Basal expression of the Aspergillus fumigatus transcriptional activator CpcA is sufficient to support pulmonary aspergillosis

Aspergillosis is a disease determined by various factors that influence fungal growth and fitness. A conserved signal transduction cascade linking environmental stress to amino acid homeostasis is the Cross-Pathway Control (CPC) system that acts via phosphorylation of the translation initiation factor eIF2 by a sensor kinase to elevate expression of a transcription factor. Ingestion of Aspergillus fumigatus conidia by macrophages does not trigger this stress response, suggesting that their phagosomal microenvironment is not deficient in amino acids. The cpcC gene encodes the CPC eIF2 alpha kinase, and deletion mutants show increased sensitivity towards amino acid starvation. CpcC is specifically required for the CPC response but has limited influence on the amount of phosphorylated eIF2 alpha. Strains deleted for the cpcC locus are not impaired in virulence in a murine model of pulmonary aspergillosis. Accordingly, basal expression of the Cross-Pathway Control transcriptional activator appears sufficient to support aspergillosis in this disease model. (c) 2008 Elsevier Inc. All rights reserved.