Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes
Streptococcus pneumoniae colonizes human airways, where it acquires sugars from glycosylated mucins using glycoside hydrolases and sugar transport systems. This study identifies widespread nucleotide sequence variation in the promoter of a pneumococcal operon encoding a glycan scavenging system. We identify 78 promoter sequence patterns across 21,155 genomes, with variation clustered within a stretch of adenines, where mutations accumulate via strand slippage during DNA replication. Promoter mutations influence operon transcription, and multiple promoter patterns are co-identified during single-carriage episodes, suggesting that heterogeneous gene expression provides population-level benefits. In a mouse nasopharyngeal colonization model, promoter mutations arise and undergo selection, with nucleotide insertion promoting gene expression and prolonging carriage longevity. Pre-existing immunity confers resistance to colonization by strains carrying single promoter patterns but does not protect against mixed infections with otherwise isogenic strains differing in promoter sequence. Promoter region sequence variation offers an evolutionary strategy for exploration of phenotypic space to maximize fitness within-host.
Authors
- Jason W. Rosch (ORCID: https://orcid.org/0000-0002-1798-1760)
- Stephanie W. Lo (ORCID: https://orcid.org/0000-0002-2182-0222)
- Markus Hilty (ORCID: https://orcid.org/0000-0002-2418-6474)
- Daniel R. Neill (ORCID: https://orcid.org/0000-0002-7911-8153)
- Katharina Bacher (ORCID: https://orcid.org/0000-0003-4668-309X)
- Abigail McKnight
- Angharad E. Green (ORCID: https://orcid.org/0000-0002-8683-8191)
- Sumit Kumar (ORCID: https://orcid.org/0000-0002-0985-5000)
- Kate C. Mellor (ORCID: https://orcid.org/0000-0002-2247-4675)
- Felix S. Dube (ORCID: https://orcid.org/0000-0003-2775-7786)
- Oliver Lorenz (ORCID: https://orcid.org/0000-0003-0840-3202)
- Stephen D. Bentley (ORCID: https://orcid.org/0000-0001-8094-3751)
- Thomas E. Barton (ORCID: https://orcid.org/0000-0002-4592-4261)
- Heather Joy Zar (ORCID: https://orcid.org/0000-0002-9046-759X)
- Mark Patrick Nicol (ORCID: https://orcid.org/0000-0002-1366-4805)
- K. M. Newbold
- A. Bryson
- Manal S. Monshi
- Elizabeth Pohler
Institutions
- University of Bern (CH)
- St. Jude Children's Research Hospital (US)
- University of Liverpool (GB)
- University of Cape Town (ZA)
- University of Dundee (GB)
- The University of Western Australia (AU)
- Wellcome Sanger Institute (GB)
- Arctic Research Centre (SE)
- University College London (GB)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.chom.2025.08.005
- Citations
- 2
- Primary Topic
- Pneumonia and Respiratory Infections
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- National Science Foundation
- Bill and Melinda Gates Foundation
- University of Dundee
- Wellcome Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung