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Genome Med

Title:		Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA
Author(s):		Kwun MJ; Ion AV; Cheng HC; D'Aeth JC; Dougan S; Oggioni MR; Goulding DA; Bentley SD; Croucher NJ;
Address:		"MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, White City Campus, Imperial College London, London, W12 0BZ, UK. Parasites & Microbes, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH, UK. Dipartimento di Farmacia e Biotecnologie, Universita di Bologna, Via Irnerio 42, 40126, Bologna, Italy. MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, White City Campus, Imperial College London, London, W12 0BZ, UK. n.croucher@imperial.ac.uk"
Journal Title:		Genome Med
Year:		2022
Volume:		20221220
Issue:		1
Page Number:		144 -
DOI:		10.1186/s13073-022-01147-2
ISSN/ISBN:		1756-994X (Electronic) 1756-994X (Linking)
Abstract:		"BACKGROUND: 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). METHODS: 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. RESULTS: GPSC12 was split into clades by a genomic analysis. Clade I, the most common, rarely underwent transformation, but was typically infected with the prophage varphiOXC141. Prior to the introduction of PCV13, this clade's composition shifted towards a varphiOXC141-negative subpopulation in a systematically sampled UK collection. In the post-PCV13 era, more rapidly recombining non-Clade I isolates, also varphiOXC141-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 varphiOXC141 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. CONCLUSION: 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"
Keywords:		"Humans *Streptococcus pneumoniae/genetics Serogroup *Pneumococcal Infections/epidemiology/prevention & control/microbiology Prophages/genetics Pneumococcal Vaccines Vaccines, Conjugate RNA, Untranslated/genetics/pharmacology Genomic epidemiology Non-codin;"
Notes:		"MedlineKwun, Min Jung Ion, Alexandru V Cheng, Hsueh-Chien D'Aeth, Joshua C Dougan, Sam Oggioni, Marco R Goulding, David A Bentley, Stephen D Croucher, Nicholas J eng 102169/Z/13/Z/WT_/Wellcome Trust/United Kingdom MR/T016434/1/MRC_/Medical Research Council/United Kingdom BB/N002903/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom 206194/WT_/Wellcome Trust/United Kingdom 104169/Z/14/A/WT_/Wellcome Trust/United Kingdom WT_/Wellcome Trust/United Kingdom MR/R015600/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't England 2022/12/21 Genome Med. 2022 Dec 20; 14(1):144. doi: 10.1186/s13073-022-01147-2"