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 GrootNatasja 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, Diederik van de Beek

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34 Citations (Scopus)


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.

Original languageEnglish
Article number2176
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2019

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