Functional characterization of clinical isolates of the opportunistic fungal pathogenAspergillus nidulans
Authors: Bastos Rafael Wesley , Valero Clara , Silva Lilian Pereira , Schoen Taylor , Drott Milton , Brauer Verônica , Silva-Rocha Rafael , Lind Abigail , Steenwyk Jacob L. , Rokas Antonis , Rodrigues Fernando , Resendiz-Sharpe Agustin , Lagrou Katrien , Marcet-Houben Marina , Gabaldón Toni , McDonnell Erin , Reid Ian , Tsang Adrian , Oakley Berl R. , Loures Flávia Vieira , Almeida Fausto , Huttenlocher Anna , Keller Nancy P. , Annick Ries Laure Nicolas , Goldmana Gustavo H. 
Published: January 2020

Aspergillus nidulansis an opportunistic fungal pathogen in patients with immunodeficiency and virulence ofA. nidulansisolates has mainly been studied in the context of the 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 twoA. nidulansclinical 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, non-clinical A4 strain. Both CIs presented increased growth in comparison to 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 frame-shift variants in genes encoding cell wall integrity (CWI) signalling components. Significant differences in CWI signalling were confirmed by western blotting among the three strains.In vivovirulence studies using several different models revealed that strain MO80069 had significantly higher virulence in hosts with impaired neutrophil function when compared to the other strains. In summary, this study presents detailed biological characterization of twoA. nidulans sensu strictoclinical isolates. Just like inA. fumigatus,strain heterogeneity exists inA. nidulansclinical strains that can define virulence traits. Further studies are required to fully characterizeA. nidulansstrain-specific virulence traits and pathogenicity.

Importance

Immunocompromised patients are susceptible to infections with opportunistic filamentous fungi from the genusAspergillus.AlthoughA. fumigatusis the main etiological agent ofAspergillusspp.-related infections, other species, such asA. nidulansare prevalent in a condition-specific manner.A. nidulansis a predominant infective agent in patients suffering from chronic granulomatous disease (CGD).A. nidulansisolates have mainly been studied in the context of CGD, although infection withA. nidulansalso occurs in non-CGD patients. This study carried out a detailed biological characterization of two non-CGDA. nidulansclinical isolates and compared it to 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 inA. fumigatus,strain heterogeneity exists inA. nidulansclinical strains that can define virulence traits.