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Warmer temperatures may increase mutation rate in human fungal pathogen

According to a recent study from Duke University School of Medicine (published in PNAS), a warmer climate could drive mutations in pathogenic fungi, making them better suited to infecting humans.

Sound familiar? For those of you currently watching The Last of Us (a TV series gaining popularity at the moment), this paper may well strike fear into your heart. As it turns out, the plot of this videogame-turned-series is (somewhat) entirely plausible. Deep breath.

Fungi: Friend or Foe?

To the general public, bacteria and viruses are the obvious “bad guys” of the microbial universe. Most people (particularly after the last few pandemic-peppered years) are well aware that these microscopic creatures cause infection and disease. But fungi? They seem pretty harmless. After all, aren’t they simply the key ingredient in a well risen bread or a tasty risotto? This might be true – but the humble fungus has a sinister side too.

We already know fungi are a threat to immunocompromised individuals – just think of the candidiasis infections prevalent among HIV patients. But on the whole, healthy people haven’t had to worry too much about fungal infections. Why? Mainly because they don’t survive too well in the balmy 37-degree temperatures of our bodies. That is, until now.

Mutation melting point

Researchers at Duke University School of Medicine decided to investigate how heat stress might impact the rate at which a pathogenic fungus, Cryptococcus deneoformans, mutates. To do this, the team analysed whole genomes using long-read sequencing. This allowed them to identify native transposable elements (or “jumping genes”) and further computational analysis meant they could map how the transposons moved within the fungal DNA.

Following 800 generations of growth in laboratory medium, the rate of transposon mutations was five-times higher in fungi raised at body temperature (37 Celsius) compared with fungi raised at 30°C.

“These mobile elements are likely to contribute to adaptation in the environment and during an infection,” said postdoctoral researcher Asiya Gusa Ph.D. of Molecular Genetics and Microbiology in the Duke School of Medicine who led the research. “This could happen even faster because heat stress speeds up the number of mutations occurring.” More mutations, more chance that these mutations will help the microbe infect humans.

Tracking transposons

Overall, the team tracked 3 key transposable elements – though there are many more that need further investigation. Of the 3, the T1 transposon had a tendency to insert between coding genes and would do so at both 37°C and 30°C. The retrotransposon Tcn12 integrated into genes at the higher temperature, and the Cnl1 transposon tended to insert near telomere sequences.

Importantly, the rate at which these elements mobilized seemed to increase in fungi isolated from mice compared to those in lab culture. “We saw evidence of all three transposable elements mobilizing in the fungus genome within just ten days of infecting the mouse,” Gusa said. The suggestion is that the more challenging environment of a mouse, laden with additional stressors, may drive the transposons to be more active – adding to evidence that mobile elements aid microevolution and rapid adaptation during infection.

So, what now? Well, it appears there’s no need to go full survivalist mode quite yet. It’s clear that more research is needed, and the next step for the team is to look at pathogens from human patients who have had a relapsing fungal infection.

However, Gusa stressed that fungi should be taken more seriously: “These kinds of stress-stimulated changes may contribute to the evolution of pathogenic traits in fungi both in the environment and during infection,” she said. “They may be evolving faster than we expected.”

More on these topics

Fungal / Fungi / long reads / Microbiology / Sequencing