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. 2012 Mar 20;109(12):4550-5.
doi: 10.1073/pnas.1113219109. Epub 2012 Mar 5.

Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease

Bernadette C Young  1 , Tanya Golubchik, Elizabeth M Batty, Rowena Fung, Hanna Larner-Svensson, Antonina A Votintseva, Ruth R Miller, Heather Godwin, Kyle Knox, Richard G Everitt, Zamin Iqbal, Andrew J Rimmer, Madeleine Cule, Camilla L C Ip, Xavier Didelot, Rosalind M Harding, Peter Donnelly, Tim E Peto, Derrick W Crook, Rory Bowden, Daniel J Wilson
Affiliations

Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease

Bernadette C Young et al. Proc Natl Acad Sci U S A. .

Abstract

Whole-genome sequencing offers new insights into the evolution of bacterial pathogens and the etiology of bacterial disease. Staphylococcus aureus is a major cause of bacteria-associated mortality and invasive disease and is carried asymptomatically by 27% of adults. Eighty percent of bacteremias match the carried strain. However, the role of evolutionary change in the pathogen during the progression from carriage to disease is incompletely understood. Here we use high-throughput genome sequencing to discover the genetic changes that accompany the transition from nasal carriage to fatal bloodstream infection in an individual colonized with methicillin-sensitive S. aureus. We found a single, cohesive population exhibiting a repertoire of 30 single-nucleotide polymorphisms and four insertion/deletion variants. Mutations accumulated at a steady rate over a 13-mo period, except for a cluster of mutations preceding the transition to disease. Although bloodstream bacteria differed by just eight mutations from the original nasally carried bacteria, half of those mutations caused truncation of proteins, including a premature stop codon in an AraC-family transcriptional regulator that has been implicated in pathogenicity. Comparison with evolution in two asymptomatic carriers supported the conclusion that clusters of protein-truncating mutations are highly unusual. Our results demonstrate that bacterial diversity in vivo is limited but nonetheless detectable by whole-genome sequencing, enabling the study of evolutionary dynamics within the host. Regulatory or structural changes that occur during carriage may be functionally important for pathogenesis; therefore identifying those changes is a crucial step in understanding the biological causes of invasive bacterial disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Molecular diversity during progression from carriage to disease in participant P. (A) Sampling frame, variants, and the time line of disease progression. Seven groups of colonies sequenced from six nasal swabs and blood culture are shaded from light to dark gray. (B) The location of virulence factors and variants in the chromosome (outer ring) and plasmid (inner ring). Positions are inferred by mapping to MSSA476 and pSAS. From the outermost track inwards: Virulence-associated surface proteins (dark red), toxins (olive green), and regulatory genes (dark blue) are identified in the bacterial chromosome. Variants detected in the bacterial chromosome are the following by type: synonymous (green), nonsynonymous (orange), premature stop codon (red), and intergenic (gray). Solid lines represent SNPs and dashed lines represent indels. Variants detected in the plasmid are the same color scheme. (C) The maximum-likelihood unrooted tree relating all sequences. Nodes represent genotypes, where area is proportional to sample frequency, and small black circles represent hypothetical intermediate genotypes. Shading within the circles indicates the sample, and darker shading corresponds to later samples as in A. Edges represent mutations, color-coded as in B. The ordering of mutations among hypothetical genotypes is arbitrary. Numbers represent genotypes observed more than once for cross-reference with Fig. 2.
Fig. 2.
Fig. 2.
Bayesian coalescent tree. The maximum clade credibility tree representing the genealogy of sequences in the study, reconstructed from SNPs using BEAST. Genotypes are enumerated as in Fig. 1C. SNPs (filled circles) and indels (open circles) are superimposed on the tree and color-coded by type: synonymous (green), nonsynonymous (orange), premature stop codon (red), and intergenic (gray). The ordering of mutations within a branch is arbitrary.
See this image and copyright information in PMC

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