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

Mohammad H. Mirhakkak, Xiuqiang Chen, Yueqiong Ni, Thorsten Heinekamp, Tongta Sae-Ong, Lin-Lin Xu, Oliver Kurzai, Amelia E. Barber, Axel A. Brakhage, Sebastien Boutin, Sascha Schäuble () and Gianni Panagiotou ()
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Mohammad H. Mirhakkak: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Xiuqiang Chen: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Yueqiong Ni: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Thorsten Heinekamp: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Tongta Sae-Ong: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Lin-Lin Xu: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Oliver Kurzai: University of Würzburg
Amelia E. Barber: Friedrich-Schiller-University Jena
Axel A. Brakhage: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Sebastien Boutin: University of Lübeck
Sascha Schäuble: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Gianni Panagiotou: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39982-5

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