Pneumococcal genetic variability in age-dependent bacterial carriage
Philip H. C. Kremer, Bart Ferwerda, Hester J. Bootsma, Nienke Y Rots, Alienke J. Wijmenga‐Monsuur, Elisabeth A. M. Sanders, Krzysztof Trzciński, Anne L. Wyllie, Paul Turner, Arie van der Ende, Matthijs C. Brouwer, Stephen D. Bentley, Diederik van de Beek, John A. Lees
Abstract
The characteristics of pneumococcal carriage vary between infants and adults. Host immune factors have been shown to contribute to these age-specific differences, but the role of pathogen sequence variation is currently less well-known. Identification of age-associated pathogen genetic factors could leadto improved vaccine formulations. We therefore performed genome sequencing in a large carriage cohort of children and adults and combined this with data from an existing age-stratified carriage study. We compiled a dictionary of pathogen genetic variation, including serotype, strain, sequence elements, single-nucleotide polymorphisms (SNPs), and clusters of orthologous genes (COGs) for each cohort – all of which were used in a genome-wide association with host age. Age-dependent colonization showed weak evidence of being heritable in the first cohort ( h 2 = 0.10, 95% CI 0.00–0.69) and stronger evidence in the second cohort ( h 2 = 0.56, 95% CI 0.23–0.87). We found that serotypes and genetic background (strain) explained a proportion of the heritability in the first cohort ( h 2 serotype = 0.07, 95% CI 0.04–0.14 and h 2 GPSC = 0.06, 95% CI 0.03–0.13) and the second cohort ( h 2 serotype = 0.11, 95% CI 0.05–0.21 and h 2 GPSC = 0.20, 95% CI 0.12–0.31). In a meta-analysis of these cohorts, we found one candidate association (p=1.2 × 10 -9 ) upstream of an accessory Sec-dependent serine-rich glycoprotein adhesin. Overall, while we did find a small effect of pathogen genome variation on pneumococcal carriage between child and adult hosts, this was variable between populations and does not appear to be caused by strong effects of individual genes. This supports proposals for adaptive future vaccination strategies that are primarily targeted at dominant circulating serotypes and tailored to the composition of the pathogen populations.