The television series “The Last of Us” describes a human pandemic with a mind controlling cordyceps fungus. When asked whether a COVID-19 pandemic with a pathogenic fungus is possible, my answer has generally been some variation of “yes, but it’s unlikely.”
Cordyceps fungi turn ants into zombies, establishing the precedent that this group of organisms can be pathogenic to animals. However, ants and humans are very different animals. Ants are ectothermic or cold-blooded, while humans are endothermic or warm-blooded. This matters because temperature provides a great defense barrier to humans since most fungal species cannot grow at mammalian temperatures. Furthermore, humans, like all vertebrates, have an advanced immune system that includes two great immune mechanisms, innate and adaptive immunity. Ants, like all insects, have only innate immunity, and lack the ability to make antibodies and specialized immune cells such as T cells that are powerful in fighting off fungi.
Could fungi adapt with global warming to defeat our temperature defenses? Possibly, and this is a real concern. The emergence of Candida auris, a new drug-resistant pathogenic fungus that is associated with high mortality, was proposed to have emerged after adaptation to increasing global temperatures associated with climate warming. However, even if a pathogenic cordyceps were to adapt to human temperatures it would still have to defeat our immune defenses — and that is a tall order for most fungi.
Could fungi turn humans into zombies? Again, unlikely, but don’t forget that fungi makes mind-altering drugs such as lysergic acid diethylamide (LSD) and the hallucinogens psilocybin and psilocin. Hence, the idea of an infection with a fungus that produces mind-altering secondary metabolites is not out of the question.
Could we face a fungal pandemic in the future? Perhaps. To date, two types of microbes have been associated with human pandemics: bacteria and viruses. A bacterium known as Yersinia pestis was responsible for the black death that devastated Europe in the mid-14th century. Viral pandemics are much more common, and recent ones include the influenza virus in 1918, HIV in 1981, and most recently coronavirus in late 2019. However, just because something has not happened yet does not mean it will never happen. When I began medical school, retroviruses such as HIV had not been associated with human disease, but the AIDS epidemic was just beginning. Similarly, until 2003, coronaviruses were not thought to cause disease worse than a cold; that year we had the outbreak of SARS, a deadly and contagious respiratory disease that showed the threats posed by coronavirus. Hence, history can inform us of what threats we will face, but it is a poor predictor of what threats are out there.
For a fungus to cause a pandemic, it would have to be easily transmissible from human to human or from the environment to humans. Today, serious human fungal diseases tend to occur in individuals with impaired immunity and are not communicable. However, communicable fungal diseases are decimating other vertebrate animal species. North American bats are dying from a new fungal disease known as white nose syndrome, which is transmissible from bat to bat, probably through physical contact. The bats are resistant to the disease in the summer when their body temperature is high, like ours, but succumb to white nose syndrome in the winter when they hibernate, and their body temperature plummets to conserve energy. The experience with white nose syndrome in bats illustrates the remarkable protection we get against pathogenic fungi from just being warm. Frogs are being decimated throughout the world by a chytrid fungus that is acquired from water in infected ponds. Like hibernating bats, frogs are cold-blooded and lack the protection provided by an elevated temperature, but both can be cured if taken to laboratories and warmed to higher temperatures. The experience of bats and frogs shows us that fungal disease contagiousness is possible.
The disasters befalling bats and frogs are a warning signal to humans. Right now, none of the human pathogenic fungi that exist can cause a COVID-19-style pandemic. However, we should not let down our guard. The fungal kingdom is immense and includes hundreds of species that are pathogenic to plants and animals. Most of these are not currently a threat to humans because they cannot tolerate our high body temperatures or breach our immune defenses. However, as the earth warms, fungi will adapt to higher temperatures and that could give some the ability to survive in our bodies. When that happens, humanity may confront a pathogenic fungus currently unknown to medicine. We don’t know if our antifungal drugs will be effective against new threats; note that when C. auris arrived as a human pathogen, it was already drug resistant.
So how do we prepare? Historically, fungal threats have been largely ignored, but recently the World Health Organization developed the first list of fungal priority pathogens. We need a careful survey of the natural world to learn what potential threats exist, and we must continue to invest in basic research to understand fungal physiology and human defenses against the fungi. Knowledge is our best defense against threats from nature.
Arturo Casadevall, MD, PhD, is a Bloomberg Distinguished Professor and chair of the Department of Molecular Microbiology and Immunology at Johns Hopkins University School of Public Health in Baltimore.