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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 \u0394crzACEA17 mutant, the \u0394crzAAf293 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.<\/jats:p>","DOI":"10.1093\/genetics\/iyab183","type":"journal-article","created":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T13:54:41Z","timestamp":1635688481000},"source":"Crossref","is-referenced-by-count":21,"title":["Heterogeneity in the transcriptional response of the human pathogen\n                    <i>Aspergillus fumigatus<\/i>\n                    to the antifungal agent caspofungin"],"prefix":"10.1093","volume":"220","author":[{"given":"Ana Cristina","family":"Colabardini","sequence":"first","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto , S\u00e3o Paulo CEP 14040-903, Brazil"},{"name":"Faculty of Health Sciences, University of Macau , Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau , Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Dong","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau , Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakhansing","family":"Pardeshi","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau , Macau 999078, China"},{"name":"Genomics, Bioinformatics and Single Cell Analysis Core, Faculty of Health Sciences, University of Macau , Macau, 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Campos","family":"Rocha","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica e Evolu\u00e7\u00e3o, Centro de Ci\u00eancias Biol\u00f3gicas e da Sa\u00fade, Universidade Federal de S\u00e3o Carlos, S\u00e3o Carlos CEP 13565-905, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas Henrique","family":"Costa","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Universidade Estadual de Campinas, Campinas , S\u00e3o Paulo CEP 13083-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7776-977X","authenticated-orcid":false,"given":"Thaila Fernanda","family":"dos Reis","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto , S\u00e3o Paulo CEP 14040-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University , Nashville, TN 37235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qais Z","family":"Jaber","sequence":"additional","affiliation":[{"name":"School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University , Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha","family":"Fridman","sequence":"additional","affiliation":[{"name":"School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University , Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taicia","family":"Fill","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Universidade Estadual de Campinas, Campinas , S\u00e3o Paulo CEP 13083-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7248-6551","authenticated-orcid":false,"given":"Antonis","family":"Rokas","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University , Nashville, TN 37235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iran","family":"Malavazi","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica e Evolu\u00e7\u00e3o, Centro de Ci\u00eancias Biol\u00f3gicas e da Sa\u00fade, Universidade Federal de S\u00e3o Carlos, S\u00e3o Carlos CEP 13565-905, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9264-5118","authenticated-orcid":false,"given":"Koon Ho","family":"Wong","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, University of Macau , Macau 999078, China"},{"name":"Faculty of Health Sciences, Institute of Translational Medicine, University of Macau , Macau 999078, China"},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macau , Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Henrique","family":"Goldman","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, Ribeir\u00e3o Preto , S\u00e3o Paulo CEP 14040-903, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"key":"2024042402104916500_iyab183-B1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.riam.2010.10.003","article-title":"What makes Aspergillus fumigatus a successful pathogen? 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