A host-pathogen metabolic synchrony that facilitates disease tolerance
Abstract Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, whi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59134-1 |
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| author | Ying-Tsun Chen Gaurav Kumar Lohia Samantha Chen Zihua Liu Tania Wong Fok Lung Chu Wang Sebastián A. Riquelme |
| author_facet | Ying-Tsun Chen Gaurav Kumar Lohia Samantha Chen Zihua Liu Tania Wong Fok Lung Chu Wang Sebastián A. Riquelme |
| author_sort | Ying-Tsun Chen |
| collection | DOAJ |
| description | Abstract Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production—particularly alginate—which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance. |
| format | Article |
| id | doaj-art-8fcf6af5b1d44faf8c97bd03dc93005b |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8fcf6af5b1d44faf8c97bd03dc93005b2025-08-20T02:17:52ZengNature PortfolioNature Communications2041-17232025-04-0116111710.1038/s41467-025-59134-1A host-pathogen metabolic synchrony that facilitates disease toleranceYing-Tsun Chen0Gaurav Kumar Lohia1Samantha Chen2Zihua Liu3Tania Wong Fok Lung4Chu Wang5Sebastián A. Riquelme6Department of Pediatrics, Columbia UniversityDepartment of Pediatrics, Columbia UniversityDepartment of Pediatrics, Columbia UniversitySynthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking UniversityDepartment of Pediatrics, Columbia UniversitySynthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking UniversityDepartment of Pediatrics, Columbia UniversityAbstract Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production—particularly alginate—which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.https://doi.org/10.1038/s41467-025-59134-1 |
| spellingShingle | Ying-Tsun Chen Gaurav Kumar Lohia Samantha Chen Zihua Liu Tania Wong Fok Lung Chu Wang Sebastián A. Riquelme A host-pathogen metabolic synchrony that facilitates disease tolerance Nature Communications |
| title | A host-pathogen metabolic synchrony that facilitates disease tolerance |
| title_full | A host-pathogen metabolic synchrony that facilitates disease tolerance |
| title_fullStr | A host-pathogen metabolic synchrony that facilitates disease tolerance |
| title_full_unstemmed | A host-pathogen metabolic synchrony that facilitates disease tolerance |
| title_short | A host-pathogen metabolic synchrony that facilitates disease tolerance |
| title_sort | host pathogen metabolic synchrony that facilitates disease tolerance |
| url | https://doi.org/10.1038/s41467-025-59134-1 |
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