Pneumococcal genetic variability in age-dependent bacterial carriage

  1. Philip HC Kremer  Is a corresponding author
  2. Bart Ferwerda
  3. Hester J Bootsma
  4. Nienke Y Rots
  5. Alienke J Wijmenga-Monsuur
  6. Elisabeth AM Sanders
  7. Krzysztof Trzciński
  8. Anne L Wyllie
  9. Paul Turner
  10. Arie van der Ende
  11. Matthijs C Brouwer
  12. Stephen D Bentley
  13. Diederik van de Beek
  14. John Lees
  1. Amsterdam UMC, University of Amsterdam, Netherlands
  2. National Institute for Public Health and the Environment, Netherlands
  3. Wilhelmina Children's Hospital, Netherlands
  4. Yale School of Public Health, United States
  5. Angkor Hospital for Children, Cambodia
  6. Amsterdam UMC, Netherlands
  7. Wellcome Sanger Institute, United Kingdom
  8. European Bioinformatics Institute, United Kingdom

Abstract

The characteristics of pneumococcal carriage vary between infants and adults, with onward implications for transmission rates, and disease control using vaccines. Host immune factors have been shown to contribute to these age-specific differences, but the role of pathogen variation is currently less well-known. Indeed, identification of specific pneumococcal genetic factors associated with carriage in younger or older age groups may suggest alternative vaccine formulations would reduce overall disease. To search for such factors, we used whole genome sequencing to understand how pneumococcal variation is associated with age. We performed genome sequencing in a large carriage cohort, and conducted a meta-analysis with an existing carriage study. We compiled a dictionary of pathogen genetic variation including serotype, sequence cluster, sequence elements, SNPs, burden combined rare variants, and clusters of orthologous genes (COGs) for each cohort - all of which used in a genome-wide association with host age. Age-dependent colonization showed weak evidence for heritability in the first cohort (h2 = 0.10, 0.00 - 0.69 95% CI), and stronger evidence in the second cohort (h2 = 0.56, 0.23 - 0.87 95% CI). We found that serotypes and genetic background (strain) explained a proportion of the heritability in the first cohort (h2serotype = 0.07, 0.04 - 0.14 95% CI and h2GPSC = 0.06, 0.03 - 0.13 95% CI) and the second cohort (h2serotype = 0.11, 0.05 - 0.21 95% CI and h2GPSC = 0.20, 0.12 - 0.31 95% CI). In a meta-analysis of these cohorts, we found one candidate association (p = 1.2x10-9) upstream of an accessory Sec-dependent serine-rich glycoprotein adhesin. Overall, while we did find an effect of pathogen genome variation on pneumococcal carriage in children versus adult hosts, this was variable between populations and does not appear have a strong relationship with individual genes. This supports proposals for adaptive future vaccination strategies which are primarily targeted at dominant circulating serotypes, and tailored to the composition of the pathogen populations.

Data availability

Fastq sequences of bacterial isolates from the Dutch cohort were deposited in the European Nucleotide Archive (ENA, study and accession numbers in Supplementary Table S2). Sequences of bacterial isolates in the Maela cohort are available at ENA under study numbers ERP000435, ERP000483, ERP000485, ERP000487, ERP000598 and ERP000599 (Supplementary Table S3). Summary statistics for the results from the genome wide association studies can be found at https://figshare.com/articles/dataset/S_pneumoniae_carriage_GWAS/14431313

The following data sets were generated

Article and author information

Author details

  1. Philip HC Kremer

    Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef, Netherlands
    For correspondence
    philip_kremer@hotmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0483-841X
  2. Bart Ferwerda

    Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Hester J Bootsma

    Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Nienke Y Rots

    Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Alienke J Wijmenga-Monsuur

    Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5663-860X
  6. Elisabeth AM Sanders

    Department of Pediatric Immunology and Infectious D, Wilhelmina Children's Hospital, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Krzysztof Trzciński

    Department of Pediatric Immunology and Infectious D, Wilhelmina Children's Hospital, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Anne L Wyllie

    Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6015-0279
  9. Paul Turner

    Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, 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
  10. Arie van der Ende

    Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Matthijs C Brouwer

    Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Stephen D Bentley

    Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Diederik van de Beek

    Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  14. John Lees

    European Bioinformatics Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Funding

European Research Council (281156)

  • Diederik van de Beek

ZonMw (91819627)

  • Diederik van de Beek

Wellcome Trust (219699)

  • John Lees

Wellcome Trust (083735/Z/07/Z)

  • Paul Turner

Rijksinstituut voor Volksgezondheid en Milieu

  • Arie van der Ende

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

Ethics

Human subjects: in children and their parents (NL24116 and NL40288/NTR3613) were received from the National Ethics Committee in the Netherlands (CCMO and METC Noord-Holland). For the 2010/2011 study, a National Ethics Committee in The Netherlands (STEG-METC, Almere) waived the requirement for EC approval. Informed consent for the Maela cohort was described elsewhere.(6) Studies were conducted in accordance with the European Statements for Good Clinical Practice and the Declaration of Helsinki of the World Medical Association.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Preprint posted: March 3, 2021 (view preprint)
  2. Received: April 8, 2021
  3. Accepted: July 3, 2022
  4. Accepted Manuscript published: July 26, 2022 (version 1)
  5. Version of Record published: August 22, 2022 (version 2)
  6. Version of Record updated: December 16, 2022 (version 3)

Copyright

© 2022, Kremer 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. Philip HC Kremer
  2. Bart Ferwerda
  3. Hester J Bootsma
  4. Nienke Y Rots
  5. Alienke J Wijmenga-Monsuur
  6. Elisabeth AM Sanders
  7. Krzysztof Trzciński
  8. Anne L Wyllie
  9. Paul Turner
  10. Arie van der Ende
  11. Matthijs C Brouwer
  12. Stephen D Bentley
  13. Diederik van de Beek
  14. John Lees
(2022)
Pneumococcal genetic variability in age-dependent bacterial carriage
eLife 11:e69244.
https://doi.org/10.7554/eLife.69244

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