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 & 20 others 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, Diederik van de Beek

Research output: Contribution to journalArticleAcademicpeer-review

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.

LanguageEnglish
Article number2176
Number of pages14
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 15 May 2019

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meningitis
Pneumococcal Meningitis
sequencing
pathogens
genome
Pathogens
Human Genome
Genes
Joints
Pneumococcal Vaccines
Empyema
genes
Genome-Wide Association Study
Bacteremia
Streptococcus pneumoniae
Meningitis
Bacteria
streptococcus
pneumonia
vaccines

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Lees, J. A., Ferwerda, B., Kremer, P. H. C., Wheeler, N. E., Valls Serón, M., Croucher, N. J., ... van de Beek, D. (2019). Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis. Nature Communications, 10(1), [2176]. https://doi.org/10.1038/s41467-019-09976-3
Lees, John A. ; Ferwerda, Bart ; Kremer, Philip H.C. ; Wheeler, Nicole E. ; Valls Serón, Mercedes ; Croucher, Nicholas J. ; Gladstone, Rebecca A. ; Bootsma, Hester J. ; Rots, Nynke Y. ; Wijmega-Monsuur, Alienke J. ; Sanders, Elisabeth A.M. ; Trzciński, Krzysztof ; Wyllie, Anne L. ; Zwinderman, Aeilko H. ; van den Berg, Leonard H. ; van Rheenen, Wouter ; Veldink, Jan H. ; Harboe, Zitta B. ; Lundbo, Lene F. ; de Groot, Lisette C.P.G.M. ; van Schoor, Natasja M. ; van der Velde, Nathalie ; Ängquist, Lars H. ; Sørensen, Thorkild I.A. ; Nohr, Ellen A. ; Mentzer, Alexander J. ; Mills, Tara C. ; Knight, Julian C. ; du Plessis, Mignon ; Nzenze, Susan ; Weiser, Jeffrey N. ; Parkhill, Julian ; Madhi, Shabir ; Benfield, Thomas ; von Gottberg, Anne ; van der Ende, Arie ; Brouwer, Matthijs C. ; Barrett, Jeffrey C. ; Bentley, Stephen D. ; van de Beek, Diederik. / Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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.",
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Lees, JA, Ferwerda, B, Kremer, PHC, Wheeler, NE, Valls Serón, M, Croucher, NJ, Gladstone, RA, Bootsma, HJ, Rots, NY, Wijmega-Monsuur, AJ, Sanders, EAM, Trzciński, K, Wyllie, AL, Zwinderman, AH, van den Berg, LH, van Rheenen, W, Veldink, JH, Harboe, ZB, Lundbo, LF, de Groot, LCPGM, van Schoor, NM, van der Velde, N, Ängquist, LH, Sørensen, TIA, Nohr, EA, Mentzer, AJ, Mills, TC, Knight, JC, du Plessis, M, Nzenze, S, Weiser, JN, Parkhill, J, Madhi, S, Benfield, T, von Gottberg, A, van der Ende, A, Brouwer, MC, Barrett, JC, Bentley, SD & van de Beek, D 2019, 'Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis', Nature Communications, vol. 10, no. 1, 2176. https://doi.org/10.1038/s41467-019-09976-3

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis. / Lees, John A.; Ferwerda, Bart; Kremer, Philip H.C.; Wheeler, Nicole E.; Valls Serón, Mercedes; Croucher, Nicholas J.; Gladstone, Rebecca A.; Bootsma, Hester J.; Rots, Nynke Y.; Wijmega-Monsuur, Alienke J.; Sanders, Elisabeth A.M.; Trzciński, Krzysztof; Wyllie, Anne L.; Zwinderman, Aeilko H.; van den Berg, Leonard H.; van Rheenen, Wouter; Veldink, Jan H.; Harboe, Zitta B.; Lundbo, Lene F.; de Groot, Lisette C.P.G.M.; van Schoor, Natasja M.; van der Velde, Nathalie; Ängquist, Lars H.; Sørensen, Thorkild I.A.; Nohr, Ellen A.; Mentzer, Alexander J.; Mills, Tara C.; Knight, Julian C.; du Plessis, Mignon; Nzenze, Susan; Weiser, Jeffrey N.; Parkhill, Julian; Madhi, Shabir; Benfield, Thomas; von Gottberg, Anne; van der Ende, Arie; Brouwer, Matthijs C.; Barrett, Jeffrey C.; Bentley, Stephen D.; van de Beek, Diederik.

In: Nature Communications, Vol. 10, No. 1, 2176, 15.05.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis

AU - Lees, John A.

AU - Ferwerda, Bart

AU - Kremer, Philip H.C.

AU - Wheeler, Nicole E.

AU - Valls Serón, Mercedes

AU - Croucher, Nicholas J.

AU - Gladstone, Rebecca A.

AU - Bootsma, Hester J.

AU - Rots, Nynke Y.

AU - Wijmega-Monsuur, Alienke J.

AU - Sanders, Elisabeth A.M.

AU - Trzciński, Krzysztof

AU - Wyllie, Anne L.

AU - Zwinderman, Aeilko H.

AU - van den Berg, Leonard H.

AU - van Rheenen, Wouter

AU - Veldink, Jan H.

AU - Harboe, Zitta B.

AU - Lundbo, Lene F.

AU - de Groot, Lisette C.P.G.M.

AU - van Schoor, Natasja M.

AU - van der Velde, Nathalie

AU - Ängquist, Lars H.

AU - Sørensen, Thorkild I.A.

AU - Nohr, Ellen A.

AU - Mentzer, Alexander J.

AU - Mills, Tara C.

AU - Knight, Julian C.

AU - du Plessis, Mignon

AU - Nzenze, Susan

AU - Weiser, Jeffrey N.

AU - Parkhill, Julian

AU - Madhi, Shabir

AU - Benfield, Thomas

AU - von Gottberg, Anne

AU - van der Ende, Arie

AU - Brouwer, Matthijs C.

AU - Barrett, Jeffrey C.

AU - Bentley, Stephen D.

AU - van de Beek, Diederik

PY - 2019/5/15

Y1 - 2019/5/15

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-09976-3

DO - 10.1038/s41467-019-09976-3

M3 - Article

VL - 10

JO - Nature Communications

T2 - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2176

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Lees JA, Ferwerda B, Kremer PHC, Wheeler NE, Valls Serón M, Croucher NJ et al. Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis. Nature Communications. 2019 May 15;10(1). 2176. https://doi.org/10.1038/s41467-019-09976-3