver, using the ant as its food source. Because the fungus has instructed the ant to climb up a plant near the colony, its location above the ground serves as an ideal place for the fungus to spread. Subsequently, the fungus produces sexual spores that are dispersed out of the host’s cadaver and spread through the air, infecting other ants just below (de Bekker et al., 2014).

Figure 2: The cycle by which O. Unilateralis spreads through ants (adapted from de Bekker, 2019).

Fungi are extraordinary organisms. Although there exist variations between different fungal species, fungi generally live as single cells, while they are also able to live in a colony as a multi-cellular organism. Only a single cell of O. unilateralis is required to start an infection, as it reproduces in the ant’s bloodstream (de Bekker et al., 2014). Over time, it multiplies and forms stalks within the body of the ant. Each of these stalks consists of multiple cells that communicate with one another. Adding to this complexity, the stalks also communicate with each other through the shedding of chemicals. Furthermore, researchers in this field have discovered that the fungus is able to exert its psychological control on the ant even without directly coming into contact with the host's brain (de Bekker et al., 2014).

There is compelling evidence for two theorised mechanisms by which the fungus controls the ant. First, the chemicals secreted by the fungus within the body seem to be capable of influencing the ant’s physiology and behaviour. Since there is limited research on ant behaviour in general, analysing the way it is manipulated by O. unilateralis proves to be incredibly difficult. In one study performed by Charissa de Bekker, a true pioneer in the field of this zombie fungus, the expression of mRNA and proteins was analysed in infected ants. Certain proteins were found to be much more expressed in comparison to ants that were not infected, although their specific roles remain a mystery. It is thought that many of these proteins are alkaloids that resemble neuromodulators in ants. These are molecules that bind specific receptors in the brain to either promote or inhibit certain neural pathways, which in turn influence behaviour (de Bekker et al., 2015). In fact, they can be compared to how hormones affect the human body. In the case of a fungal infection, instead of the brain releasing these hormones in a highly organised fashion, the parasitic fungus releases specific chemicals necessary to control the ant's behaviour so that it is beneficial for the survival of the fungus. In other words, the fungus makes the ant go into this behaviour involuntarily.

Figure 3: A schematic overview of how O. unilateralis successfully infects ants (Hirata, n.d.).

Another theorised mechanism may sound more frightening. By studying an infected ant in incredibly thin slices with advanced microscopes, it was shown that these bundles of fungal cells integrate into and around the muscle tissues of the ant (de Bekker et al., 2014). Additionally, it was observed that ants’ nervous cells seem to die after infection by O. unilateralis. When the nerve cells between the brain and the muscles of the ant start to disintegrate, the ant’s brain can no longer establish voluntary control and communication with the muscles. The fungal tissue wrapped around the muscles, however, can secrete necessary molecules that allow for the contraction and expansion of these tissues. This may begin with some involuntary movements of a certain limb, but eventually it can spread until the ant's entire body is trapped under fungal control (Yong, 2017).

This example of a parasite manipulating its host’s psychology is not the only one. Other fungal infections, including Cryptococcul meningoencephalitis, have been found to have a very strong effect on their host’s health and behaviour. Luckily, cases in humans are very rare, and infections do not take place in immunocompetent patients. These are patients with an immune system that works well enough to fight incoming pathogens. Occasionally, however, such a fungal infection may still present symptoms such as tremors, general cognitive decline, and a loss of memory. (Yerram & Naresh, 2017).

Figure 4: Fungal infections in the brain (Conceição et al., 2017).

