Study Yields Insights Into Pathogenic Fungi—and Beer

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Source: Whitehead Institute for Biomedical Research Released:

Wed 03-Aug-2005, 11:15 ET

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http://www.newswise.com/articles/view/513583/

Study Yields Insights Into Pathogenic Fungi—and Beer

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PATHOGENIC FUNGI, DRUG RESISTENT PATHOGENIC FUNGI, IMMUNE SYSTEM

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Chemotherapy and organ transplantation can compromise the immune

system and leave patients vulnerable to infections from pathogenic

fungi. Researchers have discovered one possible reason why these

fungal microbes are such a scourge.

Newswise — 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.

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—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.

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.