Staphylococcus aureus adapts to exploit collagen-derived proline during chronic infection
Staphylococcus aureus is a pulmonary pathogen associated with substantial human morbidity and mortality. As vaccines targeting virulence determinants have failed to be protective in humans, other factors are likely involved in pathogenesis. Here we analysed transcriptomic responses of human clinical isolates of S. aureus from initial and chronic infections. We observed upregulated collagenase and proline transporter gene expression in chronic infection isolates. Metabolomics of bronchiolar lavage fluid and fibroblast infection, growth assays and analysis of bacterial mutant strains showed that airway fibroblasts produce collagen during S. aureus infection. Host-adapted bacteria upregulate collagenase, which degrades collagen and releases proline. S. aureus then imports proline, which fuels oxidative metabolism via the tricarboxylic acid cycle. Proline metabolism provides host-adapted S. aureus with a metabolic benefit enabling out-competition of non-adapted strains. These data suggest that clinical settings characterized by airway repair processes and fibrosis provide a milieu that promotes S. aureus adaptation and supports infection.
Authors
- Benjamin P. Howden (ORCID: https://orcid.org/0000-0003-0237-1473)
- Ian R. Monk (ORCID: https://orcid.org/0000-0001-6982-8074)
- Swikrity Upadhyay Baskota (ORCID: https://orcid.org/0000-0002-8955-280X)
- Sofya S. Perelman (ORCID: https://orcid.org/0000-0001-9706-8156)
- Victor J. Torres (ORCID: https://orcid.org/0000-0002-7126-0489)
- N. Valerio Dorrello (ORCID: https://orcid.org/0000-0002-1801-4975)
- Timothy P. Stinear (ORCID: https://orcid.org/0000-0003-0150-123X)
- Andreacarola Urso (ORCID: https://orcid.org/0000-0002-9769-0903)
- J. M. Boylan (ORCID: https://orcid.org/0000-0002-2563-3192)
- Ahmed M. Moustafa (ORCID: https://orcid.org/0000-0002-9949-6936)
- Ying-Tsun Chen (ORCID: https://orcid.org/0000-0002-2966-3153)
- Camilla Predella (ORCID: https://orcid.org/0000-0003-3699-0256)
- Tania Wong Fok Lung (ORCID: https://orcid.org/0000-0002-9318-9572)
- Gaurav Kumar Lohia (ORCID: https://orcid.org/0000-0002-4186-621X)
- Ian A. Lewis (ORCID: https://orcid.org/0000-0002-5753-499X)
- Alice Prince (ORCID: https://orcid.org/0000-0002-7399-9295)
- Erin Theiller
Institutions
- Children's Hospital of Philadelphia (US)
- The University of Melbourne (AU)
- University of Calgary (CA)
- Columbia University Irving Medical Center (US)
- Peter Doherty Institute (AU)
- New York University (US)
- Columbia University (US)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1038/s41564-024-01769-9
- Citations
- 21
- Primary Topic
- Antimicrobial Resistance in Staphylococcus
- Type
- article
- Field-Weighted Citation Impact
- 8.17
Funders
- National Science Foundation
- Yale University
- Alberta Innovates
- National Institutes of Health
- International Microbiome Centre, University of Calgary
- National Cancer Institute