Gene that governs toxin production in deadly mold found

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Gene that governs toxin production in deadly mold found

EurekAlert (press release) - Washington,DC,

http://www.eurekalert.org/pub_releases/2007-04/uow-gtg041107.php

MADISON - For the growing number of people with diminished immune

systems - cancer patients, transplant recipients, those with

HIV/AIDS - infection by a ubiquitous mold known as Aspergillus

fumigatus can be a death sentence.

The fungus, which is found in the soil, on plant debris and indoor

air, is easily managed by the healthy immune system. But as medical

advances contribute to a growing population of people whose immune

systems are weakened by disease or treatment, the opportunistic

fungus poses a serious risk.

Now, however, scientists may have found a master switch, an über

gene, that seems to control the mold's ability to make poison. The

new finding was reported today (April 12) in the journal Public

Library of Science Pathogens by a team led by P. Keller, a

biologist from the University of Wisconsin-Madison.

" There is a growing problem with medical fungi in the United

States, " says Keller, a UW-Madison professor of plant pathology and

medical microbiology. " Aspergillus fumigatus is among the most

important. "

Like many fungi, Aspergillus fumigatus makes a variety of poisons,

presumably to give the microbe a competitive advantage in the

environments it inhabits. In humans with suppressed immune systems,

the mold can cause a number of diseases with mortality rates of 60

percent or more.

" The infection can be treated, but not easily, " Keller

explains. " Once an immunocompromised individual gets any fungal

disease, it's pretty hard to treat, and the treatments themselves

are often toxic. There is a 60-90 percent mortality rate with

invasive aspergillosis. "

Thus, knowing how the fungus makes its chemical arsenal is important

and opens an avenue to devising novel treatments that can disarm the

pathogen before it does its dirty work.

In fungi, there are typically many genes at work making toxins and

other chemical metabolites. The genes tend to be clustered in groups

on the organism's genome. In Aspergillus fumigatus, there are as

many as 22 such gene groupings.

How those posses of genes are triggered and governed, however, has

been a mystery. But now Keller's group has found that a key gene

known as LaeA controls at least half of those toxin-producing gene

clusters, suggesting there may be a way to modulate the virulence of

the deadly microbe.

" We now have a very good idea that (the gene) is central to the

toxic nature of the fungus, " Keller says.

The LaeA gene, she believes, is like a maestro, directing the mold's

toxin-producing genes in an orchestrated chorus that, in the right

host, can be fatal.

Knowing this, Keller explains, " suggests that if you can find a way

to regulate the activity of LeaA you might have a novel target " for

new therapies to treat Aspergillus fumigatus infection.

" The gene is not expressed all the time, which means there must be a

signal that says 'turn me on.' "

Removing the gene from the equation, she says, may cripple the

microbe's ability to infect and sicken people.

" The loss of LaeA results in a great decrease in the repertoire of

secondary metabolites, which appears to impact the infection

process, " making the gene an ideal prospect for new ways to fight

infection.

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The new work was supported by grants from the National Institutes of

Health. In addition to Keller, authors of the new PloS Pathogens

manuscript include Robyn M. Perrin and Jin Woo Bok of UW-Madison;

D. Fedorova and C. Nierman of the Institute for

Genomic Research in Rockville, Md.; A. Cramer of Duke

University Medical Center; and H. Stanley Kim of Korea University

Medical College, Seoul, Korea.