Severe infections emerge from commensal bacteria by adaptive evolution

Bernadette C. Young*, Chieh Hsi Wu, N. Claire Gordon, Kevin Cole, James R. Price, Elian Liu, Anna E. Sheppard, Sanuki Perera, Jane Charlesworth, Tanya Golubchik, Zamin Iqbal, Rory Bowden, Ruth C. Massey, John Paul, Derrick W. Crook, Timothy E. Peto, A. Sarah Walker, Martin J. Llewelyn, David Wyllie, Daniel J. Wilson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

Bacteria responsible for the greatest global mortality colonize the human microbiota far more frequently than they cause severe infections. Whether mutation and selection among commensal bacteria are associated with infection is unknown. We investigated de novo mutation in 1163 Staphylococcus aureus genomes from 105 infected patients with nose colonization. We report that 72% of infections emerged from the nose, with infecting and nose-colonizing bacteria showing parallel adaptive differences. We found 2.8-to-3.6-fold adaptive enrichments of protein-altering variants in genes responding to rsp, which regulates surface antigens and toxin production; agr, which regulates quorum-sensing, toxin production and abscess formation; and host-derived antimicrobial peptides. Adaptive mutations in pathogenesis-associated genes were 3.1-fold enriched in infecting but not nose-colonizing bacteria. None of these signatures were observed in healthy carriers nor at the species-level, suggesting infection-associated, short-term, within-host selection pressures. Our results show that signatures of spontaneous adaptive evolution are specifically associated with infection, raising new possibilities for diagnosis and treatment.

Original languageEnglish
Article numbere30637
JournaleLife
Volume6
DOIs
Publication statusPublished - 19 Dec 2017

Bibliographical note

Funding Information:
We would like to thank Ed Feil, Stephen Leslie, Gil McVean and Richard Moxon for helpful insights and useful discussions. Sequencing reads uploaded to short read archive (SRA) under BioProject PRJNA369475. RNAseq data relating to isolate from P005 (aka ‘patient S’) previously submitted under BioProject PRJNA279958. The views expressed in this publication are those of the authors and not necessarily those of the funders. This study was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), a Mérieux Research Grant, the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) (grant HPRU-2012–10041), and the Health Innovation Challenge Fund (a parallel funding partnership between the Wellcome Trust (grant WT098615/Z/12/Z) and the Department of Health (grant HICF-T5-358)). TEP and DWC are NIHR Senior Investigators. DJW and ZI are Sir Henry Dale Fellows, jointly funded by the Wellcome Trust and the Royal Society (Grants 101237/Z/ 13/Z and 102541/Z/13/Z). BCY is a Research Training Fellow funded by the Wellcome Trust (Grant 101611/Z/13/Z). We acknowledge the support of Wellcome Trust Centre for Human Genetics core funding (Grant 090532/Z/09/Z).

Funding Information:
We would like to thank Ed Feil, Stephen Leslie, Gil McVean and Richard Moxon for helpful insights and useful discussions. Sequencing reads uploaded to short read archive (SRA) under BioProject PRJNA369475. RNAseq data relating to isolate from P005 (aka ‘patient S’) previously submitted under BioProject PRJNA279958. The views expressed in this publication are those of the authors and not necessarily those of the funders. This study was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), a Mérieux Research Grant, the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) (grant HPRU-2012–10041), and the Health Innovation Challenge Fund (a parallel funding partnership between the Wellcome Trust (grant WT098615/Z/12/Z) and the Department of Health (grant HICF-T5-358)). TEP and DWC are NIHR Senior Investigators. DJW and ZI are Sir Henry Dale Fellows, jointly funded by the Wellcome Trust and the Royal Society (Grants 101237/Z/13/Z and 102541/Z/13/Z). BCY is a Research Training Fellow funded by the Wellcome Trust (Grant 101611/Z/13/Z). We acknowledge the support of Wellcome Trust Centre for Human Genetics core funding (Grant 090532/Z/09/Z).

Publisher Copyright:
© Young et al.

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