Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial GWAS

  1. Bernadette C Young
  2. Sarah G Earle
  3. Sona Soeng
  4. Poda Sar
  5. Varun Kumar
  6. Songly Hor
  7. Vuthy Sar
  8. Rachel Bousfield
  9. Nicholas D Sanderson
  10. Leanne Barker
  11. Nicole Stoesser
  12. Katherine RW Emary
  13. Christopher M Parry
  14. Emma K Nickerson
  15. Paul Turner
  16. Rory Bowden
  17. Derrick W Crook
  18. David J Wyllie
  19. Nicholas PJ Day
  20. Daniel J Wilson
  21. Catrin E Moore  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. Cambodia Oxford Medical Research Unit, Cambodia
  3. East Tennessee State University, United States
  4. Cambridge University Hospitals NHS Foundation Trust, United Kingdom
  5. Oxford University Hospitals NHS Foundation Trust, United Kingdom
  6. Liverpool School of Tropical Medicine, United Kingdom
  7. Wellcome Trust Center Human Genetics, United Kingdom
  8. Mahidol University, Thailand

Abstract

Pyomyositis is a severe bacterial infection of skeletal muscle, commonly affecting children in tropical regions, predominantly caused by Staphylococcus aureus. To understand the contribution of bacterial genomic factors to pyomyositis, we conducted a genome-wide association study of S. aureus cultured from 101 children with pyomyositis and 417 children with asymptomatic nasal carriage attending the Angkor Hospital for Children, Cambodia. We found a strong relationship between bacterial genetic variation and pyomyositis, with estimated heritability 63.8% (95% CI 49.2-78.4%). The presence of the Panton-Valentine leucocidin (PVL) locus increased the odds of pyomyositis 130-fold (p=10-17.9). The signal of association mapped both to the PVL-coding sequence and the sequence immediately upstream. Together these regions explained over 99.9% of heritability (95% CI 93.5-100%). Our results establish staphylococcal pyomyositis, like tetanus and diphtheria, as critically dependent on a single toxin and demonstrate the potential for association studies to identify specific bacterial genes promoting severe human disease.

Data availability

Sequence data has been submitted to Short Read Archive (Bioproject ID PRJNA418899).

The following data sets were generated

Article and author information

Author details

  1. Bernadette C Young

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6071-6770
  2. Sarah G Earle

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Sona Soeng

    Microbiology, Angkor Hospital for Children, Cambodia Oxford Medical Research Unit, Siem Reap, Cambodia
    Competing interests
    The authors declare that no competing interests exist.
  4. Poda Sar

    Microbiology, Angkor Hospital for Children, Cambodia Oxford Medical Research Unit, Siem Reap, Cambodia
    Competing interests
    The authors declare that no competing interests exist.
  5. Varun Kumar

    Department of Pediatrics, East Tennessee State University, Johnson City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Songly Hor

    Angkor Hospital for Children, Cambodia Oxford Medical Research Unit, Siem Reap, Cambodia
    Competing interests
    The authors declare that no competing interests exist.
  7. Vuthy Sar

    Angkor Hospital for Children, Cambodia Oxford Medical Research Unit, Siem Reap, Cambodia
    Competing interests
    The authors declare that no competing interests exist.
  8. Rachel Bousfield

    Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Nicholas D Sanderson

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Leanne Barker

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Nicole Stoesser

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Katherine RW Emary

    NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Christopher M Parry

    Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Emma K Nickerson

    Department of Infectious Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Paul Turner

    Angkor Hospital for Children, Cambodia Oxford Medical Research Unit, Siem Reap, Cambodia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1013-7815
  16. Rory Bowden

    Bioinformatics, Wellcome Trust Center Human Genetics, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Derrick W Crook

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0590-2850
  18. David J Wyllie

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Nicholas PJ Day

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  20. Daniel J Wilson

    Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0940-3311
  21. Catrin E Moore

    Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom
    For correspondence
    catrin.moore@ndm.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8639-9846

Funding

Wellcome (089275/H/09/Z)

  • Nicholas PJ Day

University Of Oxford (MRF/MT2015/2180)

  • Catrin E Moore

Royal Society (101237/Z/13/Z)

  • Daniel J Wilson

National Institute for Health Research

  • Daniel J Wilson

Seventh Framework Programme (601783)

  • David J Wyllie

Wellcome (090532/Z/09/Z)

  • Rory Bowden

Wellcome (089275/Z/09/Z)

  • Nicholas PJ Day

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Approval for this study was provided by the AHC institutional review board and the Oxford Tropical Ethics Committee (507-12).

Reviewing Editor

  1. Julian Parkhill, The Wellcome Trust Sanger Institute, United Kingdom

Version history

  1. Received: October 1, 2018
  2. Accepted: February 21, 2019
  3. Accepted Manuscript published: February 22, 2019 (version 1)
  4. Version of Record published: April 10, 2019 (version 2)

Copyright

© 2019, Young et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Bernadette C Young
  2. Sarah G Earle
  3. Sona Soeng
  4. Poda Sar
  5. Varun Kumar
  6. Songly Hor
  7. Vuthy Sar
  8. Rachel Bousfield
  9. Nicholas D Sanderson
  10. Leanne Barker
  11. Nicole Stoesser
  12. Katherine RW Emary
  13. Christopher M Parry
  14. Emma K Nickerson
  15. Paul Turner
  16. Rory Bowden
  17. Derrick W Crook
  18. David J Wyllie
  19. Nicholas PJ Day
  20. Daniel J Wilson
  21. Catrin E Moore
(2019)
Panton-Valentine leucocidin is the key determinant of Staphylococcus aureus pyomyositis in a bacterial GWAS
eLife 8:e42486.
https://doi.org/10.7554/eLife.42486

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