Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis
Lees, John A.; Ferwerda, Bart; Kremer, Philip H.C.; Wheeler, Nicole E.; Serón, Mercedes Valls; Croucher, Nicholas J.; Gladstone, Rebecca A.; Bootsma, Hester J.; Rots, Nynke Y.; Wijmega-Monsuur, Alienke J.; Sanders, Elisabeth A.M.; Trzciński, Krzysztof; Wyllie, Anne L.; Zwinderman, Aeilko H.; van den Berg, Leonard H.; van Rheenen, Wouter; Veldink, Jan H.; Harboe, Zitta B.; Lundbo, Lene F.; de Groot, Lisette C.P.G.M.; van Schoor, Natasja M.; van der Velde, Nathalie; Ängquist, Lars H.; Sørensen, Thorkild I.A.; Nohr, Ellen A.; Mentzer, Alexander J.; Mills, Tara C.; Knight, Julian C.; du Plessis, Mignon; Nzenze, Susan; Weiser, Jeffrey N.; Parkhill, Julian; Madhi, Shabir; Benfield, Thomas; von Gottberg, Anne; van der Ende, Arie; Brouwer, Matthijs C.; Barrett, Jeffrey C.; Bentley, Stephen D.; van de Beek, Diederik
(2019) Nature Communications, volume 10, issue 1
(Article)
Abstract
Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and
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pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.
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Keywords: Adult, Aged, Bacterial Proteins/genetics, Female, Genetic Predisposition to Disease, Genetic Variation, Genome, Bacterial/genetics, Genome, Human/genetics, Genome-Wide Association Study, Host-Pathogen Interactions/genetics, Humans, Male, Meningitis, Pneumococcal/genetics, Middle Aged, Prospective Studies, Proteins/genetics, Streptococcus pneumoniae/genetics, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: Competing interests: N.J.C. and S.D.B. were consultants for Antigen Discovery, Inc involved in the design of a proteome array for S. pneumoniae. E.A.M.S. reports grants from the pharmaceutical companies GlaxoSmithKline and Pfizer outside the submitted work. K.T. reports grants from Pfizer and consultancy fees from Pfizer paid to University Medical Centre Utrecht, both received outside the submitted work. A.L.W. received consulting fees for participation in advisory boards for Pfizer, outside the submitted work. D.v.d.B. received departmental honoraria for serving on a scientific advisory board for GlaxoSmithKline and InflaRx paid to the Amsterdam UMC, outside the submitted work. All the other authors declare no competing interests. Funding Information: Win Kit Man isolated genomic DNA from bacteria in the Dutch cohort. We would like to thank Chao Tan and David Hinds from 23andme for sharing summary statistics from their association with self-reported bacterial meningitis. We also thank all members of the GenOSept consortium for making their data available and Anna Rautanen in particular for her preparation of the genetic data. This research has been conducted using the UK Biobank Resource under Application Number 25747. This study also makes use of data generated by the Genome of The Netherlands Project (GoNL). Funding for the GoNL project was provided by The Netherlands Organization for Scientific Research under award number 184021007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). Work at the Wellcome Trust Sanger Institute was supported by Wellcome Trust (098051). This work was also supported by grants from the European Research Council (ERC Starting Grant, proposal/contract 281156; https://erc.europa.eu/) to D.v.d.B. and the Netherlands Organization for Health Research and Development (ZonMw; NWO-Vidi grant 2010, proposal/contract 016.116.358 to D.v.d.B.; NWO-Veni Grant NWO-Veni grant 2012 proposal/contract 916.13.078 to M.B.; www.zonmw.nl/). The Netherlands Reference Laboratory for Bacterial Meningitis was supported by the National Institute for Health and Environmental Protection, Bilthoven (www.rivm.nl/). J.A.L. was supported by a Medical Research Council studentship grant (1365620). N.J.C. was supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (grant number 104169/Z/14/Z). J.N.W. is funded by grants from the United States Public Health Service (AI038446 and AI105168). The B-PROOF cohort was funded by The Netherlands Organization for Health Research and Development (ZonMw, Grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15–004–003), the Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam; Unilever, Colworth, UK. Dutch Carriage studies at RIVM were funded by the Dutch Ministry of Health, Welfare and Sport. Genotyping for GOYA was funded by the Wellcome Trust (WT 084762MA). GOYA is a nested study within The Danish National Birth Cohort, which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Funding for the Danish Invasive Pneumococcal Disease Cohort was kindly provided by the Lundbeck Foundation, the Novo Nordisk Foundation, King Christian the 10th Foundation, Jacob Madsen’s Foundation, TrygVesta, Ebba Celinder’s Foundation, the Danish Medical Association Foundation, the Foundation for Advancement of Medical Science, the Augustinus Foundation, Peder Laurits Pedersen’s Foundation, A.P. Møller Foundation for the Advancement of Medical Science, the Danish Medical Research Council, Preben and Anna Simon-sen’s Foundation, Ferdinand and Ellen Hindsgaul’s Foundation, the Hartmann’s Foundation and Dagmar Marshalls Fond. The GenOSept study was supported by the European Union (6th framework programme of RTD funding) and the National Institute for Health Research, through the Comprehensive Clinical Research Network. J.C.K. was supported by NIHR Oxford Biomedical Research Centre and a Wellcome Trust Investigator Award (204969/Z/16/Z) and A.J.W.-M. was supported by a Wellcome Trust Fellowship with reference 106289/Z/14/Z. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2019, The Author(s).
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