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Review
. 2015 Apr 16:6:325.
doi: 10.3389/fmicb.2015.00325. eCollection 2015.

The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence

Affiliations
Review

The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence

Vito Valiante et al. Front Microbiol. .

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.

Keywords: Aspergillus fumigatus; cell wall integrity; mitogen activated protein kinases (MAPKs); signaling pathways; virulence.

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Figures

FIGURE 1
FIGURE 1
Mode of actions of antifungal drugs commonly used against invasive and systemic Aspergillus fumigatus infection (Ullmann and Cornely, 2006). (A) Polyenes (in this case amphotericin B) bind to sterols, forming pores in the cell membrane. The formation of these pores leads to increased membrane permeability. Additionally, amphotericin B induces the accumulation of reactive oxygen species (ROS), which have multiple toxic effects on fungal cells; (B) Azoles (in this case voriconazole) inhibit the ERG11 enzyme thereby blocking the ergosterol biosynthesis. ERG11 catalyses the formation of 4,4-dimethylcholesta-8,14,24-trienol from lanosterol. The lack of ergosterol and the subsequent accumulation of lanosterol, results in high toxicity for the cell; (C) Echinocandins (in this case caspofungin) inhibit the β-1,3-glucan synthesis. As a response to the reduction of glucan content there is an increase in chitin biosynthesis.
FIGURE 2
FIGURE 2
Schematic representation of the cell wall integrity (CWI) signaling pathway in A. fumigatus and colony growth of indicated deletion mutants on agar plates in comparison to the wild type. The picture shows those elements that were experimentally proven to be part of the A. fumigatus CWI pathway, plus some important elements, whose action was predicted based on data reported in other organisms (Fks1, Rho1, and PkcA). Once phosphorylated, MpkA translocates in the nucleus, where specific transcription factors (TFs) are activated. The deletion of genes constituting the central MAPK module have identical phenotypes, resulting in a compact colony and sensitivity to all cell wall (CW)-acting compounds (Valiante et al., 2008, 2009; Jain et al., 2011; Dichtl et al., 2012).

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