Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen <named-content content-type="genus-species">Aspergillus nidulans</named-content>
Rafael Wesley Bastos,
Clara Valero,
Lilian Pereira Silva,
Taylor Schoen,
Milton Drott,
Verônica Brauer,
Rafael Silva-Rocha,
Abigail Lind,
Jacob L. Steenwyk,
Antonis Rokas,
Fernando Rodrigues,
Agustin Resendiz-Sharpe,
Katrien Lagrou,
Marina Marcet-Houben,
Toni Gabaldón,
Erin McDonnell,
Ian Reid,
Adrian Tsang,
Berl R. Oakley,
Flávio Vieira Loures,
Fausto Almeida,
Anna Huttenlocher,
Nancy P. Keller,
Laure Nicolas Annick Ries,
Gustavo H. Goldman
Affiliations
Rafael Wesley Bastos
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Clara Valero
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Lilian Pereira Silva
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Taylor Schoen
Department of Medical Microbiology and Immunology, University of Wisconsin—Madison, Madison, Wisconsin, USA
Milton Drott
Department of Medical Microbiology and Immunology, University of Wisconsin—Madison, Madison, Wisconsin, USA
Verônica Brauer
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Rafael Silva-Rocha
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Abigail Lind
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Jacob L. Steenwyk
Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Antonis Rokas
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Fernando Rodrigues
Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
Agustin Resendiz-Sharpe
Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
Katrien Lagrou
Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
Marina Marcet-Houben
Centre for Genomic Regulation, Barcelona, Spain
Toni Gabaldón
Centre for Genomic Regulation, Barcelona, Spain
Erin McDonnell
Centre for Structural and Functional Genomics, Concordia University, Montreal, Quebec, Canada
Ian Reid
Centre for Structural and Functional Genomics, Concordia University, Montreal, Quebec, Canada
Adrian Tsang
Centre for Structural and Functional Genomics, Concordia University, Montreal, Quebec, Canada
Berl R. Oakley
Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA
Flávio Vieira Loures
Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, Brazil
Fausto Almeida
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Anna Huttenlocher
Department of Medical Microbiology and Immunology, University of Wisconsin—Madison, Madison, Wisconsin, USA
Nancy P. Keller
Department of Medical Microbiology and Immunology, University of Wisconsin—Madison, Madison, Wisconsin, USA
Laure Nicolas Annick Ries
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
Gustavo H. Goldman
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
ABSTRACT 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.