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Nat Commun. 2019 May 15;10(1):2176. doi: 10.1038/s41467-019-09976-3.

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Author information

1
Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
2
Parasites and Microbes, Wellcome Sanger Institute, Cambridge, CB10 1SA, UK.
3
Amsterdam UMC, University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
4
The Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Cambridge, CB10 1SA, UK.
5
MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, W2 1PG, UK.
6
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, 3721 MA, The Netherlands.
7
Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, 3508 AB, The Netherlands.
8
Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, 06520, USA.
9
Amsterdam UMC, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
10
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
11
Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, DK-2300, Denmark.
12
Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, 2650, Denmark.
13
Department of Human Nutrition, Wageningen University, P.O. Box 17, 6700 AA, Wageningen, The Netherlands.
14
Amsterdam UMC, VU University, Department of Epidemiology and Biostatistics, Amsterdam Public Health, Van der Boechorststraat 7, Amsterdam, 1007 MB, The Netherlands.
15
Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Geriatrics, Amsterdam Public Health, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
16
Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
17
Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, DK-2000, Denmark.
18
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Copenhagen, DK-2200, Denmark.
19
The Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-1014, Denmark.
20
Institute of Clinical Research, University of Southern Denmark, Odense, DK-5000, Denmark.
21
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
22
School of Pathology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, 2000, South Africa.
23
National Institute for Communicable Diseases, Johannesburg, 2192, South Africa.
24
Amsterdam UMC, University of Amsterdam, Department of Medical Microbiology, Amsterdam Infection and Immunity, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
25
Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC/RIVM, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
26
Genomics Plc, East Road, Cambridge, CB1 1BH, UK.
27
Parasites and Microbes, Wellcome Sanger Institute, Cambridge, CB10 1SA, UK. sdb@sanger.ac.uk.
28
Amsterdam UMC, University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands. d.vandebeek@amc.uva.nl.

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 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.

PMID:
31092817
PMCID:
PMC6520353
DOI:
10.1038/s41467-019-09976-3
[Indexed for MEDLINE]
Free PMC Article

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