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Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin
Colabardini, Ana Cristina1,2; Wang, Fang2; Dong, Zhiqiang2; Pardeshi, Lakhansing2,3; Rocha, Marina Campos4; Costa, Jonas Henrique5; Dos Reis, Thaila Fernanda1; Brown, Alec6; Jaber, Qais Z.7; Fridman, Micha7; Fill, Taicia5; Rokas, Antonis6; Malavazi, Iran4; Wong, Koon Ho2,8,9; Goldman, Gustavo Henrique1
2022-01-04
Source PublicationGenetics
ISSN0016-6731
Volume220Issue:1Pages:iyab183
Abstract

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 ΔcrzACEA17 mutant, the ΔcrzAAf293 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.

KeywordA. fumigA.us Caspofungin Crza Transcriptome
DOI10.1093/genetics/iyab183
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaGenetics & Heredity
WOS SubjectGenetics & Heredity
WOS IDWOS:000743887000022
PublisherOXFORD UNIV PRESS INCJOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513
Scopus ID2-s2.0-85123431341
Fulltext Access
Citation statistics
Document TypeJournal article
CollectionFaculty of Health Sciences
Institute of Translational Medicine
Genomics, Bioinformatics and Single Cell Analysis Core
Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau
Corresponding AuthorWong, Koon Ho; Goldman, Gustavo Henrique
Affiliation1.Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
2.Faculty of Health Sciences, University of Macau, Macau, 999078, China
3.Genomics, Bioinformatics and Single Cell Analysis Core, Faculty of Health Sciences, University of Macau, Macau, 999078, China
4.Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos 13565-905, Brazil
5.Instituto de Química, Universidade Estadual de Campinas, Campinas, Brazil
6.Department of Biological Sciences, Vanderbilt University, Nashville, United States
7.School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, 6997801, Israel
8.Faculty of Health Sciences, Institute of Translational Medicine, University of Macau, Macau, 999078, China
9.MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau, 999078, China
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences;  University of Macau
Recommended Citation
GB/T 7714
Colabardini, Ana Cristina,Wang, Fang,Dong, Zhiqiang,et al. Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin[J]. Genetics, 2022, 220(1), iyab183.
APA Colabardini, Ana Cristina., Wang, Fang., Dong, Zhiqiang., Pardeshi, Lakhansing., Rocha, Marina Campos., Costa, Jonas Henrique., Dos Reis, Thaila Fernanda., Brown, Alec., Jaber, Qais Z.., Fridman, Micha., Fill, Taicia., Rokas, Antonis., Malavazi, Iran., Wong, Koon Ho., & Goldman, Gustavo Henrique (2022). Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin. Genetics, 220(1), iyab183.
MLA Colabardini, Ana Cristina,et al."Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin".Genetics 220.1(2022):iyab183.
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