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

John A. Lees, Bart Ferwerda, Philip H. C. Kremer, Nicole E. Wheeler, Mercedes Valls Serón, Nicholas J. Croucher, Rebecca A. Gladstone, Hester J. Bootsma, Nynke Y. Rots, Alienke J. Wijmega-Monsuur, Elisabeth A. M. Sanders, Krzysztof Trzciński, Anne L. Wyllie, Aeilko H. Zwinderman, Leonard H. van den Berg, Wouter van Rheenen, Jan H. Veldink, Zitta B. Harboe, Lene F. Lundbo, Lisette C. P. G. M. de Groot, Natasja M. van Schoor, Nathalie van der Velde, Lars H. Ängquist, Thorkild I. A. Sørensen, Ellen A. Nohr, Alexander J. Mentzer, Tara C. Mills, Julian C. Knight, Mignon du Plessis, Susan Nzenze, Jeffrey N. Weiser, Julian Parkhill, Shabir Madhi, Thomas Benfield, Anne von Gottberg, Arie van der Ende, Matthijs C. Brouwer, Jeffrey C. Barrett, Stephen D. Bentley () and Diederik van de Beek ()
Additional contact information
John A. Lees: New York University School of Medicine
Bart Ferwerda: Amsterdam Neuroscience
Philip H. C. Kremer: Amsterdam Neuroscience
Nicole E. Wheeler: Wellcome Sanger Institute
Mercedes Valls Serón: Amsterdam Neuroscience
Nicholas J. Croucher: Imperial College London
Rebecca A. Gladstone: Wellcome Sanger Institute
Hester J. Bootsma: National Institute for Public Health and the Environment
Nynke Y. Rots: National Institute for Public Health and the Environment
Alienke J. Wijmega-Monsuur: National Institute for Public Health and the Environment
Elisabeth A. M. Sanders: National Institute for Public Health and the Environment
Krzysztof Trzciński: University Medical Centre Utrecht
Anne L. Wyllie: University Medical Centre Utrecht
Aeilko H. Zwinderman: Amsterdam Public Health
Leonard H. van den Berg: University Medical Center Utrecht
Wouter van Rheenen: University Medical Center Utrecht
Jan H. Veldink: University Medical Center Utrecht
Zitta B. Harboe: Statens Serum Institut
Lene F. Lundbo: University of Copenhagen
Lisette C. P. G. M. de Groot: Wageningen University
Natasja M. van Schoor: Amsterdam Public Health
Nathalie van der Velde: Amsterdam Public Health
Lars H. Ängquist: Bispebjerg and Frederiksberg Hospitals, The Capital Region
Thorkild I. A. Sørensen: Section of Metabolic Genetics
Ellen A. Nohr: University of Southern Denmark
Alexander J. Mentzer: University of Oxford
Tara C. Mills: University of Oxford
Julian C. Knight: University of Oxford
Mignon du Plessis: University of Witwatersrand
Susan Nzenze: University of Witwatersrand
Jeffrey N. Weiser: New York University School of Medicine
Julian Parkhill: Wellcome Sanger Institute
Shabir Madhi: National Institute for Communicable Diseases
Thomas Benfield: University of Copenhagen
Anne von Gottberg: University of Witwatersrand
Arie van der Ende: Amsterdam Infection and Immunity
Matthijs C. Brouwer: Amsterdam Neuroscience
Jeffrey C. Barrett: Wellcome Sanger Institute
Stephen D. Bentley: Wellcome Sanger Institute
Diederik van de Beek: Amsterdam Neuroscience

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09976-3

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