Abstract
Acquisition and subsequent metabolism of different carbon and nitrogen sources have been shown to play an important role in virulence attributes of the fungal pathogen Aspergillus fumigatus, such as the secretion of host tissue-damaging proteases and fungal cell wall integrity. We examined the relationship between the metabolic processes of carbon catabolite repression (CCR), nitrogen catabolite repression (NCR) and virulence in a variety of A. fumigatus clinical isolates. A considerable amount of heterogeneity with respect to the degree of CCR and NCR was observed and a positive correlation between NCR and virulence in a neutropenic mouse model of pulmonary aspergillosis (PA) was found. Isolate Afs35 was selected for further analysis and compared to the reference strain A1163, with both strains presenting the same degree of virulence in a neutropenic mouse model of PA. Afs35 metabolome analysis in physiological-relevant carbon sources indicated an accumulation of intracellular sugars that also serve as cell wall polysaccharide precursors. Genome analysis showed an accumulation of missense substitutions in the regulator of protease secretion and in genes encoding enzymes required for cell wall sugar metabolism. Based on these results, the virulence of strains Afs35 and A1163 was assessed in a triamcinolone murine model of PA and found to be significantly different, confirming the known importance of using different mouse models to assess strain-specific pathogenicity. These results highlight the importance of nitrogen metabolism for virulence and provide a detailed example of the heterogeneity that exists between A. fumigatus isolates with consequences for virulence in a strain-specific and host-dependent manner.
Highlights
Opportunistic fungal infections have become a major concern for global population health, as they are predicted to lead to more deaths annually than malaria and tuberculosis (Denning and Bromley, 2015)
To determine whether a potential correlation exists between carbon or nitrogen catabolite repression (CCR and NCR) and virulence in A. fumigatus, a phenotypic characterization of 13 clinically isolated strains (Table 1), as well as of the reference strain A1163/CEA10 was first carried out
Both 2DG and allyl alcohol (AA) are reporters of defects in carbon catabolite repression (CCR), with 2DG not being metabolized after the second step in glycolysis, whereas AA is converted to acrolein by alcohol dehydrogenase (ADH), whose transcriptional expression is under the control of CCR (Felenbok et al, 2001)
Summary
Opportunistic fungal infections have become a major concern for global population health, as they are predicted to lead to more deaths annually than malaria and tuberculosis (Denning and Bromley, 2015). The importance of carbon and nitrogen utilization during infection is largely based on transcriptional studies where A. fumigatus has been exposed to immune cells in vitro (Sugui et al, 2008) or on studies where genes encoding enzymes of central carbon and nitrogen metabolism have been deleted, resulting in strains with attenuated virulence in a murine model of invasive aspergillosis [for extensive reviews please refer to Krappmann and Braus (2005), Rhodes (2006), Willger et al (2009), Beattie et al (2017), and Ries et al (2018a)]. Carbon and nitrogen primary metabolic features are important for A. fumigatus pathogenesis, as was shown recently for the transcriptional mediator of carbon catabolite repression (CCR) CreA, that is required for growth and disease progression in a murine model of invasive pulmonary aspergillosis (IPA) (Beattie et al, 2017). Nitrogen catabolite repression (NCR) favors the utilization of ammonium and glutamine because they are assimilated and can readily be used for protein synthesis (Wong et al, 2008)
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