University of Toronto scientists are re-thinking how a lethal fungus grows and kills immune cells. They published a study in Nature Communications that suggests a new approach to therapy for Candida albicans, one of the most common causes of bloodstream infections.
Previously, researchers thought that C. albicans spread by changing from a single, round cell to a long filament. They thought this shape change allowed the fungus to move through the bloodstream and let its filaments penetrate tissues and destroy immune cells.
But the new study shows that a little bit of sugar on the surface of fungal cells triggers the death of immune cells that would otherwise kill the fungus.
“It's not the shape-change per se that enables the fungus to kill the immune cell, but what happens along with it,” says Leah Cowen, Ph.D., lead researcher on the study who holds the Canada Research Chair in microbial genomics and infectious disease in U of T's department of molecular genetics. “The addition of glycosylated proteins re-models the surface of the fungal cells.”
Dr. Cowen and her lab found that C. albicans can kill immune cells even after its cells have died. They let macrophages consume the fungus, and after an hour they removed the fungal cells from the macrophages. Then they exposed new macrophages to fungal cells that had been consumed and those that had not, and they compared the results.
“The fungal cells that were never internalized by macrophages couldn't kill the fresh macrophages, but those that had been inside a macrophage could kill beautifully,” says Dr. Cowen. That finding was a clue. The researchers reasoned that the change in the fungal cells that turned them into killers was probably on their surface, since dead cells have no active internal processes.
The researchers then used an enzyme called Endo H to snip off sugars on the glycosylated proteins attached to the dead fungal cells. The change completely blocked the ability of the fungus to kill, which represents a strong lead on a new and needed therapeutic strategy for C. albicans.
Globally, fungi kill more than 1.5 million people a year. In the U.S., Candida fungi account for almost 90% of hospital-acquired fungal infections, and in Canada they're the third most common cause of bloodstream infections in intensive care units. More than 40% of people with a systemic C. albicans infection will die.
A therapy that targets the ability of fungal cells to outfox the immune system would be promising, continues Dr. Cowen, because it might minimize effects on healthy microbes and avoid spurring drug resistance.
