SECRETION STRESS & ANTIFUNGAL RESISTANCE: AN ACHILLES’ HEEL FOR A. FUMIGATUS?

David S. Askew, PhD

Author address: 

University of Cincinnati, USA

Abstract: 

The ability of A. fumigatus to cause infection requires a steady supply of nutrients to fuel energy production and growth. Like other filamentous fungi, A. fumigatus acquires these nutrients by absorption, a mode of nutrition that depends upon the secretion of extracellular hydrolases to break down the complex polymers that are present in human tissues. A high rate of protein secretion exerts stress on the protein folding capacity of the fungal endoplasmic reticulum (ER), which is alleviated by the activation of a stress response pathway called the unfolded protein response (UPR). Using mutants of the UPR we have examined the contribution of ER homeostasis to A. fumigatus virulence. Our findings demonstrate that A. fumigatus relies upon the UPR, in addition to other mechanisms of ER quality control (ERQC), to sustain a high rate of protease secretion and to grow on polymeric substrates. In addition, the UPR is essential to maintain cell wall integrity, particularly in areas of remodeling such as the hyphal tips and is essential for growth under conditions of thermal stress. Finally, the ability of A. fumigatus to thrive in the host environment and to resist attack from antifungal drugs relies heavily upon the UPR. Taken together, these data suggest that pharmacologic inhibition of ER homeostasis would enhance the efficacy of current antifungal therapy.
2010

abstract No: 

none

Full conference title: 

4th Advances Against Aspergillosis
    • AAA 4th (2010)