Ongoing research is still studying the exact mechanisms by which fungal infections influence human or animal behaviour. Interestingly, apart from fungi, this ability can also be found in other branches of life. Toxoplasma gondii is a type of bacteria that is very prevalent throughout the world. Although it may infect rats, humans, and other mammals, its main reservoir consists of felines. Cats have a certain lipid that creates an ideal environment for T. gondii to which the bacterium has adapted itself. Even though it may infect other animals, it always “wants” to infect cats. To this end, the bacterium has evolved a mechanism for manipulating mice behaviour. While normal mice typically avoid the smell of cat urine so that they can stay within a safe distance from their predator, evidence shows that mice lose this fear once they are infected with T. gondii. This allows infected mice to transmit the bacterium to its ideal host: cats. Although the evolutionary mechanisms remain unclear, experts believe that T. gondii may also alter human behaviour and even cause suicidal thinking. The fact that so much is unknown about its impact on humans is a significant problem, especially given its high prevalence. Estimates show that at any point in time, about 30% of people have been in contact with the pathogen in the past. In other words, pretty much everyone has the possibility to be infected, though only a very limited number of people will actually suffer from symptoms as far as we know (Desmettre, 2020).

The ability of a bacterium or a fungus to manipulate its host behaviour, albeit disturbing, is truly special. It is a real-world example showing how evolution may develop mechanisms that are incredibly complex but interesting nonetheless. After all, an organism always evolves in a way that increases its fitness in the environment and maximises its chance of reproduction. Although it is difficult to pinpoint the exact evolutionary rationale for diseases or infections to affect human behaviour, the examples of T. gondii and O. unilateralis described above clearly show that manipulating behaviour can be very beneficial for the pathogen’s spreading. It highlights how evolution can greatly increase the survival competency of these pathogens (de Bekker, 2019).

Figure 5: T. gondii has been shown to make mice less afraid of cats, increasing its transmission to felines (Barford, 2013).

At the end of the day, viewers do not need to fear The Last of Us becoming a reality. There are immense evolutionary obstacles that hinder the way fungi are transmitted between people. It is slow and inefficient, which is in large contrast to how SARS-CoV2 and many other viruses or bacteria spread. However, it is still important to note that current science on fungi is still lacking, and if past research has shown anything, it is that fungal organisms can adapt well and display incredibly complex behaviour like turning hosts into zombies. Luckily for humans, no such equivalent has been found.

Bibliographical References

Benadjaoud, Y., & Brownstein, J. (2023). The Science Behind the Zombie Fungus From ‘The Last of Us’. https://abcnews.go.com/Health/science-zombie-fungus-us/story?id=96819243%23:~:text=Originally%20a%20video%20game%2C%20the,actually%20based%20in%20scientific%20reality

de Bekker, C. (2019). Ophiocordyceps–ant interactions as an integrative model to understand the molecular basis of parasitic behavioral manipulation. Current Opinion in Insect Science, 33, 19–24. https://doi.org/10.1016/j.cois.2019.01.005

de Bekker, C., Merrow, M., & Hughes, D. P. (2014). From behavior to mechanisms: an integrative approach to the manipulation by a parasitic fungus (Ophiocordyceps unilateralis s.l.) of its host ants (Camponotus spp.). Integrative and Comparative Biology, 54(2), 166–176. https://doi.org/10.1093/icb/icu063

de Bekker, C., Ohm, R. A., Loreto, R. G., Sebastian, A., Albert, I., Merrow, M., Brachmann, A., & Hughes, D. P. (2015). Gene expression during zombie ant biting behavior reflects the complexity underlying fungal parasitic behavioral manipulation. BMC Genomics, 16(1), 620. https://doi.org/10.1186/s12864-015-1812-x

Desmettre, T. (2020). Toxoplasmosis and behavioural changes. Journal Français d’Ophtalmologie, 43(3), e89–e93. https://doi.org/10.1016/j.jfo.2020.01.001

Schwander, T., Rosset, H., & Chapuisat, M. (2005). Division of labour and worker size polymorphism in ant colonies: the impact of social and genetic factors. Behavioral Ecology and Sociobiology, 59(2), 215–221. https://doi.org/10.1007/s00265-005-0027-6

Yerram, S. R. , & Naresh, M. (2017). Cryptococcal meningitis with behavioral changes as presentation. SM J Neurol Neurosci, 3(2), 1010.

Yong, E. (2017). zombie fungus 2. The Atlantic. https://www.theatlantic.com/science/archive/2017/11/how-the-zombie-fungus-takes-over-ants-bodies-to-control-their-minds/545864/

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