How A Benign Fungus Can Become Life-Threatening

C. albicans can cause serious and potentially life-threatening infections in the mouth, blood and other tissues of people who are undergoing cancer chemotherapy or radiation treatments, or who have developed AIDS or other diseases that damage the immunity of the individual.

In two separate papers recently published in Developmental Cell and the EMBO journal, the team of scientists led by Wang Yue, principal investigator at IMCB, have managed to reveal previously unknown mechanisms which are responsible for causing the infectious phase of C. albicans.

The fungus starts its 'attack' on a patient by changing its oval shape into a filamentous form, which has thin, threadlike appendages emerging from the cell body. Wang's team, who has been studying C. albicans for more than seven years, was responsible for identifying the master "controller" protein called Hgc1 in 20041.

This "controller" functions like a regulator and tells the fungus when to start the transformation from the harmless oval shape to the infectious filamentous form.

"One question remained, however - how does it activate the cellular machineries that determine the fungal cell shape?" said Wang.

Wang's team found the answer to this question in two proteins called Rga2 and Cdc11. They discovered that they each function like a switch on two different cellular machineries that normally determines cell shape. "The master regulator Hgc1 acts like the 'finger' that flips the switches to start the infection process," said Wang.

"Our findings have uncovered detailed molecular mechanisms which define how these two proteins interact with the master 'controller' to cause infections. This has opened new opportunities for us to investigate further into a new range of therapeutic targets for fungal infections," explained Wang.

In the same issue of Developmental Cell, the team's work was given an expert mention by a leading C. albicans researcher, Dr. Peter Sudbery, stating its importance in bringing awareness of the cellular processes that is necessary for C. albicans to transform to its infectious state.

In addition, the new knowledge of the detailed interaction of these proteins with other cellular machineries has also revealed critical information on how cells in general determine their shape, a fundamental question in biology as Rga2 and Cdc11 are also found in nearly all eukaryotic organisms.

Largely due to the AIDS pandemic in the last 25 years, the once nearly harmless and commensal fungus Candida albicans has become one of the most prevalent microbial pathogens in AIDS patients, causing life-threatening infections with high death rate, especially in infected children.

References: XD Zheng, RTH Lee, YM Wang, QS Lin, and Y Wang. Phosphorylation of Rga2, a Cdc42 GAP, by CDK/Hgc1 is crucial for Candida albicans hyphal growth. The EMBO Journal 26, 3760-3769 (2007).

I Sinha, YM Wang, R Philp, CR Li, WH Yap, and Y Wang Cyclin-Dependent Kinases Control Septin Phosphorylation in Candida albicans Hyphal Development.  Developmental Cell 13: 421-432 (2007).