Genome-scale metabolic modeling of Aspergillus fumigatus strains reveals growth dependencies on the lung microbiome

Abstract

Aspergillus fumigatus, an opportunistic human pathogen, frequently infects the lungs of people with cystic fibrosis and is one of the most common causes of infectious-disease death in immunocompromised patients. Here, we construct 252 strain-specific, genome-scale metabolic models of this important fungal pathogen to study and better understand the metabolic component of its pathogenic versatility. The models show that 23.1% of A. fumigatus metabolic reactions are not conserved across strains and are mainly associated with amino acid, nucleotide, and nitrogen metabolism. Profiles of non-conserved reactions and growth-supporting reaction fluxes are sufficient to differentiate strains, for example by environmental or clinical origin. In addition, shotgun metagenomics analysis of sputum from 40 cystic fibrosis patients (15 females, 25 males) before and after diagnosis with an A. fumigatus colonization suggests that the fungus shapes the lung microbiome towards a more beneficial fungal growth environment associated with aromatic amino acid availability and the shikimate pathway. Our findings are starting points for the development of drugs or microbiome intervention strategies targeting fungal metabolic needs for survival and colonization in the non-native environment of the human lung.

Growth, morphology, and formation of cinnabarin in Pycnoporus cinnabarinus in relation to different irradiation spectra

“…2 , 3 ). For fungi, such strain-specific responses are widely found in literature, [ 44 – 46 ]. In addition, also the correlation between growth limitation, i.e., lower biomass formation, accompanied with increased levels of primary or secondary metabolite formation are frequently documented [ 47 – 49 ].…”

Know the enemy and know yourself: Addressing cryptic fungal pathogens of humans and beyond

“…Perturbations in the mycobiome, induced by antifungal treatments, can exacerbate allergic airway disease, indicating mycobiome imbalances contribute to disease severity [15]. Pathogens can also influence the mycobiome; for example, A. fumigatus colonization of the lung shifts microbiome composition to be more beneficial for fungal growth [16]. This and other findings suggest that targeting the mycobiome may have therapeutic potential.…”

“…Pathogens can also influence the mycobiome; for example, A . fumigatus colonization of the lung shifts microbiome composition to be more beneficial for fungal growth [ 16 ]. This and other findings suggest that targeting the mycobiome may have therapeutic potential.…”

“…For example, cryptic Aspergillus pathogens often go undetected because only genus-level identification is possible ( Table 1 ). Accurate species and strain-specific identification is particularly important due to genomic and phenotypic strain heterogeneity among clinically relevant traits of pathogenic microbes [ 4 , 9 , 16 ]. As a result, some dimensions of the microbiome go undetected, limiting our understanding of the relationship between the microbiome and the host.…”

Harnessing inter-kingdom metabolic disparities at the human-fungal interface for novel therapeutic approaches

“…Indeed, the commensal nature of C. albicans may turn into a pathogenic one when the mucosal homeostasis is compromised, as observed in the course of antibiotic and/or chemotherapeutic treatments, which alter the composition and function of the bacterial communities, the integrity of the epithelial lining, and the interaction with the host immune system ( Brock, 2009 ; Romani, 2011 ). Similarly, the environmental fungus Aspergillus fumigatus may cause respiratory infections in immunocompromised individuals, a process that requires not only an intrinsic metabolic adaptation to the host environment ( van de Veerdonk et al, 2017 ) but also a rewiring process of the metabolism in the lung microbiome to be favorable for its growth ( Mirhakkak et al, 2023 ).…”