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

Laure N A Ries; Lakhansing Pardeshi; Zhiqiang Dong; Kaeling Tan; Jacob L Steenwyk; Ana Cristina Colabardini; Jaire A  Ferreira Filho; Patricia A de Castro; Lilian P Silva; Nycolas W Preite; Fausto  Almeida; Leandro J de Assis; Renato A C dos Santos; Paul Bowyer; Michael Bromley; Rebecca A Owens; Sean  Doyle; Marilene Demasi; Diego C R  Hemandez; Luis Eduardo S Netto; Monica T  Pupo; Antonis Rokas; Flavio V Loures; Koon H Wong; Gustavo H Goldman

doi:10.1371/journal.ppat.1008645

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

Laure N A Ries, Lakhansing Pardeshi, Zhiqiang Dong, Kaeling Tan, Jacob L Steenwyk, Ana Cristina Colabardini, Jaire A Ferreira Filho, Patricia A de Castro, Lilian P Silva, Nycolas W Preite, Fausto Almeida, Leandro J de Assis, Renato A C dos Santos, Paul Bowyer, Michael Bromley, Rebecca A Owens, Sean Doyle, Marilene Demasi, Diego C R Hemandez, Luis Eduardo S NettoMonica T Pupo, Antonis Rokas, Flavio V Loures, Koon H Wong, Gustavo H Goldman

Division of Immunology, Immunity to Infection and Respiratory Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Aspergillus fumigatus is 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 eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and selfprotection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT , 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 RglTmediated 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 Aspergillus
species.

Original language	English
Journal	PL o S Pathogens
Early online date	15 Jul 2020
DOIs	https://doi.org/10.1371/journal.ppat.1008645
Publication status	E-pub ahead of print - 15 Jul 2020

Keywords

Aspergillus fumigatus
gliotoxin
virulence
neutropenic model
oxidative stress

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10.1371/journal.ppat.1008645

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Ries, L. N. A., Pardeshi, L., Dong, Z., Tan, K., Steenwyk, J. L., Colabardini, A. C., Ferreira Filho, J. A., Castro, P. A. D., Silva, L. P., Preite, N. W., Almeida, F., Assis, L. J. D., Santos, R. A. C. D., Bowyer, P., Bromley, M., Owens, R. A., Doyle, S., Demasi, M., Hemandez, D. C. R., ... Goldman, G. H. (2020). The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence. PL o S Pathogens. Advance online publication. https://doi.org/10.1371/journal.ppat.1008645

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

abstract = "Aspergillus fumigatus is an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), whichcontribute 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 eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and selfprotection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT , by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important forvirulence 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 RglTmediated 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.",

keywords = "Aspergillus fumigatus, gliotoxin, virulence, neutropenic model, oxidative stress",

author = "Ries, {Laure N A} and Lakhansing Pardeshi and Zhiqiang Dong and Kaeling Tan and Steenwyk, {Jacob L} and Colabardini, {Ana Cristina} and {Ferreira Filho}, {Jaire A} and Castro, {Patricia A de} and Silva, {Lilian P} and Preite, {Nycolas W} and Fausto Almeida and Assis, {Leandro J de} and Santos, {Renato A C dos} and Paul Bowyer and Michael Bromley and Owens, {Rebecca A} and Sean Doyle and Marilene Demasi and Hemandez, {Diego C R} and Netto, {Luis Eduardo S} and Pupo, {Monica T} and Antonis Rokas and Loures, {Flavio V} and Wong, {Koon H} and Goldman, {Gustavo H}",

year = "2020",

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doi = "10.1371/journal.ppat.1008645",

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Ries, LNA, Pardeshi, L, Dong, Z, Tan, K, Steenwyk, JL, Colabardini, AC, Ferreira Filho, JA, Castro, PAD, Silva, LP, Preite, NW, Almeida, F, Assis, LJD, Santos, RACD, Bowyer, P , Bromley, M, Owens, RA, Doyle, S, Demasi, M, Hemandez, DCR, Netto, LES, Pupo, MT, Rokas, A, Loures, FV, Wong, KH & Goldman, GH 2020, 'The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence', PL o S Pathogens. https://doi.org/10.1371/journal.ppat.1008645

TY - JOUR

T1 - The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence

AU - Ries, Laure N A

AU - Pardeshi, Lakhansing

AU - Dong, Zhiqiang

AU - Tan, Kaeling

AU - Steenwyk, Jacob L

AU - Colabardini, Ana Cristina

AU - Ferreira Filho, Jaire A

AU - Castro, Patricia A de

AU - Silva, Lilian P

AU - Preite, Nycolas W

AU - Almeida, Fausto

AU - Assis, Leandro J de

AU - Santos, Renato A C dos

AU - Bowyer, Paul

AU - Bromley, Michael

AU - Owens, Rebecca A

AU - Doyle, Sean

AU - Demasi, Marilene

AU - Hemandez, Diego C R

AU - Netto, Luis Eduardo S

AU - Pupo, Monica T

AU - Rokas, Antonis

AU - Loures, Flavio V

AU - Wong, Koon H

AU - Goldman, Gustavo H

PY - 2020/7/15

Y1 - 2020/7/15

N2 - Aspergillus fumigatus is an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), whichcontribute 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 eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and selfprotection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT , by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important forvirulence 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 RglTmediated 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.

AB - Aspergillus fumigatus is an opportunistic fungal pathogen that secretes an array of immune-modulatory molecules, including secondary metabolites (SMs), whichcontribute 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 eliminating A. fumigatus during invasive infections. We identified a C6 Zn cluster-type transcription factor (TF), subsequently named RglT, important for A. fumigatus oxidative stress resistance, GT biosynthesis and selfprotection. RglT regulates the expression of several gli genes of the GT biosynthetic gene cluster, including the oxidoreductase-encoding gene gliT , by directly binding to their respective promoter regions. Subsequently, RglT was shown to be important forvirulence 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 RglTmediated 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.

KW - Aspergillus fumigatus

KW - gliotoxin

KW - virulence

KW - neutropenic model

KW - oxidative stress

U2 - 10.1371/journal.ppat.1008645

DO - 10.1371/journal.ppat.1008645

M3 - Article

SN - 1553-7374

JO - PL o S Pathogens

JF - PL o S Pathogens

ER -

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

Abstract

Keywords

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