The Dance of Virulence
Double Agent: The fungus Candida albicans lives a double life. It co-exists as a harmless “commensal” inside our mouth, gut and urino-genital tract. Occasionally, it flares up as thrush, treatable with over the counter medication. But given the opportunity to breach our defenses, Candida can cross into the bloodstream and switch from peaceful coexistence to attack mode, producing long filaments that dig into tissues and destroy them. You can see the yeast-like buds germinating into hyphae on the left image. On the right, hyphae labeled with green fluorescent protein insert between intestinal cells (marked in red, with blue nuclei) in a macabre dance of virulence. This is particularly dangerous to people with weak immune systems (HIV/AIDS, cancer) who have less than 50% survival rates with systemic candidiasis.
More than a Junk Yard: In a study just published, we showed that the pH of the fungal vacuole (seen as dark holes inside the fungi on left) was crucial for the switch from yeast to hyphae. This was a surprising finding, because the vacuole is best known as the cell’s recycling center – a junk yard. But our previous study showed that an popular antifungal drug, fluconazole, blocked the vacuole from becoming acid, leading us to suspect that this may be important for fungal virulence. We focused on the V-ATPase, a cellular pump that has wide-reaching functions and acidifies many parts of the fungal cell. One component or subunit of this pump exists in duplicate forms, coded by two separate genes. Inactivating either one has no effect because the other one serves as a back-up, compensating every function – except one. We found that the vacuole exclusively depends on one version of the duplicated genes to become acidic. Without this one crucial function, Candida could no longer morph from yeast to hyphae. It also lost all ability to kill infected mice. In contrast, mice injected with the healthy Candida strain succumbed to infection.
A Chink in the Armor: The study revealed a vulnerability that could be exploited by targeting the vacuole’s pH, rendering Candida harmless while potentially posing little risk to infected patients. For example, FDA-approved drugs known to alter cellular pH could be repurposed to treat fungal infections. This is important because there are relatively few classes of antifungals known, and it is particularly dangerous when fungi become drug resistant. That is why we are always looking for new chinks in the fungal armor. This may be one.
News Report: Science Daily “Possible way to turn fungus from foe to friend” http://goo.gl/mtXLGM
REF: C. Patenaude, Y. Zhang, B. Cormack, J. Kohler, R. Rao. Essential Role for Vacuolar Acidification in Candida albicans Virulence. Journal of Biological Chemistry, 2013; 288 (36): 26256 DOI: 10.1074/jbc.M113.494815