eterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungi

Author(s):Show less -

Colabardini, Ana Cristina ^{[1, 2]} ; Wang, Fang ^[2] ; Dong, Zhiqiang ^[2] ; Pardeshi, Lakhansing ^{[2, 3]} ; Rocha, Marina Campos ^[4] ; Costa, Jonas Henrique ^[5] ; dos Reis, Thaila Fernanda ^[1] ; Brown, Alec ^[6] ; Jaber, Qais Z. ^[7] ; Fridman, Micha ^[7] ; Fill, Taicia ^[5] ; Rokas, Antonis ^[6] ; Malavazi, Iran ^[4] ; Wong, Koon Ho ^{[2, 8, 9]} ; Goldman, Gustavo Henrique ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Macau, Fac Hlth Sci, Macau 999078 - Peoples R China

^[3] Univ Macau, Fac Hlth Sci, Genom Bioinformat & Single Cell Anal Core, Macau 999078 - Peoples R China

^[4] Univ Fed Sao Carlos, Ctr Ciencias Biol & Saude, Dept Genet & Evoluc, BR-13565905 Sao Carlos - Brazil

^[5] Univ Estadual Campinas, Inst Quim, BR-13083970 Campinas - Brazil

^[6] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 - USA

^[7] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Chem, IL-6997801 Tel Aviv - Israel

^[8] Univ Macau, Fac Hlth Sci, Inst Translat Med, Macau 999078 - Peoples R China

^[9] Univ Macau, MoE Frontiers Sci Ctr Precis Oncol, Macau 999078 - Peoples R China

• Document type: Journal article
• Source: Genetics; v. 220, n. 1 JAN 2022.
• Web of Science Citations: 0

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 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. (AU)

• FAPESP's process: 18/00315-5 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
• Grantee: Marina Campos Rocha
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/07536-4 - Molecular Mechanisms Involved in Paradoxal Growth Induced by Caspofungin in Aspergillus fumigatus
• Grantee: Ana Cristina Colabardini
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/19694-3 - The role of heat shock proteins HsfA and Hsp90 and the regulator SmiA at cell wall integrity pathway activity in the opportunistic human pathogen Aspergillus fumigatus
• Grantee: Iran Malavazi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07870-9 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Research Projects - Thematic Grants