Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans

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Bastos, Rafael Wesley ^[1] ; Valero, Clara ^[1] ; Silva, Lilian Pereira ^[1] ; Schoen, Taylor ^{[2, 3]} ; Drott, Milton ^[2] ; Brauer, Veronica ^[4] ; Silva-Rocha, Rafael ^[4] ; Lind, Abigail ^[5] ; Steenwyk, Jacob L. ^[6] ; Rokas, Antonis ^{[6, 5]} ; Rodrigues, Fernando ^{[7, 8]} ; Resendiz-Sharpe, Agustin ^[9] ; Lagrou, Katrien ^{[9, 10]} ; Marcet-Houben, Marina ^{[11, 12, 13]} ; Gabaldon, Toni ^{[14, 11, 12, 13]} ; McDonnell, Erin ^[15] ; Reid, Ian ^[15] ; Tsang, Adrian ^[15] ; Oakley, Berl R. ^[16] ; Loures, Flavio Vieira ^[17] ; Almeida, Fausto ^[4] ; Huttenlocher, Anna ^{[2, 3]} ; Keller, Nancy P. ^[2] ; Annick Ries, Laure Nicolas ^[4] ; Goldman, Gustavo H. ^[1]

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^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto - Brazil

^[2] Univ Wisconsin, Dept Med Microbiol & Immunol, Madison, WI 53706 - USA

^[3] Univ Wisconsin, Dept Pediat, Madison, WI - USA

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Ribeirao Preto - Brazil

^[5] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 - USA

^[6] Vanderbilt Univ, Sch Med, Dept Biol Sci, Nashville, TN 37212 - USA

^[7] Univ Minho, Sch Med, Life & Hlth Sci Res Inst, Braga - Portugal

^[8] Life & Hlth Sci Res Inst, 3Bs Associate Lab, Guimaraes - Portugal

^[9] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Lab Clin Bacteriol & Mycol, Leuven - Belgium

^[10] Univ Hosp Leuven, Natl Reference Ctr Mycosis, Leuven - Belgium

^[11] Ctr Genom Regulat, Barcelona - Spain

^[12] Barcelona Supercomp Ctr, Life Sci Program, Barcelona - Spain

^[13] Inst Res Biomed, Mech Dis Program, Barcelona - Spain

^[14] ICREA, Barcelona - Spain

^[15] Concordia Univ, Ctr Struct & Funct Genom, Montreal, PQ - Canada

^[16] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 - USA

^[17] Univ Fed Sao Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MSPHERE; v. 5, n. 2 MAR-APR 2020.
• Citações Web of Science: 1

Resumo

Aspergillus nidulans is an opportunistic fungal pathogen in patients with immunodeficiency, and virulence of A. nidulans isolates has mainly been studied in the context of chronic granulomatous disease (CGD), with characterization of clinical isolates obtained from non-CGD patients remaining elusive. This study therefore carried out a detailed biological characterization of two A. nidulans clinical isolates (CIs), obtained from a patient with breast carcinoma and pneumonia and from a patient with cystic fibrosis that underwent lung transplantation, and compared them to the reference, nonclinical FGSC A4 strain. Both CIs presented increased growth in comparison to that of the reference strain in the presence of physiologically relevant carbon sources. Metabolomic analyses showed that the three strains are metabolically very different from each other in these carbon sources. Furthermore, the CIs were highly susceptible to cell wall-perturbing agents but not to other physiologically relevant stresses. Genome analyses identified several frameshift variants in genes encoding cell wall integrity (CWI) signaling components. Significant differences in CWI signaling were confirmed by Western blotting among the three strains. In vivo virulence studies using several different models revealed that strain MO80069 had significantly higher virulence in hosts with impaired neutrophil function than the other strains. In summary, this study presents detailed biological characterization of two A. nidulans sensu stricto clinical isolates. Just as in Aspergillus fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits. Further studies are required to fully characterize A. nidulans strain-specific virulence traits and pathogenicity. IMPORTANCE Immunocompromised patients are susceptible to infections with opportunistic filamentous fungi from the genus Aspergillus. Although A. fumigatus is the main etiological agent of Aspergillus species-related infections, other species, such as A. nidulans, are prevalent in a condition-specific manner. A. nidulans is a predominant infective agent in patients suffering from chronic granulomatous disease (CGD). A. nidulans isolates have mainly been studied in the context of CGD although infection with A. nidulans also occurs in non-CGD patients. This study carried out a detailed biological characterization of two non-CGD A. nidulans clinical isolates and compared the results to those with a reference strain. Phenotypic, metabolomic, and genomic analyses highlight fundamental differences in carbon source utilization, stress responses, and maintenance of cell wall integrity among the strains. One clinical strain had increased virulence in models with impaired neutrophil function. Just as in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits. (AU)

• Processo FAPESP: 18/14762-3 - Imunossupressão na paracoccidioidomicose: função reguladora das células supressoras derivadas da linhagem mieloide (MDSC) na imunidade do hospedeiro, na patologia tecidual e adaptação genética das células fúngicas
• Beneficiário: Flávio Vieira Loures
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores - Fase 2
• Processo FAPESP: 17/14159-2 - O papel do metabolismo da lactose e do acetato na virulência de Aspergillus fumigatus
• Beneficiário: Laure Nicolas Annick Ries
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
• 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
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/19821-5 - Caracterização molecular, fenotípica e da resposta imune de isolados clínicos de Aspergillus nidulans
• Beneficiário: Rafael Wesley Bastos
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/00631-7 - Caracterização da virulência e da resposta imune de isolados clínicos de Aspergillus nidulans em modelo de infecção em zebrafish
• Beneficiário: Rafael Wesley Bastos
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado