Pneumococcal Capsule Synthesis Locus cps as Evolutionary Hotspot with Potential to Generate Novel Serotypes by Recombination.

Rafał J Mostowy,Claire Chewapreecha,Stephen D Bentley,Nicola De Maio,Susannah J Salter,Xavier Didelot,Christophe Fraser,Paul Turner,David M Aanensen,Nicholas J Croucher

doi:10.1093/molbev/msx173

Abstract

Diversity of the polysaccharide capsule in Streptococcus pneumoniae—main surface antigen and the target of the currently used pneumococcal vaccines—constitutes a major obstacle in eliminating pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule biosynthesis locus, cps. However, the evolutionary dynamics of the capsule remains not fully understood. Here, using genetic data from 4,519 bacterial isolates, we found cps to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of relaxed purifying selection and positive, diversifying selection acting at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared with the rest of the genome. Diversifying selection was particularly evident in the region of wzd/wze genes, which are known to regulate capsule expression and hence the bacterium’s ability to cause disease. Using a novel, capsule-centered approach, we analyzed the evolutionary history of 12 major serogroups. Such analysis revealed their complex diversification scenarios, which were principally driven by recombination with other serogroups and other streptococci. Patterns of recombinational exchanges between serogroups could not be explained by serotype frequency alone, thus pointing to nonrandom associations between co-colonizing serotypes. Finally, we discovered a previously unobserved mosaic serotype 39X, which was confirmed to carry a viable and structurally novel capsule. Adding to previous discoveries of other mosaic capsules in densely sampled collections, these results emphasize the strong adaptive potential of the bacterium by its ability to generate novel antigenic diversity by recombination.

Highlights

Streptococcus pneumoniae is a human bacterial commensal and pathogen, estimated to be the cause of death in over 500,000 children under 5 years of age each year worldwide (WHO 2012)
We found the mean jumping-rate between clonal complex (CC) to be 5.8 Â 10À3 jumps per isolate per year, and between clonal complex group (CCG) to be 5.6 Â 10À4 jumps per isolate per year
The pneumococcal capsule biosynthesis locus, cps, is an evolutionary hotspot, presumably underlying immune selective pressures acting on this major antigen

Summary

Introduction

Streptococcus pneumoniae is a human bacterial commensal and pathogen, estimated to be the cause of death in over 500,000 children under 5 years of age each year worldwide (WHO 2012). The bacterium’s capacity to cause disease is associated with its possession of several virulence factors, of which the most important is the surface polysaccharide capsule (Briles et al 1992; Morona et al 2004; Kadioglu et al 2008; Hyams et al 2010). As the outermost layer of the bacterium, the capsule is the target of all licensed pneumococcal vaccines. The large diversity of capsular polysaccharides constitutes a major challenge for eliminating pneumococcal disease.

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