Discovery Of Cell Wall "Scaffold" In Filamentous Fungi Could Help Lead To Better Medical Treatment For Some Diseases

March 10, 1997

ATHENS, Ga. -- A botanist at the University of Georgia and a colleague at Purdue University have shown for the first time that filamentous fungi contain crucial "scaffold" proteins called septins. Perhaps even more important, the researchers have found that the gene which directs the production of septins in one fungus (Aspergillus nidulans) is crucial to the survival of the organism.

The discovery could point toward a method of treating fungal diseases, which have dramatically increased in the past decade.

"Septins are the scaffolds that other parts of the fungal cell wall are built around," said Dr. Michelle Momany, a molecular mycologist. "My work shows that the septins have to be there or the fungus dies."

The study will be published later this month in the journal Fungal Genetics and Biology.

While there are more than 1.5 million species of fungi, only about 400 have been proved to be agents of disease in humans and animals. All fungi come in one of two basic forms, molds or yeasts. Molds grow with long, threadlike filaments, while yeasts are characterized by solitary cells that reproduce by budding.

The genus Aspergillus consists of filamentous fungi that can cause disease depending on the condition of their host. People undergoing chemotherapy or those with diseases such as AIDS or tuberculosis are often susceptible to diseases caused by fungi. Worse, pathogenic fungi are becoming harder to kill, and the numbers of those with fungal disease in the U.S. have dramatically increased, according to the Centers for Disease Control.

The very nature of fungi makes human diseases they cause difficult to treat, since fungi, like humans, are eurycaryotes -- organisms composed of one or more cells that contain well-defined nuclei. Penicillin is an effective oral antibiotic because it attacks the bacterial cell wall.

"We hope to use a similar strategy to attack the fungal wall," said Momany.

The discovery by Momany and Dr. John Hamer of Purdue could help pinpoint the cell wall of these opportunistic fungi as a point of attack in therapy. Very few new cell wall components have been identified in fungi in the last 30 years, and many of the processes in the wall remain poorly understood.

"Septins seem to act like a temporary scaffold," said Momany. "They allow the `steel girders' to be put in the right place for wall assembly. Any new wall component could be a target for antifungal agents. Because human cells do not have walls, fungal wall components should be unique to the pathogen, so drugs developed to interfere with fungal cell wall synthesis, assembly or maturation have less chance of host toxicity than those targeting more universal processes.

"We know that certain cell wall mutants cause cell walls to lose their integrity, and what we have to find out now is which ones do it and how they accomplish it." Momany and Hamer hope to use the septins as a "hook" to fish out other important wall components.

Septins are not just found in filamentous fungi. They have been found in yeasts and even fruit flies and mice. In all cases investigated so far, septins appear to play a role in the construction of the special cross walls that divide cells and possibly in organizing the cell surface.

In a related attempt to find new cell wall components, Momany and colleagues in her lab are investigating a group of temperature-sensitive mutants with swollen cells -- a characteristic which has been associated with defects in cell-wall synthesis.

Momany's team is now screening a group of mutants to see which ones may be caused by the alteration of a single gene. Starting out with some 52 potential candidates, they have whittled this number to 13. Of this number perhaps half will actually turn out to be involved with cell wall bulging. When the genes that direct the construction of faulty cell walls are discovered, Momany will clone them and see in repeated tests how they work.

"We're not really sure what we're looking for, but it will be something that disrupts the cell wall," said Momany. "Looking at cell wall mutants is like looking at buildings that didn't hold up during an earthquake and then asking what's missing that made them fall. Then you rebuild them with the missing piece and shake them again to see if they stand this time. If they don't fall down, then you know you've found what you're after."

The stakes for research on disease-causing fungi are high, since many are now becoming resistent to common drugs just as some bacteria have. According to an Associated Press story, the number of hospital-related fungal infections nearly doubled between 1980 and 1990.

-30-

University of Georgia

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