Pathogen mutations intensify as heat rises, raising concerns of new infectivity –

The world is full of tiny creatures that find us delicious. Bacteria and viruses are the obvious villains, driving deadly global pandemics and troublesome infections. But the pathogens we haven’t had to reckon with so much – yet – are fungi.

Pathogenic fungi (Candida, Aspergillus, Cryptococcus and others) are notorious killers of immunocompromised people. But for the most part, healthy people haven’t had to worry about that, and the vast majority of potentially pathogenic fungi on the planet don’t handle our body heat well.

But all of that may be about to change.

High temperatures cause a pathogenic fungus known as Cryptococcus deneoformans to turn its adaptive responses into overdrive, a new study from Duke University School of Medicine reveals. This increases its number of genetic changes, some of which could presumably lead to greater heat resistance, and others possibly to greater pathogenic potential.

Specifically, higher heat causes more of the fungus’ transposable elements, or jumping genes, to rise up and move through the fungal DNA, leading to changes in how its genes are used and regulated. The conclusions were published on January 20 in the Proceedings of the National Academy of Sciences.

« These mobile elements are likely to contribute to adaptation in the environment and during infection, » said postdoctoral researcher Asiya Gusa Ph.D. of Molecular Genetics and Microbiology at Duke School of Medicine. “It could happen even faster because heat stress accelerates the number of mutations that occur. »

That may ring a bell with viewers of the new HBO series « The Last of Us, » where a dystopian hellscape is precipitated by a heat-adapted fungus that grabs hold of humans and turns them into zombies. “That’s exactly the kind of thing I’m talking about – minus the zombie part! said Gusa, who just watched the first episode and will join the Duke faculty as an assistant professor later this year.

“These are not infectious diseases in the transmissible sense; we don’t pass fungus to each other,” Gusa said. “But the spores are in the air. We breathe in fungal spores all the time and our immune system is equipped to fight them. »

Fungal spores are usually larger than viruses, so your existing supply of Covid face masks would likely be enough to stop them. That, and your body heat, for now.

“Fungal diseases are on the rise, largely due to the increase in people with weakened immune systems or with underlying health conditions,” Gusa said. But at the same time, pathogenic fungi can also adapt to warmer temperatures.

Working in the laboratory of Professor Sue Jinks-Robertson, Gusa conducted research focusing on three transposable elements that are particularly active under heat stress in C. deneoformans. But there are easily 25 or more other transposable elements in this species that could be mobilizing, she said.

The team used “long read” DNA sequencing to see changes that might otherwise have been missed, Gusa said. Computer analysis allowed them to map the transposons and then see how they had moved. “We now have improved tools to see those movements that were previously hiding in our blind spots. »

Heat stress accelerated the mutations. After 800 generations of growth in a laboratory medium, the transposon mutation rate was five times higher in fungi grown at body temperature (37 degrees Celsius) than in fungi grown at 30 °C.

One of the transposable elements, called T1, tended to insert between coding genes, which could lead to changes in gene control. An element called Tcn12 often landed in the sequence of a gene, potentially disrupting that gene’s function and possibly leading to drug resistance. And a third type, Cnl1, tended to land near or in telomere sequences at the ends of chromosomes, an effect that Gusa says isn’t fully understood.

Mobilization of transposable elements also appeared to increase more in fungi living in mice than in laboratory culture. « We saw evidence of mobilization of all three transposable elements in the fungus genome within just ten 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 may drive the transposons to be even more active.

« This is a fascinating study, which shows how increasing global temperature can affect fungal evolution in unpredictable directions, » said Arturo Casadevall MD, PhD, Molecular Microbiology and D. immunology at Johns Hopkins University. “As the world warms, transposons from soil fungi like Cryptococcus neoformans could become more motile and increase genomic changes in ways that improve virulence and drug resistance. Another thing to worry about with global warming! »

Gusa’s work has been aided by collaboration with Duke Laboratories which 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 look at 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 may contribute to the evolution of pathogenic traits in fungi both in the environment and during infection. They may evolve faster than 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)

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