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.

Streptococcus pneumoniae is a causative agent of meningitis and bacteremia. In a combined pathogen and host GWAS, Lees et al. find that host genetic variation is associated with both susceptibility and severity of pneumococcal meningitis, and specific bacterial genetic variation associated with susceptibility.

Details

Title
Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis
Author
Lees, John A 1   VIAFID ORCID Logo  ; Ferwerda Bart 2   VIAFID ORCID Logo  ; Kremer, Philip H, C 2 ; Wheeler, Nicole E 3 ; Serón Mercedes Valls 2 ; Croucher, Nicholas J 4   VIAFID ORCID Logo  ; Gladstone, Rebecca A 5 ; Bootsma, Hester J 6 ; Rots, Nynke Y 6 ; Wijmega-Monsuur Alienke J 6 ; Sanders Elisabeth A M 7 ; Trzciński Krzysztof 8 ; Wyllie, Anne L 9 ; Zwinderman Aeilko H 10   VIAFID ORCID Logo  ; van den Berg Leonard H 11 ; Wouter, van Rheenen 11   VIAFID ORCID Logo  ; Veldink, Jan H 11 ; Harboe, Zitta B 12 ; Lundbo, Lene F 13 ; de Groot Lisette C P G M 14   VIAFID ORCID Logo  ; van Schoor Natasja M 15 ; van der Velde Nathalie 16 ; Ängquist, Lars H 17 ; Sørensen Thorkild I A 18   VIAFID ORCID Logo  ; Nohr, Ellen A 19 ; Mentzer, Alexander J 20   VIAFID ORCID Logo  ; Mills, Tara C 20 ; Knight, Julian C 20   VIAFID ORCID Logo  ; du Plessis Mignon 21   VIAFID ORCID Logo  ; Nzenze, Susan 21 ; Weiser, Jeffrey N 22   VIAFID ORCID Logo  ; Parkhill Julian 5   VIAFID ORCID Logo  ; Madhi Shabir 23 ; Benfield, Thomas 13 ; von Gottberg Anne 24 ; van der Ende Arie 25 ; Brouwer, Matthijs C 2 ; Barrett, Jeffrey C 26   VIAFID ORCID Logo  ; Bentley, Stephen D 5 ; van de Beek Diederik 2   VIAFID ORCID Logo 

 New York University School of Medicine, Department of Microbiology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753); Wellcome Sanger Institute, Parasites and Microbes, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
 Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Department of Neurology, Amsterdam, The Netherlands (GRID:grid.484519.5) 
 Wellcome Sanger Institute, Parasites and Microbes, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Wellcome Sanger Institute, The Centre for Genomic Pathogen Surveillance, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
 Imperial College London, MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
 Wellcome Sanger Institute, Parasites and Microbes, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
 National Institute for Public Health and the Environment, Centre for Infectious Disease Control, Bilthoven, The Netherlands (GRID:grid.31147.30) (ISNI:0000 0001 2208 0118) 
 National Institute for Public Health and the Environment, Centre for Infectious Disease Control, Bilthoven, The Netherlands (GRID:grid.31147.30) (ISNI:0000 0001 2208 0118); University Medical Centre Utrecht, Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
 University Medical Centre Utrecht, Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
 University Medical Centre Utrecht, Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352); Yale School of Public Health, Epidemiology of Microbial Diseases, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
10  Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
11  University Medical Center Utrecht, Department of Neurology, Brain Center Rudolf Magnus, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
12  Statens Serum Institut, Department of Microbiological Surveillance and Research, Copenhagen, Denmark (GRID:grid.6203.7) (ISNI:0000 0004 0417 4147) 
13  University of Copenhagen, Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
14  Wageningen University, Department of Human Nutrition, Wageningen, The Netherlands (GRID:grid.4818.5) (ISNI:0000 0001 0791 5666) 
15  Amsterdam Public Health, Amsterdam UMC, VU University, Department of Epidemiology and Biostatistics, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
16  Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Geriatrics, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X); University Medical Centre Rotterdam, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
17  Bispebjerg and Frederiksberg Hospitals, The Capital Region, Center for Clinical Research and Disease Prevention, Copenhagen, Denmark (GRID:grid.5645.2) 
18  Section of Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark (GRID:grid.5645.2); University of Copenhagen, The Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
19  University of Southern Denmark, Institute of Clinical Research, Odense, Denmark (GRID:grid.10825.3e) (ISNI:0000 0001 0728 0170) 
20  University of Oxford, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
21  University of Witwatersrand, School of Pathology, Faculty of Health Sciences, Johannesburg, South Africa (GRID:grid.11951.3d) (ISNI:0000 0004 1937 1135) 
22  New York University School of Medicine, Department of Microbiology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
23  National Institute for Communicable Diseases, Johannesburg, South Africa (GRID:grid.416657.7) (ISNI:0000 0004 0630 4574) 
24  University of Witwatersrand, School of Pathology, Faculty of Health Sciences, Johannesburg, South Africa (GRID:grid.11951.3d) (ISNI:0000 0004 1937 1135); National Institute for Communicable Diseases, Johannesburg, South Africa (GRID:grid.416657.7) (ISNI:0000 0004 0630 4574) 
25  Amsterdam Infection and Immunity, Amsterdam UMC, University of Amsterdam, Department of Medical Microbiology, Amsterdam, The Netherlands (GRID:grid.416657.7); University of Amsterdam, Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam UMC/RIVM, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
26  Wellcome Sanger Institute, Parasites and Microbes, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Genomics Plc, Cambridge, UK (GRID:grid.10306.34) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2225813772
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.