Pneumococcal genetic variability in age-dependent bacterial carriage
- Amsterdam UMC, University of Amsterdam, Netherlands
- National Institute for Public Health and the Environment, Netherlands
- Wilhelmina Children's Hospital, Netherlands
- Yale School of Public Health, United States
- Angkor Hospital for Children, Cambodia
- Amsterdam UMC, Netherlands
- Wellcome Sanger Institute, United Kingdom
- 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
Article and author information
Author details
Alienke J Wijmenga-Monsuur
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.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
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.
Version history
- Preprint posted: March 3, 2021 (view preprint)
- Received: April 8, 2021
- Accepted: July 3, 2022
- Accepted Manuscript published: July 26, 2022 (version 1)
- Version of Record published: August 22, 2022 (version 2)
- 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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Pneumococcal genetic variability in age-dependent bacterial carriage
eLife 11:e69244.
https://doi.org/10.7554/eLife.69244
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