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Joint Sequencing of Human and Pathogen Genomes Reveals the Genetics of Pneumococcal Meningitis

74 Pages Posted: 16 Aug 2018 Last revised: 24 Sep 2018 Sneak Peek Status: Review Complete

See all articles by John Lees

John Lees

New York University (NYU) - Department of Microbiology

Bart Ferwerda

University of Amsterdam - Department of Neurology

Philip H. C. Kremer

University of Amsterdam - Department of Neurology

Nicole E. Wheeler

Wellcome Genome Campus - Infection Genomics

Mercedes Valls Serón

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Nicholas J. Croucher

Imperial College London - Department of Infectious Disease

Rebecca A. Gladstone

Wellcome Genome Campus - Infection Genomics

Hester J. Bootsma

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Nynke Rots

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Alienke J. Wijmega-Monsuur

Wellcome Genome Campus - Infection Genomics

Elisabeth A. M. Sanders

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Krzysztof Trzciński

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Anne L. Wyllie

Utrecht University - Department of Pediatric Immunology and Infectious Diseases

Aeilko H. Zwinderman

University of Amsterdam - Department of Biostatistics

Leonard H. van den Berg

Utrecht University - Department of Neurology

Wouter van Rheenen

Utrecht University - Department of Neurology

Jan H. Veldink

Utrecht University - Department of Neurology

Zitta B. Harboe

Statens Serums Institut - Department of Microbiological Surveillance and Research

Lene F. Lundbo

University of Copenhagen - Department of Infectious Diseases

Lisette C. P. G. M. de Groot

Wageningen UR - Department of Human Nutrition

Natasja M. van Schoor

University of Amsterdam - Amsterdam Public Health Research Institute

Nathalie van der Velde

University of Amsterdam - Amsterdam Public Health Research Institute

Lars H. Ängquist

Bispebjerg and Frederiksberg Hospitals - Center for Clinical Research and Disease Prevention

Thorkild I. A. Sørensen

University of Copenhagen - Section of Metabolic Genetics

Ellen A. Nohr

University of Southern Denmark - Institute of Clinical Research

Alexander J. Mentzer

University of Oxford - Wellcome Trust Centre for Human Genetics; University of Oxford - Li Ka Shing Centre for Health Information and Discovery

Tara C. Mills

University of Oxford - Wellcome Trust Centre for Human Genetics

Julian C. Knight

University of Oxford - Wellcome Trust Centre for Human Genetics

Mignon du Plessis

University of the Witwatersrand

Susan Nzenze

University of the Witwatersrand

Jeffrey N. Weiser

New York University (NYU) - Department of Microbiology

Julian Parkhill

Wellcome Genome Campus - Infection Genomics

Shabir Madhi

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases

Thomas Benfield

University of Copenhagen - Department of Infectious Diseases

Anne von Gottberg

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases; University of the Witwatersrand - School of Pathology

Arie van der Ende

University of Amsterdam - Netherlands Reference Laboratory for Bacterial Meningitis

Matthijs C. Brouwer

University of Amsterdam - Department of Neurology

Jeffrey C. Barrett

Wellcome Genome Campus - Infection Genomics

Stephen D. Bentley

Wellcome Genome Campus - Parasites and Microbes

Diederik van de Beek

University of Amsterdam - Department of Neurology

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Abstract

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause lifethreatening 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, and identified variants in CCDC33 associated with susceptibility. Pneumococcal variation explained a large amount of invasive potential, but serotype explained only half of this variation. Newly developed methods identified pneumococcal genes involved in invasiveness including pspC and zmpD, and allowed a human-bacteria interaction analysis, finding associations between pneumococcal lineage and STK32C.

Suggested Citation

Lees, John and Ferwerda, Bart and Kremer, Philip H. C. and Wheeler, Nicole E. and Serón, Mercedes Valls and Croucher, Nicholas J. and Gladstone, Rebecca A. and Bootsma, Hester J. and Rots, Nynke and Wijmega-Monsuur, Alienke J. and Sanders, Elisabeth A. M. and Trzciński, Krzysztof and Wyllie, Anne L. and Zwinderman, Aeilko H. and van den Berg, Leonard H. and Rheenen, Wouter van and Veldink, Jan H. and Harboe, Zitta B. and Lundbo, Lene F. and de Groot, Lisette C. P. G. M. and van Schoor, Natasja M. and van der Velde, Nathalie and Ängquist, Lars H. and Sørensen, Thorkild I. A. and Nohr, Ellen A. and Mentzer, Alexander J. and Mills, Tara C. and Knight, Julian C. and Plessis, Mignon du and Nzenze, Susan and Weiser, Jeffrey N. and Parkhill, Julian and Madhi, Shabir and Benfield, Thomas and von Gottberg, Anne and van der Ende, Arie and Brouwer, Matthijs C. and Barrett, Jeffrey C. and Bentley, Stephen D. and van de Beek, Diederik, Joint Sequencing of Human and Pathogen Genomes Reveals the Genetics of Pneumococcal Meningitis. Available at SSRN: https://ssrn.com/abstract=3231844 or http://dx.doi.org/10.2139/ssrn.3231844
This is a paper under consideration at Cell Press and has not been peer-reviewed.

