spergillus fumigatus Acetate Utilization Impacts Virulence Traits and Pathogenicit

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Annick Ries, Laure Nicolas ^{[1, 2]} ; de Castro, Patricia Alves ^[3] ; Silva, Lilian Pereira ^[3] ; Valero, Clara ^[3] ; dos Reis, Thaila Fernanda ^[3] ; Saborano, Raquel ^[4] ; Duarte, Iola F. ^[5] ; Persinoti, Gabriela Felix ^[6] ; Steenwyk, Jacob L. ^[7] ; Rokas, Antonis ^[7] ; Almeida, Fausto ^[1] ; Costa, Jonas Henrique ^[8] ; Fill, Taicia ^[8] ; Wong, Sarah Sze Wah ^[9] ; Aimanianda, Vishukumar ^[9] ; Santos Rodrigues, Fernando Jose ^{[10, 11]} ; Goncales, Relber A. ^{[10, 11]} ; Duarte-Oliveira, Claudio ^{[10, 11]} ; Carvalho, Agostinho ^{[10, 11]} ; Goldman, Gustavo H. ^[3]

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^[1] Univ Sao Paulo, Dept Bioquim & Imunol, Fac Med Ribeirao Preto, Sao Paulo - Brazil

^[2] Univ Exeter, MRC Ctr Med Mycol, Exeter, Devon - England

^[3] Univ Sao Paulo, Dept Ciencias Farmaceut, Fac Ciencias Farmaceut Ribeirao Preto, Sao Paulo - Brazil

^[4] Univ Birmingham, Inst Canc & Genom Sci, Birmingham - England

^[5] Univ Aveiro, CICECO Aveiro Inst Mat, Dept Chem, Aveiro - Portugal

^[6] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biorenewables Natl Lab LNBR, Campinas - Brazil

^[7] Vanderbilt Univ, Dept Biol Sci, 221 Kirkland Hall, Nashville, TN 37235 - USA

^[8] Univ Estadual Campinas, Dept Quim Organ, Inst Quim, Campinas, SP - Brazil

^[9] CNRS, Inst Pasteur, Mol Mycol Unit, UMR2000, Paris - France

^[10] ICVS 3Bs PT Govt Associate Lab, Braga - Portugal

^[11] Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Med, Braga - Portugal

• Tipo de documento: Artigo Científico
• Fonte: MBIO; v. 12, n. 4 JUL-AUG 2021.
• Citações Web of Science: 1

Resumo

Aspergillus fumigatus is a major opportunistic fungal pathogen of immunocompromised and immunocompetent hosts. To successfully establish an infection, A. fumigatus needs to use host carbon sources, such as acetate, present in the body fluids and peripheral tissues. However, utilization of acetate as a carbon source by fungi in the context of infection has not been investigated. This work shows that acetate is metabolized via different pathways in A. fumigatus and that acetate utilization is under the regulatory control of a transcription factor (TF), FacB. A. fumigatus acetate utilization is subject to carbon catabolite repression (CCR), although this is only partially dependent on the TF and main regulator of CCR CreA. The available extracellular carbon source, in this case glucose and acetate, significantly affected A. fumigatus virulence traits such as secondary metabolite secretion and cell wall composition, with the latter having consequences for resistance to oxidative stress, antifungal drugs, and human neutrophil-mediated killing. Furthermore, deletion of facB significantly impaired the in vivo virulence of A. fumigatus in both insect and mammalian models of invasive aspergillosis. This is the first report on acetate utilization in A. fumigatus, and this work further highlights the importance of available host-specific carbon sources in shaping fungal virulence traits and subsequent disease outcome, and a potential target for the development of antifungal strategies. IMPORTANCE Aspergillus fumigatus is an opportunistic fungal pathogen in humans. During infection, A. fumigatus is predicted to use host carbon sources, such as acetate, present in body fluids and peripheral tissues, to sustain growth and promote colonization and invasion. This work shows that A. fumigatus metabolizes acetate via different pathways, a process that is dependent on the transcription factor FacB. Furthermore, the type and concentration of the extracellular available carbon source were determined to shape A. fumigatus virulence determinants such as secondary metabolite secretion and cell wall composition. Subsequently, interactions with immune cells are altered in a carbon source-specific manner. FacB is required for A. fumigatus in vivo virulence in both insect and mammalian models of invasive aspergillosis. This is the first report that characterizes acetate utilization in A. fumigatus and highlights the importance of available host-specific carbon sources in shaping virulence traits and potentially subsequent disease outcome. (AU)

• Processo FAPESP: 16/07870-9 - A influência de proteínas quinases ativadas por mitógenos (MAPK) na expressão de determinantes genéticos importantes para a virulência de Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/14159-2 - O papel do metabolismo da lactose e do acetato na virulência de Aspergillus fumigatus
• Beneficiário: Laure Nicolas Annick Ries
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 17/08750-0 - Desenvolvimento de um antifúngico natural, obtido a partir de um óleo essencial, para aumentar a conservação de alimentos "in natura"
• Beneficiário: Thaila Fernanda dos Reis
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa Inovativa em Pequenas Empresas - PIPE
• Processo FAPESP: 16/12948-7 - O papel da proteína quinase ativada por mitógenos (MPKA) MpkA na regulação da produção da gliotoxina em Aspergillus fumigatus.
• Beneficiário: Patrícia Alves de Castro Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/00715-3 - Caracterização molecular de fatores de transcrição envolvidos no metabolismo de cálcio em Aspergillus fumigatus.
• Beneficiário: Clara Isabel Valero Fernández
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado