Aspergillus fumigatus Acetate Utilization Impacts Virulence Traits and Pathogenicity
| Autor: | Vishukumar Aimanianda, Jacob L. Steenwyk, Agostinho Carvalho, Cláudio Duarte-Oliveira, Laure Nicolas Annick Ries, Fernando Rodrigues, Fausto Almeida, Taicia Pacheco Fill, Antonis Rokas, Lilian Pereira Silva, Patrícia Alves de Castro, Iola F. Duarte, Sarah Sze Wah Wong, Jonas Henrique Costa, Gustavo H. Goldman, Clara Valero, Relber Aguiar Gonçales, Raquel Saborano, Gabriela F. Persinoti, Thaila Fernanda dos Reis |
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| Přispěvatelé: | Universidade de São Paulo = University of São Paulo (USP), University of Birmingham [Birmingham], Universidade de Aveiro, Centro Nacional de Pesquisa em Energia e Materiais = Brazilian Center for Research in Energy and Materials (CNPEM), Vanderbilt University [Nashville], Universidade Estadual de Campinas = University of Campinas (UNICAMP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universidade do Minho = University of Minho [Braga], Life and Health Sciences Research Institute [Braga] (ICVS), University of Minho [Braga], We thank Universidade do Minho, Portugal and Universidade do São Paulo, Brazil for providing support for the scientific collaboration (G.H.G. and A.C., Edital USP-UMinho 2019). We thank the São Paulo Research Foundation (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP], Brazil) grants 2017/14159-2 (L.N.A.R.), 2016/12948-7 (P.A.D.C.), 2017/08750-0 (T.F.D.R.), 2016/07870-9 (G.H.G.), 2018/00715-3 (C.V.), and the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) grants 301058/2019-9 and 404735/2018-5 (G.H.G.) for financial support. I.F.D. acknowledges CICECO-Aveiro Institute of Materials (UIDB/50011/2020 and UIDP/50011/2020) financed by national funds through the Foundation for Science and Technology/MCTES, and the National NMR Network (PTNMR) partially supported by Infrastructure Project 022161 (cofinanced by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). A.C., R.A.G., and C.D.-O. were supported by the Fundação para a Ciência e a Tecnologia (FCT) (PTDC/MED-GEN/28778/2017, UIDB/50026/2020, and UIDP/50026/2020). Additional support was provided by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023), the European Union’s Horizon 2020 research and innovation program under grant agreement 847507, and the 'la Caixa' Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003. Individual support was provided by FCT (SFRH/BD/141127/2018 to C.D.-O., and CEECIND/03628/2017 to A.C.). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 (J.H.C. scholarship). S.S.W.W. was supported by Pasteur-Roux-Cantarini fellowship. J.L.S. and A.R. are supported by the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program, A.R. is additionally supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (1R56AI146096-01A1)., European Project: 847507,H2020-SC1-2019-Two-Stage-RTD,HDM-FUN(2020) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Neutrophils Secondary Metabolism Acetates Moths MESH: Neutrophils MESH: Virulence Aspergillus fumigatus Mice Gene Expression Regulation Fungal MESH: Animals skin and connective tissue diseases transcription factor [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology 0303 health sciences Virulence biology secondary metabolites MESH: Moths QR1-502 MESH: Secondary Metabolism Phenotype Larva acetate assimilation MESH: Fungal Proteins MESH: Acetates MESH: Aspergillus fumigatus Acetate utilization MESH: Gene Expression Regulation Fungal Research Article MESH: Phenotype Microbiology Fungal Proteins 03 medical and health sciences MESH: Mice Inbred C57BL Virology Animals Aspergillosis Humans MESH: Aspergillosis Transcription factor MESH: Mice 030304 developmental biology Final version MESH: Humans 030306 microbiology biology.organism_classification Pathogenicity MESH: Male Mice Inbred C57BL cell wall MESH: Larva |
| Zdroj: | mBio mBio, 2021, 12 (4), pp.e0168221. ⟨10.1128/mBio.01682-21⟩ mBio, Vol 12, Iss 4 (2021) |
| ISSN: | 2161-2129 2150-7511 |
| DOI: | 10.1128/mBio.01682-21⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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