Journal
GENETICS
Volume 220, Issue 1, Pages -Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1093/genetics/iyab183
Keywords
A. fumigatus; CrzA; caspofungin; transcriptome
Categories
Funding
- Sao Paulo Research Foundation (FAPESP) from Brazil [2016/07870-9, 2017/07536-4, 2017/19694-3, 2018/00315-5]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) from Brazil
- Graduate Program in Biological Sciences at Vanderbilt University
- National Science Foundation [DEB-1442113]
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [R56AI146096]
- Burroughs Wellcome Fund
- Science and Technology Development Fund, Macao S.A.R (FDCT) [0033/2021/A1]
- Israel Science Foundation [179/19]
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This study investigates the molecular mechanisms underlying heterogeneity in the response to the antifungal drug caspofungin in different Aspergillus fumigatus strains. The study found that a core transcriptional response involving genes related to cell wall remodeling, mitochondrial function, transmembrane transport, and metabolism, as well as a variable response related to secondary metabolite biosynthesis and iron homeostasis, contribute to the heterogeneity in response. Furthermore, the study highlights the role of the transcription factor CrzA in modulating the expression of genes related to CSP tolerance and SM production, impacting the CPE response in different strains.
Aspergillus fumigatus is the main causative agent of invasive pulmonary aspergillosis (IPA), a severe disease that affects immunosuppressed patients worldwide. The fungistatic drug caspofungin (CSP) is the second line of therapy against IPA but has increasingly been used against clinical strains that are resistant to azoles, the first line antifungal therapy. In high concentrations, CSP induces a tolerance phenotype with partial reestablishment of fungal growth called CSP paradoxical effect (CPE), resulting from a change in the composition of the cell wall. An increasing number of studies has shown that different isolates of A. fumigatus exhibit phenotypic heterogeneity, including heterogeneity in their CPE response. To gain insights into the underlying molecular mechanisms of CPE response heterogeneity, we analyzed the transcriptomes of two A. fumigatus reference strains, Af293 and CEA17, exposed to low and high CSP concentrations. We found that there is a core transcriptional response that involves genes related to cell wall remodeling processes, mitochondrial function, transmembrane transport, and amino acid and ergosterol metabolism, and a variable response related to secondary metabolite (SM) biosynthesis and iron homeostasis. Specifically, we show here that the overexpression of a SM pathway that works as an iron chelator extinguishes the CPE in both backgrounds, whereas iron depletion is detrimental for the CPE in Af293 but not in CEA17. We next investigated the function of the transcription factor CrzA, whose deletion was previously shown to result in heterogeneity in the CPE response of the Af293 and CEA17 strains. We found that CrzA constitutively binds to and modulates the expression of several genes related to processes involved in CSP tolerance and that crzA deletion differentially impacts the SM production and growth of Af293 and CEA17. As opposed to the Delta crzA(CEA17) mutant, the Delta crzA(Af293) mutant fails to activate cell wall remodeling genes upon CSP exposure, which most likely severely affects its macrostructure and extinguishes its CPE. This study describes how heterogeneity in the response to an antifungal agent between A. fumigatus strains stems from heterogeneity in the function of a transcription factor and its downstream target genes.
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