Warmer climate may drive fungi to be more dangerous to our health
Duke University
The world is filled with tiny creatures that find us delicious. Bacteria and viruses are the obvious bad guys, drivers of deadly global pandemics and annoying infections. But the pathogens we haven't had to reckon with as much -- yet -- are the fungi.
Pathogenic fungi (Candida, Aspergillus, Cryptococcus and
others) are notorious killers of immune-compromised people. But for the most
part, healthy people have not had to worry about them, and the vast majority of
the planet's potentially pathogenic fungi don't do well in the heat of our
bodies.
But
all that may be about to change.
A
new study out of Duke University School of Medicine finds that raised
temperatures cause a pathogenic fungus known as Cryptococcus deneoformans to
turn its adaptative responses into overdrive. This increases its number of
genetic changes, some of which might presumably lead to higher heat resistance,
and others perhaps toward greater disease-causing potential.
Specifically,
higher heat makes more of the fungus' transposable elements, or jumping genes,
get up and move around within the fungal DNA, leading to changes in the way its
genes are used and regulated. The findings appeared Jan. 20 in the Proceedings of the
National Academy of Sciences.
"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. "This could happen even faster because heat stress speeds up the number of mutations occurring."
This
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 takes
over humans and turns them into zombies. "That's exactly the sort of thing
I'm talking about -- minus the zombie part!" said Gusa who just watched
the first episode and who will join the Duke faculty as an assistant professor
later this year.
"These are not infectious diseases in the communicable
sense; we don't transmit fungi to each other," Gusa said. "But the
spores are in the air. We breathe in spores of fungi all the time and our
immune systems are equipped to fight them."
Fungal
spores are generally larger than viruses, so your existing stock of face masks
against Covid would probably be sufficient to stop them. That, and your body
heat, for now.
"Fungal
diseases are on the rise, largely because of an increase in the number of
people who have weakened immune systems or underlying health conditions,"
Gusa said. But at the same time, pathogenic fungi may be adapting to warmer
temperatures as well.
Working
in the lab of Professor Sue Jinks-Robertson, Gusa led research that focused on
three transposable elements that were particularly active under heat stress in
C. deneoformans. But there are easily another 25 or more transposable elements
in that species that could mobilize, she said.
The
team used 'long-read' DNA sequencing to see changes that might otherwise have
been missed, Gusa said. Computational analysis allowed them to map transposons
and then see how they had moved. "We have improved tools now to see these
movements that were previously hiding in our blind spots."
Heat
stress sped the mutations up. 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 30C.
One of the transposable elements, called T1, had a tendency to
insert itself between coding genes, which could lead to changes in the way
genes are controlled. An element called Tcn12 often landed within the sequence
of a gene, potentially disrupting that gene's function and possibly leading to
drug resistance. And a third kind, Cnl1, tended to land near or in the telomere
sequences at the ends of chromosomes, an effect which Gusa said isn't fully
understood.
The
mobilization of transposable elements also appeared to increase more in fungi
living in mice than 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 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 may
affect the fungal evolution in unpredictable directions," said Arturo
Casadevall MD, PhD, the chair of molecular microbiology & immunology at
Johns Hopkins University. "As the world warms, transposons in soil fungi
like Cryptococcus neoformans could become more mobile and increase genomic
changes in ways that could enhance virulence and drug resistance. One more
thing to worry about with global warming!"
Gusa's
work was helped by collaboration with Duke labs that also study fungi, the
Joseph Heitman lab in the school of medicine and the Paul Magwene lab in
Trinity Arts & Sciences.
The
next phase of this research will be looking at pathogens from human patients
who have had a relapsing 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 kinds of
stress-stimulated 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)