A new gene discovery has opened an experimental window for gaining insight into growth processes in disease-causing yeast, UCSF researchers say. This promising line of inquiry for understanding yeast infections, which can sometimes threaten the lives of vulnerable patients and cause significant discomfort to many otherwise healthy women, could eventually lead to a new generation of drugs.

The findings, reported by Burkhard Braun, a postdoctoral fellow who works in the laboratory of Alexander Johnson, professor of microbiology and immunology at UCSF, appear in the July 4 issue of Science. Braun identified a gene, known as TUP1, that in laboratory studies prevents a microscopic yeast, called Candida albicans, from growing into chains of cells believed to permit the yeast to infect human host cells. The discovery sheds light on the biological mechanisms that govern the activity of genes affecting yeast growth.

Previous studies have shown that the ability of C. albicans to cause infection in humans arises when at least some of the yeast cells abandon their solitary lifestyle and instead form filamentous chains that can penetrate host cells. Normally, C. albicans cells may reside unobtrusively in tolerable numbers in the mouth, throat, gastrointestinal tract and the vagina. However, disturbances that affect the body's microbial population balance, such as a weakened immune system or use of antibiotics that target a broad range of bacteria, may permit this small population of yeast cells to opportunistically multiply and to expand into the bloodstream and internal organs.

The UCSF researchers genetically manipulated C. albicans to create a mutant lacking the TUP1 gene. These mutant yeast cells, they found, always grew into the disease-associated chains.

"TUP1 studies offer an experimental entry point that will permit researchers to better define the role of filaments in infection, and to understand how the different yeast configurations are controlled," Johnson says. "There may be proteins that are part of this regulatory circuitry that could conceivably serve as targets for new anti-fungal drugs."

In otherwise healthy patients, vaginal yeast infections and oral infections, or "thrush," can usually be brought under control with the current generation of topical anti-fungal drugs. More serious infections require more intensive treatment. These include extensive mouth and throat infections that afflict many AIDS patients, and infections that can arise in hospital patients who are connected to intravenous lines or to other catheters used to deliver nutrition. The catheters can serve as a vehicle to convey yeast into the bloodstream and organs. Infection may quickly spread within the body, especially in hospital patients with weakened immune systems or in those receiving broad-spectrum antibiotics.

Other work by the researchers indicates that in C. albicans, TUP1 is a "transcription repressor" that normally turns off the activity of other genes "downstream." But under the right conditions, TUP1 relaxes its grip and permits downstream gene activation and filament formation, Johnson suggests.

By Jeffrey Norris

1st appeared 7/11/97