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Clonal differences in Staphylococcus aureus bacteraemia-associated mortality

Nature Microbiology volume 2, pages 1381–1388 (2017)Cite this article

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Abstract

The bacterium Staphylococcus aureus is a major human pathogen for which the emergence of antibiotic resistance is a global public health concern. Infection severity, and in particular bacteraemia-associated mortality, has been attributed to several host-related factors, such as age and the presence of comorbidities. The role of the bacterium in infection severity is less well understood, as it is complicated by the multifaceted nature of bacterial virulence, which has so far prevented a robust mapping between genotype, phenotype and infection outcome. To investigate the role of bacterial factors in contributing to bacteraemia-associated mortality, we phenotyped a collection of sequenced clinical S. aureus isolates from patients with bloodstream infections, representing two globally important clonal types, CC22 and CC30. By adopting a genome-wide association study approach we identified and functionally verified several genetic loci that affect the expression of cytolytic toxicity and biofilm formation. By analysing the pooled data comprising bacterial genotype and phenotype together with clinical metadata within a machine-learning framework, we found significant clonal differences in the determinants most predictive of poor infection outcome. Whereas elevated cytolytic toxicity in combination with low levels of biofilm formation was predictive of an increased risk of mortality in infections by strains of a CC22 background, these virulence-specific factors had little influence on mortality rates associated with CC30 infections. Our results therefore suggest that different clones may have adopted different strategies to overcome host responses and cause severe pathology. Our study further demonstrates the use of a combined genomics and data analytic approach to enhance our understanding of bacterial pathogenesis at the individual level, which will be an important step towards personalized medicine and infectious disease management.

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Fig. 1: Toxicity and biofilm-forming abilities of S. aureus bacteraemia isolates.
Fig. 2: Genome-wide associations and functional validation of biofilm-affecting polymorphisms.
Fig. 3: Predictive model performance and variable importance.
Fig. 4: Capsule production is affected in CC22 isolates containing a mortality-predicting SNP.

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Acknowledgements

The authors thank T. Gouliouris, for his role in collecting and supplying the clinical data, and E. Nickerson and S. Aliyu for their role in the collection of clinical information. The authors also thank the Sanger Institute’s core Pathogen Production Groups and Pathogen Informatics Group.

Author contributions

M.R., M.L., M.S.T., R.B.S., B.B., M.E.T., S.J.P. and R.C.M. collected the data. M.R., M.L. and R.C.M. designed the experiments. M.L., K.O., E.S., M.Y., L.B., J.S., L.T. and G.M. performed experiments. M.R., M.L., M.S.T., S.R., S.B., S.J.P. and R.C.M. analysed the data. M.R., M.L., S.J.P. and R.C.M. wrote the manuscript.

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  1. Mario Recker and Maisem Laabei contributed equally to this work.

Authors and Affiliations

  1. Centre for Mathematics & the Environment, University of Exeter, Penryn, TR10 9EZ, UK

    Mario Recker

  2. Department of Biology and Biochemistry and the Milner Centre for Evolution, University of Bath, Bath, BA2 7AY, UK

    Maisem Laabei, Khadija Ouadi, Emily Stevens, Maho Yokoyama, Joseph Steventon, Luke Thompson, Gregory Milne, Sion Bayliss, Leann Bacon & Ruth C. Massey

  3. Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK

    Michelle S. Toleman, Sandra Reuter, Rebecca B. Saunderson, Beth Blane, M. Estee Török & Sharon J. Peacock

  4. London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK

    Sharon J. Peacock

  5. School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK

    Ruth C. Massey

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Correspondence to Ruth C. Massey.

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Supplementary Information

Supplementary Notes, Supplementary Figures 1–4, Supplementary Table 2.

Supplementary Table 1

Strain information including clinical metadata, genome accession codes, toxicity and biofilm formation.

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Recker, M., Laabei, M., Toleman, M.S. et al. Clonal differences in Staphylococcus aureus bacteraemia-associated mortality. Nat Microbiol 2, 1381–1388 (2017). https://doi.org/10.1038/s41564-017-0001-x

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