Abstract
Invasive pulmonary aspergillosis is a life-threatening fungal infection especially in the immunocompromised patients. The low diversity of available antifungal drugs coupled with the emergence of antifungal resistance has become a worldwide clinical concern. The echinocandin Caspofungin (CSP) is recommended as a second-line therapy but resistance and tolerance mechanisms have been reported. However, how the fungal cell articulates the response to CSP is not completely understood. This work provides a detailed characterization of ZnfA, a transcription factor (TF) identified in previous screening studies that is involved in the A. fumigatus responses to calcium and CSP. This TF plays an important role in the regulation of iron homeostasis and cell wall organization in response to high CSP concentrations as revealed by Chromatin Immunoprecipitation coupled to DNA sequencing (ChIP-seq) analysis. Furthermore, ZnfA acts collaboratively with the key TF CrzA in modulating the response to calcium as well as cell wall and osmotic stresses. This study therefore describes the existence of an additional, previously unknown TF that bridges calcium signaling and the CSP cellular response and further exposes the complex connections that exist among different pathways which govern stress sensing and signaling in A. fumigatus.
Highlights
Invasive pulmonary aspergillosis is the most common human systemic infection caused by filamentous fungi (Brown et al, 2012; Bongomin et al, 2017)
ZnfA zipD behaved to zipD in all here tested conditions, except for being more sensitive to high CaCl2 concentrations and, just like the znfA crzA strain, it entirely lost the caspofungin paradoxical effect (CPE) (Figures 4B–G; Supplementary Figure 1). These results suggest that ZnfA, CrzA and ZipD act additively in the calcium and CSP cell response, while ZnfA and CrzA but not ZipD cooperate in responding to cell wall and osmotic stresses
Just the single deletion mutants had higher amounts of N-acetyl glucosamine (GlcNAc) in their cell walls (Figure 5A). These results suggest that ZnfA, CrzA and ZipD are required for regulating the maintenance of sugar concentrations in the fungal cell wall
Summary
Invasive pulmonary aspergillosis is the most common human systemic infection caused by filamentous fungi (Brown et al, 2012; Bongomin et al, 2017). Despite the continuous increase of susceptible population to fungal infections, the number of available antifungal drugs is very limited. Resistance levels are so high that azoles can no longer be used as sole first-line therapeutics (Verweij et al, 2015). Echinocandins, such as caspofungin (CSP), are the newest class of antifungal drugs approved to treat invasive fungal infections. Their mode of action relies on inhibiting the 1,3β-D-glucan synthase, which is responsible for the assembly of the β-D-glucan polymer, disrupting fungal cell wall integrity (Onishi et al, 2000). The calcium-calcineurin, Hsp and certain Mitogen-Activated Protein Kinase (MAPK) signaling pathways appear to play a major role in regulating these cellular and structural changes (Lamoth et al, 2014; Altwasser et al, 2015; Juvvadi et al, 2015; Ries et al, 2017)
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