Biological Program Prevents Development Of Pathogenic Form Of Fungi

Ustilago maydis, Cryptococcus neoformans, and Candida albicans may not sound familiar, but the effects of these fungi certainly are. Well known to any farmer, Ustilago maydis is the cause of corn smut disease. Cryptococcus neoformans is responsible for meningitis. Candida albicans, the most prevalent yeast species in the human GI tract, causes vaginal yeast infections, oral thrush, and can invade tissues and produces fatal systemic infections in immunocompromised people. Under nitrogen-poor conditions, each of these fungi switch to filament form and thus become pathogenic. This physiological response to nutrient availability has been well documented. It is only now beginning to be understood.

Schröder and colleagues have discovered that the unfolded protein response (UPR) mediates this morphological response. The UPR is a cellular stress response, conserved from yeast to humans. Normally, proteins are folded into their proper conformations in the endoplasmic reticulum (ER) compartment of a cell. When unfolded or misfolded proteins accumulate in the ER, the UPR is activated to transiently decrease the level of protein production and ensure that proper folding occurs. Schröder and colleagues have demonstrated that an active UPR represses filament formation. Their experimental data demonstrates that only under nitrogen-rich conditions is an essential UPR gene regulator produced, and therefore the UPR active. Thus, the UPR mediates the environmental regulation of pathogenicity.

The discovery that the UPR represses filament formation lends new insight into the developmental design of anti-fungal therapies. Drugs which impair protein folding or otherwise activate the UPR may serve as models in the search for new anti-fungal agents.