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
-
- 1,016
- 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
-
- Genetics and Genomics
Signaling through the platelet-derived growth factor receptor alpha (PDGFRα) plays a critical role in craniofacial development. Phosphatidylinositol 3-kinase (PI3K)/Akt is the primary effector of PDGFRα signaling during mouse skeletal development. We previously demonstrated that Akt phosphorylates the RNA-binding protein serine/arginine-rich splicing factor 3 (Srsf3) downstream of PI3K-mediated PDGFRα signaling in mouse embryonic palatal mesenchyme (MEPM) cells, leading to its nuclear translocation. We further showed that ablation of Srsf3 in the murine neural crest lineage results in severe midline facial clefting and widespread alternative RNA splicing (AS) changes. Here, we demonstrated via enhanced UV-crosslinking and immunoprecipitation of MEPM cells that PDGF-AA stimulation leads to preferential binding of Srsf3 to exons and loss of binding to canonical Srsf3 CA-rich motifs. Through the analysis of complementary RNA-seq data, we showed that Srsf3 activity results in the preferential inclusion of exons with increased GC content and lower intron to exon length ratio. We found that Srsf3 activity downstream of PDGFRα signaling leads to retention of the receptor in early endosomes and increases in downstream PI3K-mediated Akt signaling. Taken together, our findings reveal that growth factor-mediated phosphorylation of an RNA-binding protein underlies gene expression regulation necessary for mammalian craniofacial development.
-
- Genetics and Genomics
Recent studies have shown that, in human cancer cells, the tetrameric Shieldin complex (comprising REV7, SHLD1, SHLD2, and SHLD3) facilitates non-homologous end-joining (NHEJ) while blocking homologous recombination (HR). Surprisingly, several eukaryotic species lack SHLD1, SHLD2, and SHLD3 orthologs, suggesting that Rev7 may leverage an alternative mechanism to regulate the double-strand break (DSB) repair pathway choice. Exploring this hypothesis, we discovered that Saccharomyces cerevisiae Rev7 physically interacts with the Mre11–Rad50–Xrs2 (MRX) subunits, impedes G-quadruplex DNA synergized HU-induced toxicity, and facilitates NHEJ, while antagonizing HR. Notably, we reveal that a 42-amino acid C-terminal fragment of Rev7 binds to the subunits of MRX complex, protects rev7∆ cells from G-quadruplex DNA-HU-induced toxicity, and promotes NHEJ by blocking HR. By comparison, the N-terminal HORMA domain, a conserved protein–protein interaction module, was dispensable. We further show that the full-length Rev7 impedes Mre11 nuclease and Rad50’s ATPase activities without affecting the latter’s ATP-binding ability. Combined, these results provide unanticipated insights into the functional interaction between the MRX subunits and Rev7 and highlight a previously unrecognized mechanism by which Rev7 facilitates DSB repair via NHEJ, and attenuation of HR, by blocking Mre11 nuclease and Rad50’s ATPase activities in S. cerevisiae.
