1 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
2 Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
3 Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
4 Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
5 Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
6 Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
7 Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.
8 Life and Health Sciences Research Institute/3B's Associate Laboratory, Guimarães, Portugal.
9 Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
10 National Reference Center for Mycosis, University Hospitals Leuven, Leuven, Belgium.
11 Centre for Genomic Regulation, Barcelona, Spain.
12 Life Sciences Program, Barcelona Supercomputing Centre, Barcelona, Spain.
13 Mechanisms of Disease Program, Institute for Research in Biomedicine, Barcelona, Spain.
14 ICREA, Barcelona, Spain.
15 Centre for Structural and Functional Genomics, Concordia University, Montreal, Quebec, Canada.
16 Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA.
17 Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, Brazil.
18 Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil rieslaure13@gmail.com ggoldman@usp.br.
19 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil rieslaure13@gmail.com ggoldman@usp.br.

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

mSphere. 2020 Apr 08;5(2):

Authors: Bastos RW, Valero C, Silva LP, Schoen T, Drott M, Brauer V, Silva-Rocha R, Lind A, Steenwyk JL, Rokas A, Rodrigues F, Resendiz-Sharpe A, Lagrou K, Marcet-Houben M, Gabaldón T, McDonnell E, Reid I, Tsang A, Oakley BR, Loures FV, Almeida F, Huttenlocher A, Keller NP, Ries LNA, Goldman GH

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.

PMID: 32269156 [PubMed - in process]