2022 Kwun Genome Medicine.pdf (4.69 MB)
Download file

Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA.

Download (4.69 MB)
journal contribution
posted on 2023-03-10, 15:57 authored by Min Jung Kwun, Alexandru V Ion, Hsueh-Chien Cheng, Joshua C D'Aeth, Sam Dougan, Marco R Oggioni, David A Goulding, Stephen D Bentley, Nicholas J Croucher
The respiratory pathogen Streptococcus pneumoniae (the pneumococcus) is a genetically diverse bacterium associated with over 101 immunologically distinct polysaccharide capsules (serotypes). Polysaccharide conjugate vaccines (PCVs) have successfully eliminated multiple targeted serotypes, yet the mucoid serotype 3 has persisted despite its inclusion in PCV13. This capsule type is predominantly associated with a single globally disseminated strain, GPSC12 (clonal complex 180). A genomic epidemiology study combined previous surveillance datasets of serotype 3 pneumococci to analyse the population structure, dynamics, and differences in rates of diversification within GPSC12 during the period of PCV introductions. Transcriptomic analyses, whole genome sequencing, mutagenesis, and electron microscopy were used to characterise the phenotypic impact of loci hypothesised to affect this strain's evolution. GPSC12 was split into clades by a genomic analysis. Clade I, the most common, rarely underwent transformation, but was typically infected with the prophage ϕOXC141. Prior to the introduction of PCV13, this clade's composition shifted towards a ϕOXC141-negative subpopulation in a systematically sampled UK collection. In the post-PCV13 era, more rapidly recombining non-Clade I isolates, also ϕOXC141-negative, have risen in prevalence. The low in vitro transformation efficiency of a Clade I isolate could not be fully explained by the ~100-fold reduction attributable to the serotype 3 capsule. Accordingly, prophage ϕOXC141 was found to modify csRNA3, a non-coding RNA that inhibits the induction of transformation. This alteration was identified in ~30% of all pneumococci and was particularly common in the unusually clonal serotype 1 GPSC2 strain. RNA-seq and quantitative reverse transcriptase PCR experiments using a genetically tractable pneumococcus demonstrated the altered csRNA3 was more effective at inhibiting production of the competence-stimulating peptide pheromone. This resulted in a reduction in the induction of competence for transformation. This interference with the quorum sensing needed to induce competence reduces the risk of the prophage being deleted by homologous recombination. Hence the selfish prophage-driven alteration of a regulatory RNA limits cell-cell communication and horizontal gene transfer, complicating the interpretation of post-vaccine population dynamics.


MJK, AVI and NJC were funded by a Sir Henry Dale fellowship jointly funded by Wellcome and the Royal Society (grant 104169/Z/14/A) and by the UK Medical Research Council and Department for International Development (grants MR/R015600/1 and MR/T016434/1). MJK, MRO, SDB and NJC were supported by the BBSRC (grant BB/N002903/1). Wellcome supported JCD (grant 102169/Z/13/Z), and HC, SD, DAG and SDB (grant 206194). SDB was also supported by the Bill and Melinda Gates Foundation (OPP1034556).



Kwun, M.J., Ion, A.V., Cheng, HC. et al. Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA. Genome Med 14, 144 (2022). https://doi.org/10.1186/s13073-022-01147-2

Author affiliation

Department of Genetics and Genome Biology


VoR (Version of Record)

Published in

Genome Medicine






Springer Science and Business Media LLC





Acceptance date


Copyright date


Available date


Spatial coverage