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. 2011 Jan 28;331(6016):430-4.
doi: 10.1126/science.1198545.

Rapid pneumococcal evolution in response to clinical interventions

Nicholas J Croucher  1 , Simon R Harris, Christophe Fraser, Michael A Quail, John Burton, Mark van der Linden, Lesley McGee, Anne von Gottberg, Jae Hoon Song, Kwan Soo Ko, Bruno Pichon, Stephen Baker, Christopher M Parry, Lotte M Lambertsen, Dea Shahinas, Dylan R Pillai, Timothy J Mitchell, Gordon Dougan, Alexander Tomasz, Keith P Klugman, Julian Parkhill, William P Hanage, Stephen D Bentley
Affiliations

Rapid pneumococcal evolution in response to clinical interventions

Nicholas J Croucher et al. Science. .

Abstract

Epidemiological studies of the naturally transformable bacterial pathogen Streptococcus pneumoniae have previously been confounded by high rates of recombination. Sequencing 240 isolates of the PMEN1 (Spain(23F)-1) multidrug-resistant lineage enabled base substitutions to be distinguished from polymorphisms arising through horizontal sequence transfer. More than 700 recombinations were detected, with genes encoding major antigens frequently affected. Among these were 10 capsule-switching events, one of which accompanied a population shift as vaccine-escape serotype 19A isolates emerged in the USA after the introduction of the conjugate polysaccharide vaccine. The evolution of resistance to fluoroquinolones, rifampicin, and macrolides was observed to occur on multiple occasions. This study details how genomic plasticity within lineages of recombinogenic bacteria can permit adaptation to clinical interventions over remarkably short time scales.

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Figures

Fig. 1
Fig. 1
Phylogeography and sequence variation of PMEN1. (A) Global phylogeny of PMEN1. The maximum likelihood tree, constructed using substitutions outside of recombination events, is coloured according to location, as reconstructed through the phylogeny using parsimony. Shaded boxes and dashed lines indicate isolates that have switched capsule type from the ancestral 23F serotype. Specific clades referred to in the text are marked on the tree: ‘A’ (South Africa), ‘I’ (International), ‘V’ (Vietnam), ‘S’ (Spain 19A) and ‘U’ (USA 19A). (B) Recombinations detected in PMEN1. The panel shows the chromosomal locations of the putative recombination events detected in each terminal taxon. Red blocks are recombinations predicted to have occurred on an internal branch, and therefore shared by multiple isolates through common descent. Blue blocks are recombinations predicted to occur on terminal branches, and hence present in only one strain. The green blocks indicate recombinations predicted to have occurred along the branch to the outgroup (S. pneumoniae BM4200), used to root the tree. (C) Biological relevance of recombination. The heatmap shows the density of independent recombination events within PMEN1 in relation to the annotation of the reference genome. All regions that have undergone ten or more recombination events are marked and annotated (Tn916 is encompassed within ICESpn23FST81).
Fig. 2
Fig. 2
Recombinations causing serotype switching events. (A) The annotated cps locus of the reference strain. CDSs involved in capsule biosynthesis are coloured according to their role. Genes in red are regulatory; those in blue synthesise and modify the oligosaccharide subunits; those in green are involved in polymerization and transport, and those in orange are required for the synthesis of rhamnose. (B) Below are delineated the recombinations leading to changes in serotype, colored according to the serotype of the sequence donor. The different events are labeled to correspond with Fig. 1.
Fig. 3
Fig. 3
Acquisition of macrolide resistance cassettes. The three full-length resistance cassettes are shown in (A): the Omega element, which carries an aph3′ aminoglycoside resistance gene and an ermB macrolide resistance gene; Tn917, which just carries the ermB methylase; and the Mega element, which carries the mel/mef macrolide efflux system. In (B), a comparison of the different Tn916 variants in the PMEN1 lineage is displayed. Red bands between the sequences indicate BLASTN matches. The Omega element is shaded in green when present at full length, and shaded in grey where present as a remnant resulting from a recombination between the Omega repressor-encoding genes, which concomitantly leads to the fusion of an Omega transcriptional repressor domain to the 3′ of the orf20 CDS. Tn917 is boxed in purple, with the two parts of orf20, into which it inserts, indicated on either side. The Mega element is boxed in orange.
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