PLoS Pathogens (Jul 2020)

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 Hernández,
  • Luís Eduardo S Netto,
  • Monica T Pupo,
  • Antonis Rokas,
  • Flavio V Loures,
  • Koon H Wong,
  • Gustavo H Goldman

DOI
https://doi.org/10.1371/journal.ppat.1008645
Journal volume & issue
Vol. 16, no. 7
p. e1008645

Abstract

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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 self-protection. 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 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 Aspergillus species.