A warmer climate may prompt fungi to be more dangerous to our health

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The world is full of little creatures that find us delicious. Bacteria and viruses are the obvious bad guys, engines of deadly global pandemics and pesky infections. But the pathogens we haven’t had to account for much — until now — are fungi.

Pathogenic fungi (Candida, Aspergillus, Cryptococcus and others) are notorious killers for people with weakened immunity. But for the most part, healthy people didn’t have to worry about them, and the vast majority of potentially disease-causing fungi on the planet don’t do well in our body heat.

But all of that may be about to change.

A new study from Duke University School of Medicine finds that rising temperatures cause a pathogenic fungus known as Cryptococcus deneoformans to shift its adaptive responses into overdrive. This increases the number of genetic changes, some of which may likely lead to higher resistance to heat, and others may lead to an increased potential for pathogenicity.

Specifically, higher heat causes more of the fungus’ transferable elements, or transposable genes, to get up and move around within the fungus’ DNA, leading to changes in the way its genes are used and regulated. The results appeared Jan. 20 in the Proceedings of the National Academy of Sciences.

“It is likely that these mobile elements contribute to adaptation in the environment and during injury,” said postdoctoral researcher Asia Josa, Ph.D. Molecular Genetics and Microbiology at Duke Medical School. “This can happen faster because heat stress speeds up the number of mutations that occur.”

This may ring a bell with viewers of HBO’s new series “The Last of Us,” in which a heat-adapted fungus is deposited that takes over humans and turns them into zombies. “This is exactly the kind of thing I’m talking about – except for the zombie part!” said Gossa, who just watched the first episode and who will be joining Duke College as an assistant professor later this year.

“These are not infectious diseases in the general sense; we don’t pass the fungus on to each other,” Jossa said. “But germs are in the air. We breathe in fungus spores all the time and our immune systems are equipped to fight them off.”

Fungal spores are usually larger than viruses, so your current stock of COVID-19 face masks is likely to be enough to stop them. That, and your body heat, for the moment.

“Fungal diseases are on the rise, largely due to more people with compromised immune systems or underlying health conditions,” said Ghosa. But at the same time, pathogenic fungi may adapt to warmer temperatures as well.

Working in the lab of Professor Su Jinx Robertson, Jossa led research that focused on three transposable elements that were particularly active under heat stress in C. deneoformans. She said another 25 or more easily transportable elements in those species could cluster.

Jossa said the team used “long-read” DNA sequencing to see changes that might otherwise have been missed. Computational analysis allowed them to identify transposons and then see how they moved. “We’ve now improved the tools to see these motions that were previously hidden in our blind spots.”

Heat stress accelerated mutations. After 800 generations of growth in the tested medium, the mutation rate of transposons was five times higher in fungi raised at body temperature (37 °C) than in fungi raised at 30 °C.

One transposable element, called T1, tended to insert itself among coding genes, which could lead to changes in the way genes are controlled. An element called Tcn12 often gets lost within a gene’s sequence, which can disrupt the function of that gene and potentially lead to drug resistance. And the third type, Cnl1, tends to land near the telomere sequence or at the ends of chromosomes, an effect Jossa said is not fully understood.

Mobilization of transposable elements also appears to be increased in fungi living in mice than in laboratory culture. “We saw evidence of the three transposable elements assembling in the fungus genome within just 10 days of infection in the mouse,” said Ghosa. The researchers believe that the additional challenges of surviving an animal with immune responses and other stressors may prompt the transposons to be more active.

“This is a fascinating study, showing how an increase in global temperature may affect the evolution of fungi in unexpected directions,” said Arturo Casadevall MD, chair of the Department 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 increase genetic changes in ways that could enhance virulence and drug resistance. There’s one more thing to worry about with global warming!”

Gusa’s work was supported by collaborations with Duke Labs, which also studies fungi, Joseph Heitman’s lab at the School of Medicine, and Paul Magwene’s lab at Trinity Arts & Sciences.

The next phase of this research will look at pathogens from human patients who have had recurrent fungal infections. “We know that this infection can persist and then come back with possible genetic changes.”

It’s time to get serious about pathogenic fungi, Gossa said. “These kinds of stress-triggered changes may contribute to the evolution of pathogenic traits in fungi both in the environment and during infection. They may be evolving faster than we expected.”

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)

Citation: “Genome-wide analysis of heat stress-stimulated movement of transposons in the human fungal pathogen Cryptococcus deneoformans”, Asia Jossa, Vikas Yadav, Colin Roth, Jonathan Williams, Evan Mel Schoes, Paul Maguen, Joseph Heitman, Su Jinx Robertson. Proceedings of the National Academy of Sciences, January 20, 2023. DOI: 10.1073/pnas.2209831120

Connected – https://www.pnas.org/doi/10.1073/pnas.2209831120

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