By Dean A. Haycock
Special To BioWorld Today
The metamorphosis of Candida albicans from a harmless yeast into a killer fungus would thrill a horror film director. The normally benign creature undergoes a physical conversion from a passive ellipsoid cell into a spreading fungus assuming different filamentous forms called germ tubes, pseudohyphae and hypae.
The yeast (the fungus kingdom includes molds, yeasts and mushrooms) is fairly widespread in the environment. It is a normal inhabitant of the human intestinal tract but it is not always innocuous.
It causes superficial infections such as vaginitis — a common yeast infection in women — thrush and diaper rash in infants. And given the right opportunity, it can attach to cells in the body, change its shape and invade through the bloodstream. Or it may enter through catheter incisions in surgical patients. It also targets diabetics and premature infants. When it attacks patients with compromised immune systems, it kills nearly one in three of them.
Side Effects, Resistance Create Problems
Currently used antifungal drugs work by preventing the yeast from forming its cell wall, a strategy that prevents it from growing but does not eliminate the infection outright. Unfortunately, C. albicans is a eucaryote; its cells have nuclei and membrane-bound organelles just as human cells have. Drugs now used to fight the organism also affect human cells and so produce significant side effects.
"Some Candida species are resistant to these drugs de novo, right off the bat. And resistance is emerging at a fairly fast pace in a large number of other Candida species," Margaret Hostetter, American Legion and Auxiliary Heart Research chairwoman in the department of pediatrics at the University of Minnesota, Minneapolis, told BioWorld Today.
This situation may improve as a result of work described in the Feb. 17, 1998, issue of Science. Hostetter and Judith Berman are senior authors of the paper, titled "Linkage of adhesion, filamentous growth, and virulence in Candida albicans to a single gene, INT1." Berman is an associate professor in the College of Biological Sciences at the University of Minnesota, St. Paul.
The teams they led showed that a single C. albicans gene, INT1, is responsible for three important characteristics of the fungus: its ability to adhere to host cells, to change into various filamentous forms and to kill. The study is the first to show that a single protein in C. albicans is involved in both adhesion and filamentation.
The INT1 gene encodes a protein referred to as Int1p. Int1p sticks out from the outer surface of C. albicans cells. It looks a little like proteins present on vertebrate cells called integrins. Vertebrate integrins bind cells to matrix proteins in the extracellular environment and induce physical changes in cells in the presence of certain external signals.
When Int1p is expressed in another, easier-to-study yeast named Saccharomyces cerevisiae, it induces filamentous growth. This is the same type of transformation C. albicans undergoes when it becomes pathogenic. It is the ability to adhere to epithelial and endothelial cells in humans and to transform itself into a filamentous form that is thought to account for C. albicans' pathogenicity. The authors suggest that Int1p may be a "sensor that triggers the morphogenic decision process in response to a subset of environmental conditions."
"We used a system, S. cerevisiae, that is very easy to manipulate genetically to study a really difficult system, Candida," Berman said.
Candida presents a challenge for geneticists because is it is an asexual diploid. First, it is difficult to do genetics in a classic sense with an asexual organism. And when you want to knock out a gene in a diploid organism, it is necessary to knock out it out twice. It also has a different codon usage from most other organisms, according to Berman.
"By being able to move back and forth [between C. albicans and S. cerevisiae], you can learn a lot of biology," Berman said.
Berman's laboratory is now studying the signaling mechanisms that the foreign C. albicans gene uses to trigger shape changes in the Saccharomyces. Her group also is investigating how Int1p aids binding to epithelial cells.
Gene Product Deadly
In vivo studies conducted by the authors demonstrated the importance of the INT1 gene for expression of the lethal effects of the yeast. All mice that received an intravenous injection of normal C. albicans died after 11 days. In contrast, 90 percent of mice that received an injection of a mutant strain of C. albicans that lacked the ability to express normal Int1p protein were alive after the same time period.
Because Int1p appears to contribute to host death and is present on the surface of invading yeast cells, it presents an inviting target for new drug discovery efforts.
"This finding opens the door to the possibility that other fungi that are pathogens for immunocompromised hosts may have similar molecules on their surfaces. By individually targeting those molecules, we may be able to come up with therapy that is directed against the pathogen and doesn't have a spillover effect on the host. It is going to be very important to start looking at these 'antennae' that these fungi have out on their surfaces because that is where some of the action is going to be," Hostetter said. *