1. Genetics and Genomics
  2. Microbiology and Infectious Disease
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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
Research Article
  • Cited 20
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Cite this article as: eLife 2019;8:e42486 doi: 10.7554/eLife.42486

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

Publication 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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Further reading

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    Gabriel A Guerrero et al.
    Research Article Updated

    Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent, while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate a subset of PGPs. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.

    1. Epidemiology and Global Health
    2. Genetics and Genomics
    Mohd Anisul et al.
    Research Article Updated

    Background:

    The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19.

    Methods:

    To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets.

    Results:

    Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19.

    Conclusions:

    Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.

    Funding:

    MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.