Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes

TY - JOUR

T1 - Naturally acquired promoter variation influences Streptococcus pneumoniae infection outcomes

AU - Barton, Thomas E.

AU - Green, Angharad E.

AU - Mellor, Kate C.

AU - McKnight, Abigail E.

AU - Bacher, Katharina

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.

AU - Hilty, Markus

AU - Rosch, Jason W.

AU - Lo, Stephanie

AU - Neill, Daniel R.

N1 - © 2025 The Author(s).

PY - 2025/9/10

Y1 - 2025/9/10

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.

KW - S. pneumoniae

KW - gene expression

KW - promoter

KW - evolution

UR - https://www.scopus.com/pages/publications/105014983511

U2 - 10.1016/j.chom.2025.08.005

DO - 10.1016/j.chom.2025.08.005

M3 - Article

C2 - 40902603

SN - 1931-3128

VL - 33

SP - 1473-1483.e6

JO - Cell Host & Microbe

JF - Cell Host & Microbe

IS - 9

ER -