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Severe infections emerge from the microbiome by adaptive evolution

View ORCID ProfileBernadette C. Young, Chieh-Hsi Wu, N. Claire Gordon, Kevin Cole, View ORCID ProfileJames R. Price, Elian Liu, View ORCID ProfileAnna E. Sheppard, Sanuki Perera, Jane Charlesworth, Tanya Golubchik, Zamin Iqbal, View ORCID ProfileRory Bowden, View ORCID ProfileRuth C. Massey, John Paul, Derrick W. Crook, Timothy E. A. Peto, A. Sarah Walker, View ORCID ProfileMartin J. Llewelyn, David H. Wyllie, View ORCID ProfileDaniel J. Wilson
doi: https://doi.org/10.1101/116681
Bernadette C. Young
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
2Microbiology and Infectious Diseases Department, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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  • ORCID record for Bernadette C. Young
  • For correspondence: bernadette.young@ndm.ox.ac.uk daniel.wilson@ndm.ox.ac.uk
Chieh-Hsi Wu
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
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N. Claire Gordon
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Kevin Cole
3Department of Infectious Diseases and Microbiology, Royal Sussex County Hospital, Brighton BN2 5BE, UK
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James R. Price
3Department of Infectious Diseases and Microbiology, Royal Sussex County Hospital, Brighton BN2 5BE, UK
4Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Falmer BN1 9PS, UK
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Elian Liu
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
2Microbiology and Infectious Diseases Department, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Anna E. Sheppard
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
5NIHR Health Protection Unit in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK
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Sanuki Perera
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
2Microbiology and Infectious Diseases Department, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Jane Charlesworth
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Tanya Golubchik
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Zamin Iqbal
6Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
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Rory Bowden
6Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
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  • ORCID record for Rory Bowden
Ruth C. Massey
7School of Cellular and Molecular Medicine, University of Bristol, UK
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John Paul
8National Infection Service, Public Health England, London, UK
9National Institute for Health Research, Oxford Biomedical Research Centre, Oxford, UK
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Derrick W. Crook
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
8National Infection Service, Public Health England, London, UK
9National Institute for Health Research, Oxford Biomedical Research Centre, Oxford, UK
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Timothy E. A. Peto
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
9National Institute for Health Research, Oxford Biomedical Research Centre, Oxford, UK
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A. Sarah Walker
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
9National Institute for Health Research, Oxford Biomedical Research Centre, Oxford, UK
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Martin J. Llewelyn
3Department of Infectious Diseases and Microbiology, Royal Sussex County Hospital, Brighton BN2 5BE, UK
4Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Falmer BN1 9PS, UK
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David H. Wyllie
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
10Jenner Institute, Centre for Molecular and Cellular Physiology, Oxford OX3 7BN, UK
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Daniel J. Wilson
1Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
6Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
11Institute for Emerging Infections, Oxford Martin School, University of Oxford, Oxford, OX1 3BD, UK
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  • ORCID record for Daniel J. Wilson
  • For correspondence: bernadette.young@ndm.ox.ac.uk daniel.wilson@ndm.ox.ac.uk
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Abstract

Bacteria responsible for the greatest global mortality colonize the human microbiome far more frequently than they cause severe infections. Whether mutation and selection within the microbiome accompany 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 microbiome, with infecting and nose-colonizing bacteria showing parallel adaptive differences. We found 2.8-to-3.6-fold enrichments of protein-altering variants in genes responding to rsp, which regulates surface antigens and toxicity; agr, which regulates quorum-sensing, toxicity 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 disease-associated, short-term, within-host selection pressures. Our results show that infection, like a cancer of the microbiome, emerges through spontaneous adaptive evolution, raising new possibilities for diagnosis and treatment.

One Sentence Summary Life-threatening S. aureus infections emerge from nose microbiome bacteria in association with repeatable adaptive evolution.

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Posted April 19, 2017.
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Severe infections emerge from the microbiome 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. A. Peto, A. Sarah Walker, Martin J. Llewelyn, David H. Wyllie, Daniel J. Wilson
bioRxiv 116681; doi: https://doi.org/10.1101/116681
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Severe infections emerge from the microbiome 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. A. Peto, A. Sarah Walker, Martin J. Llewelyn, David H. Wyllie, Daniel J. Wilson
bioRxiv 116681; doi: https://doi.org/10.1101/116681

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