If you are one of the millions of fans of the The Last of Us saga - a success in the video game industry first and then on television - you have surely swallowed hard more than once thinking about the dystopian scenario: an apocalypse caused by a fungus capable of turning everyone it infects into a zombie. Perhaps your unease has grown a bit more if, driven by curiosity, you have discovered that the protagonist pathogen of the fiction, the Ophiocordyceps, is a real fungus, a microorganism that parasitizes some species of ants by modifying and controlling their behavior in its favor.
The scriptwriters have done a great job of documentation, no doubt. And they have raised the stakes for the second season, which has recently premiered, by showing an evolution of the pathogen that further favors the spread of the infection. But do not be alarmed: the fungus from The Last of Us does not pose any real danger. "A microorganism like this could not jump and adapt to humans overnight; it is pure science fiction," reassures Jéssica Gil-Serna, a researcher specializing in mycotoxin-producing fungi at the Complutense University of Madrid. "For multiple reasons, there are no signs that something like what the series proposes could happen," agrees Jesús Guinea, a specialist in Microbiology at the Gregorio Marañón University Hospital in Madrid and a scientist at the center's Health Research Institute, where he leads a study group on severe invasive mycoses.
Although it may be terrifying, this fungus is not precisely the one we should fear the most. Especially when there are other real fungal threats out there that are growing and against which we do not have the best weapons.
The most paradigmatic example is Candida auris, a yeast that was first described in clinical practice in 2009, in a patient in Japan suffering from an ear infection. In these scarce 16 years, the pathogen has shown an enormous ability to spread worldwide and infect many people, mainly vulnerable individuals. This fungus can cause very severe systemic conditions, with mortality rates exceeding 50% in fragile patients, in addition to a great ability to persist on surfaces. It has caused several outbreaks in hospitals due to the great difficulty in eradicating it.
"Environmental fungi are learning to adapt to humans due to the increasing temperatures caused by climate change"
"It is a species that has emerged as a new pathogen for humans," explains Guinea. "It has been researched in microbiological archives in case there was any previous record, but no trace has been found. The conclusion is that it has emerged de novo with two fundamental peculiarities: a great resistance capacity and a tremendously effective transmission."
It is not the only example of an emerging fungal pathogen. "In recent years, we are seeing that species that were environmental and did not affect humans are adapting to us. Some of them, like Candida auris, are capable of causing very serious infections and are resistant to both therapeutic treatments and disinfectants," adds Gil-Serna, who emphasizes that the hypothesis that scientists most strongly consider to explain this rise is that climate change is being an ally to fungi.
The increasing temperatures are exerting pressure on them, leading them to adapt to growing at higher temperatures, which propels them to jump to humans, as the expert explains. These conditions are also causing an increase in the geographical distribution range of some pathogens, which are emerging in areas they did not previously inhabit.
Both Guinea and Gil-Serna point out that invasive forms of fungal infections generally affect vulnerable patients, who suffer from serious illnesses and have weakened immune systems. Among them, they highlight transplant patients, those with cancer, or chronic respiratory diseases. This is an increasingly numerous and diverse group thanks to advances in Medicine. However, these types of infections can sometimes also be a problem for otherwise healthy individuals.
The issue concerns the World Health Organization (WHO), which warns that "fungal pathogens pose a significant threat to public health, as they are becoming more common and resistant to treatment." To focus on the problem and boost research in this field, the organization has compiled a list of the most dangerous fungi for health, a catalog of 19 priority pathogens.
This list includes under the "critical" category species such as the aforementioned Candida auris, its cousin Candida albicans, specimens like Cryptococcus neoformans, or threats like Aspergillus fumigatus, another expert in evading the action of available treatments. Several studies have indicated that the filamentous fungus, which in addition to causing allergic reactions and respiratory problems can also lead to severe systemic infections, shows a significant level of resistance to azoles, the most commonly used group of drugs for its treatment.
The issue of resistance to treatments of fungal pathogens is one of the most concerning problems for Ana Alastruey, a senior scientist at the Mycology Laboratory of the National Center for Microbiology of the Carlos III Health Institute (ISCIII) and an international reference in the surveillance of pathogenic fungi. "Antifungal resistances are a growing public health problem worldwide," explains the specialist, who coordinated the latest WHO global report on this threat. "Infections caused by fungi resistant to available treatments are becoming more frequent, and this is especially worrying due to the limited number of antifungals available, their limitations, and the scarce amount of new treatments in development. When talking about antimicrobial resistance, most people only think about antibiotics, but resistance to antifungals is also increasing and requires urgent and sustained attention."
In addition to species like Candida auris and Aspergillus fumigatus, Alastruey points out other prominent examples of pathogens that pose a headache for specialists. "Other species like Candida glabrata and Cryptococcus neoformans continue to represent significant therapeutic challenges, especially in immunocompromised patients," she notes. "Furthermore, there has been a worrying increase in resistant Trichophyton species, significantly complicating effective treatment of ringworm, particularly in extensive or refractory infections."
"Infections by fungi resistant to treatments are becoming more frequent and, at the same time, few new antifungal drugs are being launched"
As explained by the consulted experts, the imprudent use of antifungals over the years is largely to blame for fungi becoming immune to treatments. "Fungi are mainly plant pathogens, so similar antifungals to those used in medicine are used in agriculture to protect crops. This has contributed to the emergence of resistances, as observed in Aspergillus fumigatus," says Alastruey.
In this regard, the European Food Safety Agency published a report in January of this year emphasizing the need to promote the rational use of antifungals in human health and agriculture. "It is essential to act on this and other aspects," demands Alastruey, who warns that the situation is particularly worrying because the arsenal we have to combat pathogenic fungi is limited.
Currently, only a handful of treatments are available for clinical use, and the prospects for the immediate future are not very promising either. "In the last 10 years, only four new antifungals have been approved. Historically, only one new class has been approved per decade. A recent report has warned that there are only nine agents in clinical development. The options are clearly insufficient to address the growing threat of antifungal resistance," laments Alastruey, who also points out that pediatric indications and appropriate formulations for children are even scarcer.
"In clinical practice, we do not have many treatment options", confirms Jesús Guinea. "When we encounter a multi-resistant species, we have a huge problem because there are barely any alternatives. It is a much worse situation than resistance to antibiotics, where we have many different families and molecules within each of these families, allowing us to try different approaches," adds the specialist.
According to experts, research in this field is complicated because fungal cells closely resemble human cells as they are also eukaryotic. This makes it difficult to find specific pathogen targets and to only attack their cells. "And also for that reason, antifungals usually have quite a few side effects," points out Gil-Serna.
With new fungal pathogens emerging, treatment resistances increasing, the number of potential patients growing, and few weapons available to combat the threat, specialists are calling for coordinated measures to be able to address a problem that continues to lack the attention and resources it deserves.
In addition to promoting the rational use of antifungals in human health and agriculture, "it is essential to strengthen epidemiological surveillance of resistances, invest in research and development of new treatments, and develop faster and more accurate diagnostic tools that can be available worldwide," summarizes Alastruey. Guinea adds that it is also essential for all hospitals, like theirs, to "monitor antifungal resistance very closely, as it is the only way to detect and address problems."
All agree on a point that brings us back to The Last of Us: "It is crucial to raise awareness in the healthcare sector and in society about the importance of this emerging problem. And if the latest trendy series helps with that, it is welcome."