by The world is full of tiny creatures that find us delicious. Bacteria and viruses are the obvious villains, drivers of deadly global pandemics and nuisance infections. But the pathogens that we haven’t had to reckon with that much are the fungi.
Pathogenic fungi (Candida, Aspergillus, Cryptococcus and others) are notorious killers of immunocompromised people. But for the most part, healthy people did not have to worry about them, and the vast majority of potentially pathogenic fungi on the planet cannot tolerate the heat of our bodies.
But all of that could change.
A new study from Duke University School of Medicine finds that elevated temperatures cause a pathogenic fungus called Cryptococcus deneoformans to override its adaptive responses. This increases the number of genetic changes, some of which could presumably lead to higher heat resistance, others possibly to greater disease-causing potential.
In particular, higher heat allows more of the fungus’s transposable elements, or jumping genes, to get up and move within the fungal DNA, leading to changes in the way its genes are used and regulated. The results appeared on January 20th in the Proceedings of the National Academy of Sciences.
“These mobile elements likely contribute to adaptation in the environment and during infection,” said postdoc Asiya Gusa Ph.D. in Molecular Genetics and Microbiology from the Duke School of Medicine. “This could happen even faster because heat stress accelerates the number of mutations that occur.”
That may ring a bell for viewers of the new HBO series The Last of Us, in which a dystopian hellscape is unleashed by a heat-adapted fungus that is taking over humans and turning them into zombies. “That’s exactly what I mean – minus the zombie part!” said Gusa, who just watched the first episode and will join Duke later this year as an assistant professor.
“These are not infectious diseases in the transmissible sense, we don’t transfer fungi to each other,” Gusa said. “But the spores are in the air. We breathe in fungal spores all the time, and our immune systems are primed to fight them.”
Fungal spores are generally larger than viruses so your existing inventory of Covid face masks would probably be enough to stop them. That and for now your body heat.
“Fungal diseases are on the rise, primarily due to the rising number of people with compromised immune systems or underlying health conditions,” Gusa said. But at the same time, pathogenic fungi can also adapt to warmer temperatures.
Working in Professor Sue Jinks-Robertson’s lab, Gusa led research that focused on three transposable elements that were particularly active in C. deneoformans under heat stress. But there are easily another 25 or more transposable elements in this species that could be mobilized, she said.
The team used “long-read” DNA sequencing to detect changes that might otherwise have been missed, Gusa said. Using computer analysis, they were able to map transposons and then see how they had moved. “We now have enhanced tools to see those movements that previously hid in our blind spots.”
Heat stress accelerated the mutations. After 800 generations of growth in laboratory medium, the rate of transposon mutations in fungi grown at body temperature (37°C) was five-fold higher than in mushrooms grown at 30°C.
One of the transposable elements, called T1, had a tendency to insert itself between encoding genes, which could lead to changes in the way genes are controlled. An element called Tcn12 often ended up in the sequence of a gene and potentially disrupted the function of that gene, potentially leading to drug resistance. And a third species, Cnl1, tended to land near or in the telomere sequences at the ends of chromosomes, an effect Gusa said isn’t fully understood.
The mobilization of transposable elements also appeared to increase more in mouse-dwelling fungi than in laboratory cultures. “We saw evidence that all three transposable elements in the fungal genome were mobilized within just 10 days of infecting the mouse,” Gusa said. The researchers suspect that the added challenges of surviving in an animal with immune responses and other stressors might push the transposons to become even more active.
“This is an intriguing study that shows how increasing global temperature can affect fungal evolution in unpredictable directions,” said Arturo Casadevall MD, PhD, Chair of Molecular Microbiology and Immunology at Johns Hopkins University. “As the world warms, transposons in soil fungi like Cryptococcus neoformans could become more mobile and amplify genomic changes in ways that could increase virulence and drug resistance.” Another thing to worry about in light of global warming!”
Gusa’s work was supported by collaborations with Duke Labs, who also study fungi, the Joseph Heitman Laboratory at the School of Medicine, and the Paul Magwene Laboratory at Trinity Arts & Sciences.
The next phase of this research will examine pathogens from human patients who have had a recurrent fungal infection. “We know that these infections can persist and then come back with potential genetic changes.”
It’s time to get serious about pathogenic fungi, Gusa said. “These types of stress-stimulated changes can contribute to the development of pathogenic traits in fungi both in the environment and during infection. They may be evolving faster than we anticipated.”
This research was supported by the National Institutes of Health (R35-GM118077, R21-AI133644, 5T32AI052080, 2T32AI052080, 1K99-AI166094-01, R01-AI039115-24, R01-AI050113-17, R01-AI133654-05)
