July 26, 2000 MINNEAPOLIS / ST. PAUL--In a discovery that opens the door to understanding--and designing drugs to treat--virulence in infectious yeast, University of Minnesota scientists have found a way to induce the yeast, Candida albicans, to mate. Sexual mating was previously unknown in the yeast, which ranks among the top five causes of infections in immunocompromised or debilitated patients. The process of mating is a necessary basis for genetic experiments that could reveal the genes involved in virulence and allow development of new drugs to counteract those genes. The work will appear in the July 14 issue of Science.
"We've been looking for this phenomenon in all the 20 years we've been working with Candida albicans," said Beatrice Magee, first author of the report and a senior scientist at the unversity. "We've been able to take important findings from other laboratories and synthesize them to make our discovery." Her co-author is P.T. Magee, profressor of genetics, cell biology and development.
Candida albicans causes a variety of infections, including vaginitis and a life-threatening infection common to AIDS patients that prohibits swallowing. If it gets into the bloodstream, it can grow in kidneys or heart valves, especially artificial valves, and cause heart failure, P.T. Magee said.
The scientists induced yeast cells, which normally are diploid--that is, they have two sets of each chromosome--to fuse, forming cells with four sets of each chromosome. But in order for scientists to see patterns of inheritance that allow genes to be mapped, a second step must occur. In that step, called meiosis, each cell would split into two daughter cells that receive two copies of each chromosome in random combinations.
"This step almost certainly exists," said P.T. Magee. "We're working hard to find it, and when we do, it'll be easy to make all kinds of yeast strains that will help us find out what genes are important in virulence." Once the genes and their functions are identified, scientists can work on designing drugs to counteract those functions.
Candida has eight chromosomes, and the ability to mate is governed by a gene on chromosome 5. That gene comes in two forms, "a" and "alpha." Most cells isolated in clinical settings have both forms, one on each copy of chromosome 5. Such "a/alpha" cells cannot mate. Sometimes, however, a cell loses one copy of a chromosome. The University of Minnesota team found that they could screen for cells that had lost one copy of chromosome 5. Such cells carry either the a or the alpha form of the gene, and so can be mated--but only with cells carrying the opposite form.
When scientists get Candida cells to carry mating to completion--that is, through meiosis--it will be possible to sort out genes suspected of playing a role in the yeast's ability to cause illness, P.T. Magee said. For example, it may be that several genes perform similar functions, but whether those functions play a role in causing illness will only be testable when the individual genes are separated, through mating, into different progeny clones. Once those genes are identified and characterized, drugs can be designed to target them.
"Such drugs will save the lives of many debilitated patients and will make procedures like heart transplants much safer than they are today," said P.T. Magee.
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