Pneumococcal genetic variability in age-dependent bacterial carriage
Kremer, Philip H C; Ferwerda, Bart; Bootsma, Hester J; Rots, Nienke Y; Wijmenga-Monsuur, Alienke J; Sanders, Elisabeth A M; Trzciński, Krzysztof; Wyllie, Anne L; Turner, Paul; van der Ende, Arie; Brouwer, Matthijs C; Bentley, Stephen D; van de Beek, Diederik; Lees, John A
(2022) eLife, volume 2022, issue 11, pp. 1 - 20
(Article)
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
... read more
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 (h2 serotype = 0.07, 0.04 – 0.14 95% CI and h2 GPSC = 0.06, 0.03 – 0.13 95% CI) and the second cohort (h2 serotype = 0.11, 0.05 – 0.21 95% CI and h2 GPSC = 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.
show less
Download/Full Text
Keywords: Adult, Carrier State/microbiology, Child, Genome-Wide Association Study, Humans, Infant, Nasopharynx/microbiology, Pneumococcal Infections/genetics, Pneumococcal Vaccines, Serogroup, Streptococcus pneumoniae/genetics, Journal Article, Meta-Analysis
ISSN: 2050-084X
Publisher: eLife Sciences Publications
Note: Funding Information: This work was supported by grants from the European Research Council (ERC Starting Grant, proposal/contract 281156; https://erc.europa.eu) and the Netherlands Organization for Health Research and Development (ZonMw; NWO-Vici grant, proposal/contract 91819627; www.zonmw.nl), both to DvdB. Work at the Wellcome Trust Sanger Institute was supported by Wellcome Trust core funding (098051; https://wellcome.ac.uk). JAL was funded by Wellcome [219699], and received support from the Medical Research Council (grant number MR/R015600/1). This award is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 program supported by the European Union. PT was funded in part by the Wellcome Trust [Grant number 083735/Z/07/Z]. The Netherlands Reference Laboratory for Bacterial Meningitis was supported by the National Institute for Health and Environmental Protection, Bilthoven (www.rivm.nl). For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: This work was supported by grants from the European Research Council 縀ERC Starting Grant ? proposal 氁ခ紁瘁騁谁ȁခ騀 ? ? ? ? ? ? 嘀 https P ? ?erc ?europa ?eu ? and the Neftohre Hrleaanldths ORergseaanrizcaht iaonnd Development 縀?onMw 嘀 NWO?Vicigrant唀 proposal 氁?ontract ??? l??唀? bo? th嘀 to w DwvdwB 堁 堀찁 W紁or?kamt wth ?e Wnellcome Trust Sanger Institute was supported by Wellcome Trust core funding ? ? ht?tps P ?氃氁嘀? ellcome ? 缃a堀c ? JAuLk was funded by Wellcome 考? ? ? ? ? 唀 and received suMppeodritcafrl oRmes tehaerch Council ?grant number MR 氀R ? ? ? ? ? ? This award is jointly funded byetsheeaUrcKh MCoeudniccail R?MRC ? and the UK Department for International Development ?DFID ? under the MRCF I? D DConcordat agreement and is also part of the EDCTP program supported by the European Union 堀 PT wuansdfed in part by the Wellcome Trust 耀Grantnumber ????e氀 N?e?the?rla?nds? R?ef?ere?nceT hLaboratoryfor Bacterial Meningitis wassupported by the National Institute for Health and Environmental Protection 唀 Bilthoven 縁섁섁섃? l 缃ri堀vm F堁or? the purpose of open access 唀 the authors have applied a CC BY public copyrighlitc ence to any Author Accepted Manuscript Publisher Copyright: © 2022, eLife Sciences Publications Ltd. All rights reserved.
(Peer reviewed)