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

• Published in: PLoS pathogens Vol. 16; no. 7; p. e1008645
• Main Authors: Ries, Laure N. A., Pardeshi, Lakhansing, Dong, Zhiqiang, Tan, Kaeling, Steenwyk, Jacob L., Colabardini, Ana Cristina, Ferreira Filho, Jaire A., de Castro, Patricia A., Silva, Lilian P., Preite, Nycolas W., Almeida, Fausto, de Assis, Leandro J., dos Santos, Renato A. C., Bowyer, Paul, Bromley, Michael, Owens, Rebecca A., Doyle, Sean, Demasi, Marilene, Hernández, Diego C. R., Netto, Luís Eduardo S., Pupo, Monica T., Rokas, Antonis, Loures, Flavio V., Wong, Koon H., Goldman, Gustavo H.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2020; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Aspergillosis; Aspergillosis - metabolism; Aspergillosis - microbiology; Aspergillus; Aspergillus fumigatus; Aspergillus fumigatus - metabolism; Aspergillus fumigatus - pathogenicity; Bioinformatics; Biology; Biology and Life Sciences; Biosynthesis; Chemotherapy; Clusters; Cytokines; Defects; Enzymes; Fungal infections; Fungal Proteins - metabolism; Fungi; Gene expression; Gene Expression Regulation, Fungal - physiology; Genes; Genetic aspects; Genomics; Gliotoxin; Gliotoxin - biosynthesis; Granulocytes; Health aspects; Health sciences; Homology; Immune response; Immune system; Immunomodulation; Kinases; Medicine; Medicine and Health Sciences; Metabolites; Mice; Model testing; Neutrophils; Opportunist infection; Oxidation resistance; Oxidative stress; Oxidative Stress - physiology; Oxidoreductase; Pathogens; Pharmaceutical sciences; Phylogeny; Secondary metabolites; Transcription factors; Transcription Factors - metabolism; Virulence; Virulence - physiology; Brazil; United Kingdom > UK; United States > US; Ireland; China; Macao; Nashville Tennessee
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008645

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.