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CAMBRIDGE, Mass. (August 8, 2005) — Chemotherapy
and organ transplantation not only take a huge toll
on patients, but they can compromise the immune system
and leave patients vulnerable to infections from microbes
such as pathogenic fungi—the fastest-growing cause
of hospital-acquired infections. Now researchers from
Whitehead Institute for Biomedical Research have discovered
one possible reason why these fungal microbes are such
a scourge.
Fink believes these findings show why traditional
approaches to targeting drugs won't work on fungal
microbes. The features that drugs target may be
exactly the ones that change so readily. |
According to the research appearing in the August 7
online edition of the journal Nature Genetics, fungal
microbes can quickly alter the appearance of their cell
surfaces, their “skin,” disguising themselves
in order to slip past the immune system’s vigilant
defenses. And, for all the world’s brewers, the
study also helps explain why certain beers are cloudy
and others are clear.
“It’s all about skin,” says Whitehead
Member Gerald
Fink, who compares the fungal microbe to an M&M
candy —a sugar coating encasing the cell’s
DNA. “The skin of fungi microbes is what enables
them to stick to your organs, and thus become pathogenic.
It also enables the fungi to stick together, which is
desirable for fermentation in beer.”
The genetic core to this study is a DNA phenomenon
known as tandem repeats. Here, small units of between
3 and 200 nucleotides form within a gene and repeat
sometimes up to about 35 times. (Nucleotides, the building
blocks of our genome, are represented by the letters
A, C, T, G.) In humans, these tandem repeats received
a lot of attention when the gene responsible for Huntington’s
disease was discovered; a repeat of the letters CAG
in a gene called IT-15 causes the condition.
These tandem repeats also occur in fungal microbes.
Kevin Verstrepen, a post-doctoral researcher in Fink’s
lab, decided to find out how often they occur, and what
possible functions they might offer, by using baker’s
yeast as a model. Verstrepen scanned the entire yeast
genome with a custom computer program developed by Whitehead’s
bioinformatics group. He discovered that these repeats
are common throughout the yeast genome, and that more
than 60 percent occur in genes that code for cell-surface,
or skin, proteins. In other words, “most of these
repeats somehow affect how the yeast cell interacts
with the environment surrounding it,” says Verstrepen.
In addition, he found that the length of these repeats
varied greatly between a mother and a daughter cell.
While one yeast cell might have a 20-unit repeat on
a particular gene, when it divides, the new cell might
have only a five-unit repeat on that same gene. And
subsequently, when that cell then divides, its daughter
cell might go back to 20 repeats. “It’s
like an accordion,” says Verstrepen. “Our
study really showed how quickly and easily these repeats
can recombine, altering the properties of the cell surface
almost immediately.”
This provides a significant clue into why fungal infections
can often be so deadly. The immune system generally
recognizes invaders by certain signatures on their outer
coatings, such as protein conformations. However, if
these fungal microbes can quickly change the shape of
these proteins by changing the number of repeats in
the corresponding gene, they can then manage to stay
one step ahead of our body’s defenses.
“It’s important to remember,” says
Fink, “that these microbes have been around for
billions of years. They haven’t come this far
without learning how to fight off predators.”
Verstrepen and his colleagues took this research a
step further, focusing on a gene called FLO1, a cell-surface
gene common to both baker’s yeast and pathogenic
fungi. FLO1 creates the conditions that enable yeast
cells to adhere to surfaces. It’s also the gene
that allows pathogenic fungi to stick to host tissue.
The researchers discovered a clear correlation between
the number of repeats in FLO1 and the degree to which
these cells could adhere to a surface. When FLO1 contained
many repeats, it adhered vigorously to a plastic surface.
As the number of repeats declined, so did its ability
to adhere.
Fink believes that these findings show why traditional
approaches to targeting drugs won’t work on fungal
microbes. The features that drugs target may be exactly
the ones that change so readily. “We need to target
other aspects to the cell surface that don’t change,”
says Fink, suggesting that certain sugar molecules residing
on the inside of the cell coating may be valuable targets.
The research also may help to reveal why certain strains
of yeast brew better beers.
Both Verstrepen and Fink have consulted for a number
of commercial brewers. “Brewers have been cultivating
certain strains of yeast for hundreds of years,”
says Fink. “The secret of a good, fresh, clear
beer—the kind that Americans tend to like—is
that the yeast cells all stick together.” When
yeast cells don’t adhere, the beer tends to cloud
up. “We now know that these tandem repeats are
the molecular mechanism that yields good beer."
This research was supported by a grant from the U.S.
National Institutes of Health.
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