John Lees (Contact Author)

New York University (NYU) - Department of Microbiology ( email )

550 First Ave.
VZ30, Office 626
New York, NY 10016
United States

Bart Ferwerda

University of Amsterdam - Department of Neurology

Spui 21
Amsterdam, 1018 WB
Netherlands

Philip H. C. Kremer

University of Amsterdam - Department of Neurology

Spui 21
Amsterdam, 1018 WB
Netherlands

Nicole E. Wheeler

Wellcome Genome Campus - Infection Genomics

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Mercedes Valls Serón

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Bilthoven
Netherlands

Nicholas J. Croucher

Imperial College London - Department of Infectious Disease

United Kingdom

Rebecca A. Gladstone

Wellcome Genome Campus - Infection Genomics

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Hester J. Bootsma

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Bilthoven
Netherlands

Nynke Rots

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Bilthoven
Netherlands

Alienke J. Wijmega-Monsuur

Wellcome Genome Campus - Infection Genomics

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Elisabeth A. M. Sanders

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Bilthoven
Netherlands

Krzysztof Trzciński

National Institute for Public Health and the Environment - Centre for Infectious Disease Control

Bilthoven
Netherlands

Anne L. Wyllie

Utrecht University - Department of Pediatric Immunology and Infectious Diseases

6.119, PO Box 85500
Utrecht, 3508 GA
Netherlands

Aeilko H. Zwinderman

University of Amsterdam - Department of Biostatistics

Meibergdreef 9
Amsterdam, 1105
Netherlands

Leonard H. Van den Berg

Utrecht University - Department of Neurology

GA Utrecht
Netherlands

Wouter van Rheenen

Utrecht University - Department of Neurology

GA Utrecht
Netherlands

Jan H. Veldink

Utrecht University - Department of Neurology

GA Utrecht
Netherlands

Zitta B. Harboe

Statens Serums Institut - Department of Microbiological Surveillance and Research

Ørestads Boulevard 5
Copenhagen, 2300S
Denmark

Lene F. Lundbo

University of Copenhagen - Department of Infectious Diseases

Denmark

Lisette C. P. G. M. De Groot

Wageningen UR - Department of Human Nutrition

Hollandseweg 1
Wageningen, 6706KN
Netherlands

Natasja M. Van Schoor

University of Amsterdam - Amsterdam Public Health Research Institute

Meibergdreef 9
Amsterdam, 1105
Netherlands

Nathalie Van der Velde

University of Amsterdam - Amsterdam Public Health Research Institute

Meibergdreef 9
Amsterdam, 1105
Netherlands

Lars H. Ängquist

Bispebjerg and Frederiksberg Hospitals - Center for Clinical Research and Disease Prevention

Bispebjerg Bakke 23
2400 København
Denmark

Thorkild I. A. Sørensen

University of Copenhagen - Section of Metabolic Genetics

Blegdamsvej 3B
Copenhagen, DK-2200
Denmark

Ellen A. Nohr

University of Southern Denmark - Institute of Clinical Research

Campusvej 55
DK-5230 Odense, 5000
Denmark

Alexander J. Mentzer

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

University of Oxford - Li Ka Shing Centre for Health Information and Discovery ( email )

Oxford, OX3 7FZ
United Kingdom

Tara C. Mills

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Julian C. Knight

University of Oxford - Wellcome Trust Centre for Human Genetics

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Mignon du Plessis

University of the Witwatersrand

Susan Nzenze

University of the Witwatersrand

Jeffrey N. Weiser

New York University (NYU) - Department of Microbiology

550 First Ave.
VZ30, Office 626
New York, NY 10016
United States

Julian Parkhill

Wellcome Genome Campus - Infection Genomics

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Shabir Madhi

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases

Johannesburg
South Africa

Thomas Benfield

University of Copenhagen - Department of Infectious Diseases

Denmark

Anne Von Gottberg

National Health Laboratory Services (NHLS) - National Institute for Communicable Diseases

Johannesburg
South Africa

University of the Witwatersrand - School of Pathology

Johannesburg, 2000
South Africa

Arie Van der Ende

University of Amsterdam - Netherlands Reference Laboratory for Bacterial Meningitis

Meibergdreef 9
Amsterdam, 1105
Netherlands

Matthijs C. Brouwer

University of Amsterdam - Department of Neurology

Spui 21
Amsterdam, 1018 WB
Netherlands

Jeffrey C. Barrett

Wellcome Genome Campus - Infection Genomics

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Stephen D. Bentley

Wellcome Genome Campus - Parasites and Microbes ( email )

Hinxton
United Kingdom

Diederik Van de Beek

University of Amsterdam - Department of Neurology ( email )

Spui 21
Amsterdam, 1018 WB
Netherlands

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