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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence

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Author(s):
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Ries, Laure N. A. [1] ; Pardeshi, Lakhansing [2, 3] ; Dong, Zhicliang [3] ; Tan, Kaeling [2, 3, 4] ; Steenwyk, Jacob L. [5] ; Colabardini, Ana Cristina [6] ; Ferreira Filho, Jaire A. [6] ; de Castro, Patricia A. [6] ; Silva, Lilian P. [6] ; Preite, Nycolas W. [7] ; Almeida, Fausto [1] ; de Assis, Leandro J. [6] ; dos Santos, Renato A. C. [6] ; Bowyer, Paul [8] ; Bromley, Michael [8] ; Owens, Rebecca A. [9] ; Doyle, Sean [9] ; Demasi, Marilene [10] ; Hernandez, Diego C. R. [6] ; Netto, Luis Eduardo S. [11] ; Pupo, Monica T. [6] ; Rokas, Antonis [5] ; Loures, V, Flavio ; Wong, Koon H. [2, 12] ; Goldman, Gustavo H. [6]
Total Authors: 25
Affiliation:
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[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Ribeirao Preto - Brazil
[2] Univ Macau, Genom & Bioinformat Core, Fac Hlth Sci, Taipa, Macao - Peoples R China
[3] Univ Macau, Fac Hlth Sci, Taipa, Macao - Peoples R China
[4] Univ Macau, Ctr Precis Med & Res & Training, Taipa, Macao - Peoples R China
[5] Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 - USA
[6] Univ Sao Paulo, Fac Pharmaceut Sci, Ribeirao Preto - Brazil
[7] V, Univ Sao Paulo, Inst Sci & Technol Fed, Sao Jose Dos Campos, SP - Brazil
[8] Univ Manchester, Fac Biol Med & Hlth, Manchester Fungal Infect Grp, Div Infect Immun & Resp Med, Sch Biol Sci, Manchester, Lancs - England
[9] Maynooth Univ, Dept Biol, Maynooth, Kildare - Ireland
[10] Inst Butantan, Lab Biochem & Biophys, Sao Paulo - Brazil
[11] Univ Sao Paulo, Inst Biosci, Sao Paulo - Brazil
[12] Univ Macau, Inst Translat Med, Taipa, Macao - Peoples R China
Total Affiliations: 12
Document type: Journal article
Source: PLOS PATHOGENS; v. 16, n. 7 JUL 2020.
Web of Science Citations: 0
Abstract

Aspergillus fumigatusis an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), which contribute to enhancing fungal fitness and growth within the mammalian host. Gliotoxin (GT) is a SM that interferes with the function and recruitment of innate immune cells, which are essential for eliminatingA.fumigatusduring invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important forA.fumigatusoxidative stress resistance, GT biosynthesis and self-protection. RglT regulates the expression of severalgligenes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding genegliT, by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important for virulence in a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA). Homologues of RglT and GliT are present in eurotiomycete and sordariomycete fungi, including the non-GT-producing fungus A.nidulans, where a conservation of function was described. Phylogenetically informed model testing led to an evolutionary scenario in which the GliT-based resistance mechanism is ancestral and RglT-mediated regulation of GliT occurred subsequently. In conclusion, this work describes the function of a previously uncharacterised TF in oxidative stress resistance, GT biosynthesis and self-protection in both GT-producing and non-producing Aspergillusspecies. Author summary A.fumigatusis a prevalent opportunistic fungal pathogen that causes a wide range of diseases, in both immunocompetent and immunocompromised subjects. Contributing toA.fumigatusvirulence, is thein vivosecretion of gliotoxin, a mycotoxin with both immunosuppressive and immunomodulatory properties. Regulation of the gliotoxin-encoding biosynthetic gene cluster has proven to be a multifactorial and hierarchical process. In this work, we identify a transcription factor, named RglT (regulator of gliotoxin), that is crucial for gliotoxin biosynthesis and self-protection, a process that mainly occurs through the direct regulation of the oxidoreductase-encoding genegliT. The absence ofrglTresulted in a strain that was highly sensitive to oxidative stress, to exogenous gliotoxin and hypovirulent in a chemotherapeutic murine model of IPA. Furthermore, we show that homologues of both RglT and GliT co-exist within the class of eurotiomycetes and appear to be functionally conserved in non gliotoxin-producing fungal species. Our study therefore highlights the importance of mycotoxin self-protection in pathogenic and non-pathogenic fungal species with consequences for fungal virulence and survival. (AU)

FAPESP's process: 17/14159-2 - The role of lactose and acetate metabolism in Aspergillus fumigatus virulence
Grantee:Laure Nicolas Annick Ries
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 17/21983-3 - Genomic analysis of Aspergillus cryptic species
Grantee:Renato Augusto Corrêa dos Santos
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 18/25217-6 - Organization and integration of large scale data to study the dynamics of expression of map kinases of the fungus Aspergillus fumigatus in diverse genetic and environmental conditions
Grantee:Jaire Alves Ferreira Filho
Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
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: 17/01188-4 - Relationship of the protozoan Crithidia spp with bacterioma associated with the stingless bee Melipona scutellaris: chemical, ecological and pharmacological studies
Grantee:Diego Carlos Rodriguez Hernandez
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/50954-0 - Novel therapeutic agents from the bacterial symbionts of Brazilian invertebrates
Grantee:Mônica Tallarico Pupo
Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
FAPESP's process: 14/00789-6 - Functional characterization of Aspergillus nidulans phosphatases involved on glucose metabolism
Grantee:Leandro Jose de Assis
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
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
FAPESP's process: 19/09278-8 - The role of Myeloid-Derived Suppressor Cells (MDSCs) in Murine Paracoccidioidomycosis
Grantee:Nycolas Willian Preite
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 16/03322-7 - Role of galectin-3 in the Cryptococcus neoformans infection
Grantee:Fausto Bruno dos Reis Almeida
Support Opportunities: Research Grants - Young Investigators Grants