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.
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.
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.
Metrics
-
- 1,018
- views
-
- 231
- downloads
-
- 8
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Pneumococcal genetic variability in age-dependent bacterial carriage
eLife 11:e69244.
https://doi.org/10.7554/eLife.69244
Further reading
-
- Biochemistry and Chemical Biology
- Genetics and Genomics
Yerba mate (YM, Ilex paraguariensis) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here, we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes. Comparative analyses revealed that the large YM genome size is partly due to a whole-genome duplication (Ip-α) during the early evolutionary history of Ilex, in addition to the hexaploidization event (γ) shared by core eudicots. Characterization of the genome allowed us to clone the genes encoding methyltransferase enzymes that catalyse multiple reactions required for caffeine production. To our surprise, this species has converged upon a different biochemical pathway compared to that of coffee and tea. In order to gain insight into the structural basis for the convergent enzyme activities, we obtained a crystal structure for the terminal enzyme in the pathway that forms caffeine. The structure reveals that convergent solutions have evolved for substrate positioning because different amino acid residues facilitate a different substrate orientation such that efficient methylation occurs in the independently evolved enzymes in YM and coffee. While our results show phylogenomic constraint limits the genes coopted for convergence of caffeine biosynthesis, the X-ray diffraction data suggest structural constraints are minimal for the convergent evolution of individual reactions.
-
- Genetics and Genomics
There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that are relatively inexpensive compared to traditional drug development. In the absence of a validated drug target, phenotypic screening in model organisms provides a route for identifying candidate treatments. Success requires a screenable phenotype. However, the right phenotype and assay may not be obvious for pleiotropic neuromuscular disorders. Here, we show that high-throughput imaging and quantitative phenotyping can be conducted systematically on a panel of C. elegans disease model strains. We used CRISPR genome-editing to create 25 worm models of human Mendelian diseases and phenotyped them using a single standardised assay. All but two strains were significantly different from wild-type controls in at least one feature. The observed phenotypes were diverse, but mutations of genes predicted to have related functions led to similar behavioural differences in worms. As a proof-of-concept, we performed a drug repurposing screen of an FDA-approved compound library, and identified two compounds that rescued the behavioural phenotype of a model of UNC80 deficiency. Our results show that a single assay to measure multiple phenotypes can be applied systematically to diverse Mendelian disease models. The relatively short time and low cost associated with creating and phenotyping multiple strains suggest that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.
