Abstract
Aspergillus fumigatus is the most important airborne fungal pathogen, causing severe infections with invasive growth in immunocompromised patients. The fungal cell wall (CW) prevents the cell from lysing and protects the fungus against environmental stress conditions. Because it is absent in humans and because of its essentiality, the fungal CW is a promising target for antifungal drugs. Nowadays, compounds acting on the CW, i.e., echinocandin derivatives, are used to treat A. fumigatus infections. However, studies demonstrating the clinical effectiveness of echinocandins in comparison with antifungals currently recommended for first-line treatment of invasive aspergillosis are still lacking. Therefore, it is important to elucidate CW biosynthesis pathways and their signal transduction cascades, which potentially compensate the inhibition caused by CW- perturbing compounds. Like in other fungi, the central core of the cell wall integrity (CWI) signaling pathway in A. fumigatus is composed of three mitogen activated protein kinases. Deletion of these genes resulted in severely enhanced sensitivity of the mutants against CW-disturbing compounds and in drastic alterations of the fungal morphology. Additionally, several cross-talk interactions between the CWI pathways and other signaling pathways are emerging, raising the question about their role in the CW compensatory mechanisms. In this review we focused on recent advances in understanding the CWI signaling pathway in A. fumigatus and its role during drug stress response and virulence.
Highlights
Molecular Biotechnology of Natural Products, Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Beutenbergstrasse 11a, Specialty section: This article was submitted to Fungi and Their Interactions, a section of the journal Frontiers in Microbiology
In this review we focused on recent advances in understanding the cell wall integrity (CWI) signaling pathway in A. fumigatus and its role during drug stress response and virulence
Concerning PkcA, there are no studies describing its function in A. fumigatus, but the repression of this gene in the closely related fungus Aspergillus nidulans affected the production of penicillin, which supports the involvement of the CWI pathway in the regulation of secondary metabolism (Herrmann et al, 2006)
Summary
The fungal cell wall (CW) is the exoskeleton of fungal cells. Besides its starkness and firmness, it has a very flexible structure, which, can alter rapidly and efficiently in response to external and internal stimuli. Concerning PkcA (protein kinase C), there are no studies describing its function in A. fumigatus, but the repression of this gene in the closely related fungus Aspergillus nidulans affected the production of penicillin, which supports the involvement of the CWI pathway in the regulation of secondary metabolism (Herrmann et al, 2006). These results suggested that the role of Rho and PkcA is conserved in fungi, the link between membrane receptors and the activation of the CWI pathway was shown in model yeasts, but not experimentally confirmed in Aspergillus species until now (Levin, 2011). Besides these phenotypes, it remains to be shown whether these TFs act downstream of the CWI signaling pathway in a MAPK-dependent manner
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