Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef, Netherlands
Bart Ferwerda
Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef, Netherlands; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Amsterdam, Netherlands
Hester J Bootsma
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
Nienke Y Rots
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
Elisabeth AM Sanders
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands; Department of Pediatric Immunology and Infectious D, Wilhelmina Children's Hospital, Utrecht, Netherlands
Krzysztof Trzciński
Department of Pediatric Immunology and Infectious D, Wilhelmina Children's Hospital, Utrecht, Netherlands
Department of Pediatric Immunology and Infectious D, Wilhelmina Children's Hospital, Utrecht, Netherlands; Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, United States
Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Arie van der Ende
Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, Amsterdam, Netherlands; The Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam, Netherlands
Matthijs C Brouwer
Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef, Netherlands
Stephen D Bentley
Parasites and Microbes, Wellcome Sanger Institute, Cambridge, United Kingdom
Diederik van de Beek
Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef, Netherlands
European Molecular Biology Laboratory–European Bioinformatics Institute, Cambridge, United Kingdom; MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom
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 (h2 = 0.10, 95% CI 0.00–0.69) and stronger evidence in the second cohort (h2 = 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 (h2serotype = 0.07, 95% CI 0.04–0.14 and h2GPSC = 0.06, 95% CI 0.03–0.13) and the second cohort (h2serotype = 0.11, 95% CI 0.05–0.21 and h2GPSC = 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.
