Secretion stress and antifungal resistance: an Achilles' heel of Aspergillus fumigatus?
The ability of Aspergillus fumigatus to establish and maintain an infection requires a continuous supply of nutrients to fuel energy production and growth. Like other filamentous fungi, A. fumigatus acquires nutrients by absorption, a mode of nutrition that depends upon the secretion of extracellular hydrolases to degrade the complex organic polymers in host tissues into reduced forms of carbon and nitrogen. If the folding capacity of the endoplasmic reticulum (ER) is exceeded during periods of high secretory activity, a signaling pathway known as the unfolded protein response (UPR) is activated to relieve the stress on the ER. Current evidence indicates that A. fumigatus relies upon this pathway to sustain the high rate of protease secretion needed to grow optimally in mammalian tissue. In addition, the UPR strengthens the ability of the secretory system to deliver cell wall and membrane components to the hyphal apex, which promotes the invasive growth of the expanding hyphae and protects the fungus from damage caused by antifungal drugs. The important contribution of UPR-dependent functions to the pathogenesis of invasive aspergillosis and antifungal susceptibility suggests that components of this pathway could be promising new targets for antifungal therapy.
Richie
Daryl L
DL
Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0529, USA.
Feng
Xizhi
X
Krishnan
Karthik
K
Askew
David S
DS
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D002473:Cell Wall / Q000502:physiology; D025141:Drug Resistance, Fungal; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D025301:Hyphae / Q000502:physiology; D017510:Protein Folding; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D014774:Virulence / Q000502:physiology
D000935:Antifungal Agents