Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes

Thomas E. Barton; Angharad E. Green; Kate C. Mellor; Abigail E. McKnight; Katharina Bacher; Sumit Kumar; Kyle Newbold; Oliver Lorenz; Elizabeth Pohler; Manal S. Monshi; Adam Bryson; Felix Dube; Heather J. Zar; Mark P. Nicol; Stephen D. Bentley; Markus Hilty; Jason W. Rosch; Stephanie Lo; Daniel R. Neill

doi:10.1016/j.chom.2025.08.005

Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes

Thomas E. Barton
, Angharad E. Green
, Kate C. Mellor
, Abigail E. McKnight
, Katharina Bacher
, Sumit Kumar
, Kyle Newbold
, Oliver Lorenz
, Elizabeth Pohler
, Manal S. Monshi
, Adam Bryson
, Felix Dube
, Heather J. Zar
, Mark P. Nicol
, Stephen D. Bentley
, Markus Hilty
, Jason W. Rosch
, Stephanie Lo
, Daniel R. Neill

University of Dundee
University College London
Wellcome Sanger Institute
St. Jude Children’s Research Hospital
University of Bern
University of Liverpool
University of Cape Town
The University of Western Australia
Parasites and Microbes

Research output: Contribution to journal › Article › peer-review

2 Citations (SciVal)

Abstract

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.

Original language	English
Pages (from-to)	1473-1483.e6
Journal	Cell Host and Microbe
Volume	33
Issue number	9
Early online date	2 Sept 2025
DOIs	https://doi.org/10.1016/j.chom.2025.08.005
Publication status	Published - 10 Sept 2025

Data Availability Statement

Genome annotations for D39N are available at NCBI: PRJNA658145. Raw RNA-seq reads are available at NCBI: PRJNA1194355. Raw sequencing data from the GPS project are available via the European Nucleotide Archive (ENA): PRJEB3084 and for the Drakenstein collection ENA: PRJEB21680. Metadata, assembly, and annotation information are available via GPS: https://data-viewer.monocle.sanger.ac.uk/project/gps. Original code for in silico PCR, for indentification of poly-A signatures in pneumococcal promoters, and for strand slippage analysis is available at GitHub: https://github.com/sanger-pathogens/sh16_scripts/blob/bcd3bbb126a5abe2ef00b7cd77b1f0a312e81b6e/legacy/in_silico_pcr.py, https://github.com/Oliver-Lorenz-dev/check_polyA, and https://github.com/thomasebarton/NanB_Bioinformatics.

Funding

This work was supported by a Sir Henry Dale Fellowship, awarded by the Wellcome Trust and the Royal Society (204457/Z/16/Z) to D.R.N.; by a Harry Smith Vacation Studentship awarded by the Microbiology Society (GA002322) to T.E.B. and A.E.G.; and by a Swiss National Science Foundation award (197083) to M.H. The Drakenstein sample collection was funded by a Bill and Melinda Gates Foundation Global Health Grant (INV-003570). The Global Pneumococcal Sequencing project is funded by the Bill and Melinda Gates Foundation (OPP1189062) and Wellcome Trust (206194). We thank Dr. Megan Bergkessel, University of Dundee, for valuable advice and technical support in strand slippage analysis. We thank all members in the Global Pneumococcal Sequencing project for their contributions.

Keywords

evolution
gene expression
promoter
S. pneumoniae

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2025.08.005Licence: CC BY

Cite this

Barton, T. E., Green, A. E., Mellor, K. C., McKnight, A. E., Bacher, K., Kumar, S., Newbold, K., Lorenz, O., Pohler, E., Monshi, M. S., Bryson, A., Dube, F., Zar, H. J., Nicol, M. P., Bentley, S. D., Hilty, M., Rosch, J. W., Lo, S., & Neill, D. R. (2025). Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes. Cell Host and Microbe, 33(9), 1473-1483.e6. https://doi.org/10.1016/j.chom.2025.08.005

Barton, TE, Green, AE, Mellor, KC, McKnight, AE, Bacher, K, Kumar, S, Newbold, K, Lorenz, O, Pohler, E, Monshi, MS, Bryson, A, Dube, F, Zar, HJ, Nicol, MP, Bentley, SD, Hilty, M, Rosch, JW, Lo, S & Neill, DR 2025, 'Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes', Cell Host and Microbe, vol. 33, no. 9, pp. 1473-1483.e6. https://doi.org/10.1016/j.chom.2025.08.005

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abstract = "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.",

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AU - Kumar, Sumit

AU - Newbold, Kyle

AU - Lorenz, Oliver

AU - Pohler, Elizabeth

AU - Monshi, Manal S.

AU - Bryson, Adam

AU - Dube, Felix

AU - Zar, Heather J.

AU - Nicol, Mark P.

AU - Bentley, Stephen D.

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N2 - 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.

AB - 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.

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M3 - Article

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ER -

Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes

Abstract

Data Availability Statement

Funding

Keywords

ASJC Scopus subject areas

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