Abstract
ABSTRACTAspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the “caspofungin paradoxical effect” (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkAMPK1 and its associated transcription factor (TF) RlmARLM1, which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies.
Highlights
Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans
We show that the cell wall integrity (CWI) pathway components MpkA and RlmA as well as the calcium/calcineurin-responsive transcription factor CrzA regulate the expression of cell wall biosynthetic genes during the caspofungin paradoxical effect (CPE)
Deletion of the CWI mitogen-activated protein kinase (MAPK) gene mpkA and its associated transcription factor (TF) gene rlmA resulted in the loss of the caspofungin paradoxical effect” (CPE) when grown in the presence of increasing concentrations of caspofungin on solid medium (Fig. 1A)
Summary
Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. Differences in the CPE were observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. We show that the CWI pathway components MpkA and RlmA as well as the calcium/calcineurin-responsive transcription factor CrzA regulate the expression of cell wall biosynthetic genes during the caspofungin paradoxical effect (CPE). Invasive aspergillosis (IA) has emerged as one of the most common life-threatening fungal diseases in immunocompromised humans, and mortality rates as high as 90% have been reported [1,2,3,4,5] Systemic fungal infections such as IA are usually treated with antifungal drugs such as polyenes, azoles, and echinocandins, with the first two targeting cell membrane ergosterol biosynthesis and the latter perturbing the biosynthesis of the cell wall (CW) polysaccharide glucan [6]. The MADS box transcription factor RlmA was identified as functioning downstream of and regulating the phosphorylation of MpkA, contributing to the regulation of CWI [13]
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