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

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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]

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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

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 16, n. 7 JUL 2020.
• Citações Web of Science: 0

Resumo

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)

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