Montana State University researchers find gene that regulates mold's resistance

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Public release date: 6-Nov-2008

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Montana State University

http://www.eurekalert.org/pub_releases/2008-11/msu-msu110608.php

Montana State University researchers find gene that regulates mold's

resistance to drugs

BOZEMAN, Mont. -- Montana State University scientists concerned

about lethal mold infections have found a gene that regulates the

mold's resistance to drugs.

The gene, called srbA, allows molds to thrive during infections even

when inflammation reduces its oxygen supply, said Cramer,

senior author of a paper published in the Nov. 7 issue of PLoS

Pathogens. When the gene is removed, the mold becomes much more

vulnerable to lack of oxygen and can no longer grow to cause disease.

The gene is found in humans and molds, but the researchers studied

it in a common mold called Aspergillus fumigatus, said Cramer,

assistant professor of fungal pathogenesis in MSU's Department of

Veterinary Molecular Biology. A. fumigatus can invade the lungs and

cause dangerous diseases, including Invasive Pulmonary

Aspergillosis. Patients with a compromised immune system, especially

organ transplant patients, are particularly at risk.

" The incidence of potentially lethal infections caused by normally

benign molds has increased tremendously over the last two decades, "

the researchers wrote.

The scientists discovered the value of srbA after creating a mutant

version of the fungus without the gene, Cramer said. Tests showed

that the loss of srbA affected 87 genes in the fungus. Without the

gene, the mutant could no longer grow when oxygen was limited, which

occurs during mold infections. The mutant mold without srbA could no

longer cause disease. It was also highly susceptible to antifungal

drugs, more vulnerable than the original, complete mold.

Further study showed that srbA plays a critical role in the making

of ergosterol, the fungal-form of cholesterol, Cramer said. The gene

in humans is associated with the making of cholesterol. Ergosterol

and cholesterol are necessary components of cell membranes.

" The reason we're interested is because ergosterol is a target for

most of the antifungal drugs that are available, " Cramer

said. " These drugs target the synthesis of ergosterol. ... If you

get rid of ergosterol, you kill the mold. "

Sven Willger, a postdoctoral researcher in Cramer's lab and first

author of the PLoS Pathogens paper, said the absence of srbA changed

the way the mold cells grew. Instead of growing from the tip, they

branched off from several other locations. The confusion became

apparent under a transmission electron microscope.

The researchers said in their paper that they demonstrated for the

first time that it is significant that invasive molds adapt to

reduced oxygen levels during infection.

###

Besides Cramer and Willger, MSU co-authors of the paper are

Srisombat Puttikamonkul and Nora Grahl, both graduate students in

Cramer's lab; and Burritt, assistant professor of

microbiology. Co-authors from other institutions are Kwang-Hyung Kim

and Lawrence from the Virginia Bioinformatics Institute,

and Laurel Metzler, Barbuch and Bard from Indiana

University-Purdue University.