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.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
Publication 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
Further reading
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- Evolutionary Biology
- Genetics and Genomics
Female Aedes aegypti mosquitoes impose a severe global public health burden as vectors of multiple viral pathogens. Under optimal environmental conditions, Aedes aegypti females have access to human hosts that provide blood proteins for egg development, conspecific males that provide sperm for fertilization, and freshwater that serves as an egg-laying substrate suitable for offspring survival. As global temperatures rise, Aedes aegypti females are faced with climate challenges like intense droughts and intermittent precipitation, which create unpredictable, suboptimal conditions for egg-laying. Here we show that under drought-like conditions simulated in the laboratory, females retain mature eggs in their ovaries for extended periods, while maintaining the viability of these eggs until they can be laid in freshwater. Using transcriptomic and proteomic profiling of Aedes aegypti ovaries, we identify two previously uncharacterized genes named tweedledee and tweedledum, each encoding a small, secreted protein that both show ovary-enriched, temporally-restricted expression during egg retention. These genes are mosquito-specific, linked within a syntenic locus, and rapidly evolving under positive selection, raising the possibility that they serve an adaptive function. CRISPR-Cas9 deletion of both tweedledee and tweedledum demonstrates that they are specifically required for extended retention of viable eggs. These results highlight an elegant example of taxon-restricted genes at the heart of an important adaptation that equips Aedes aegypti females with 'insurance' to flexibly extend their reproductive schedule without losing reproductive capacity, thus allowing this species to exploit unpredictable habitats in a changing world.
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- Epidemiology and Global Health
- Genetics and Genomics
Background: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases.
Methods: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption.
Results: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 21 associations persisted after adjusting for genetically-predicted alcohol consumption. Genetically-predicted higher alcohol consumption was associated with increased risk of duodenal cancer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain after adjustment for genetic predisposition to smoking initiation.
Conclusion: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases.
Funding: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.
