Receptor-mediated signaling in Aspergillus fumigatus

Abstract

Aspergillus fumigatus is the most pathogenic species among the Aspergilli, and the major fungal agent of human pulmonary infection. To prosper in diverse ecological niches, Aspergilli have evolved numerous mechanisms for adaptive gene regulation, some of which are also crucial for mammalian infection. Among the molecules which govern such responses, integral membrane receptors are thought to be the most amenable to therapeutic modulation. This is due to the localization of these molecular sensors at the periphery of the fungal cell, and to the prevalence of small molecules and licensed drugs which target receptor-mediated signaling in higher eukaryotic cells. In this review we highlight the progress made in characterizing receptor-mediated environmental adaptation in A. fumigatus and its relevance for pathogenicity in mammals. By presenting a first genomic survey of integral membrane proteins in this organism, we highlight an abundance of putative seven transmembrane domain (7TMD) receptors, the majority of which remain uncharacterized. Given the dependency of A. fumigatus upon stress adaptation for colonization and infection of mammalian hosts, and the merits of targeting receptor-mediated signaling as an antifungal strategy, a closer scrutiny of sensory perception and signal transduction in this organism is warranted.

Erg4A and Erg4B Are Required for Conidiation and Azole Resistance via Regulation of Ergosterol Biosynthesis in Aspergillus fumigatus

“…Interestingly, the conidiation-defective phenotype in Δerg4A Δerg4B was similar to that of the ΔfluG, ΔbrlA, and ΔflbB strains, with a fluffy appearance, which implies that loss of both erg4A and erg4B may cause dysfunction of asexual development-related proteins (26). In addition, trimeric G-protein signaling has been reported to be involved in the regulation of vegetative growth and asexual development (28)(29)(30). Therefore, we speculate that ergosterol-enriched in plasma membranes may be necessary for the transduction of the extracellular signal into cells.…”

Hitting the Caspofungin Salvage Pathway of Human-Pathogenic Fungi with the Novel Lasso Peptide Humidimycin (MDN-0010)

“…This hypothesis is suggested by the decrease in the total number of differentially expressed genes detected by using the two drugs in combination in comparison to the response induced by CAS alone. However, all sensor kinases studied so far in filamentous fungi are mainly involved in morphology and differentiation, but none of them was related to stress sensing, besides some role in osmosensing (38). Therefore, the role of hybrid sensor kinases in stress sensing in filamentous fungi remains to be elucidated.…”

pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

“…While multiple targets can be envisioned to inhibit the Pac/Rim pathway, targets that are both well conserved in pathogenic fungi and are fungus specific should be prioritized (25,28,99,146). Fungus-specific components of the Pac/Rim pathways in pathogenic yeasts and fungi need to be fully characterized, both from a genetic and a biochemical point of view, in terms of mutant phenotype, protein structure, subcellular localization, and interactions.…”

“…The A. nidulans pHresponsive transcription factor PacC thus plays a key role in pulmonary pathogenesis. The PalH homologue was recently shown to be required for murine infection (99).…”