Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq

Kin Ki Jim; Rieza Aprianto; Rutger Koning; Arnau Domenech; Jun Kurushima; Diederik van de Beek; Christina M.J.E. Vandenbroucke-Grauls; Wilbert Bitter; Jan Willem Veening

doi:10.1016/j.celrep.2022.111851

Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq

Kin Ki Jim, Rieza Aprianto, Rutger Koning, Arnau Domenech, Jun Kurushima, Diederik van de Beek, Christina M.J.E. Vandenbroucke-Grauls, Wilbert Bitter, Jan Willem Veening^*

^*Corresponding author for this work

AIMMS

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Pneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole-animal in vivo dual RNA sequencing (RNA-seq) approach, we identify pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis, we identify host pathways known to be activated by pneumolysin and discover the importance of necroptosis for host survival. Inhibition of this pathway using the drug GSK′872 increases host mortality during pneumococcal meningitis. On the pathogen's side, we show that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis.

Original language	English
Article number	111851
Pages (from-to)	1-22
Number of pages	22
Journal	Cell Reports
Volume	41
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2022.111851
Publication status	Published - 20 Dec 2022

Bibliographical note

Funding Information:
We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792); a JPIAMR grant (40AR40_185533) from SNSF; NCCR “AntiResist” from SNSF (51NF40_180541); and ERC consolidator grant 771534-PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant (Vici 91819627). Conceptualization and methodology, K.K.J. R.A. W.B. and J.-W.V.; investigation, K.K.J. R.A. R.K. A.D. and J.K.; writing – original draft, K.K.J. R.A. W.B. and J.-W.V.; resources, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V.; writing – review & editing, K.K.J. R.A. D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. with input from all authors; funding acquisition, D.v.d.B. W.B. and J.-W.V.; supervision, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. The authors declare no competing interests.

Funding Information:
We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792 ); a JPIAMR grant ( 40AR40_185533 ) from SNSF; NCCR “AntiResist” from SNSF ( 51NF40_180541 ); and ERC consolidator grant 771534 -PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant ( Vici 91819627 ).

Publisher Copyright:
© 2022 The Author(s)

Funding

We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792); a JPIAMR grant (40AR40_185533) from SNSF; NCCR “AntiResist” from SNSF (51NF40_180541); and ERC consolidator grant 771534-PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant (Vici 91819627). Conceptualization and methodology, K.K.J. R.A. W.B. and J.-W.V.; investigation, K.K.J. R.A. R.K. A.D. and J.K.; writing – original draft, K.K.J. R.A. W.B. and J.-W.V.; resources, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V.; writing – review & editing, K.K.J. R.A. D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. with input from all authors; funding acquisition, D.v.d.B. W.B. and J.-W.V.; supervision, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. The authors declare no competing interests. We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792 ); a JPIAMR grant ( 40AR40_185533 ) from SNSF; NCCR “AntiResist” from SNSF ( 51NF40_180541 ); and ERC consolidator grant 771534 -PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant ( Vici 91819627 ).

Funders	Funder number
Université de Lausanne
Center for Information Technology of the University of Groningen
Universiteit Leiden
European Molecular Biology Laboratory
European Research Council
Doran Pauka
ZonMw Vici	91819627
Horizon 2020 Framework Programme	771534
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	180541, 310030_192517, 310030_200792
Joint Programming Initiative on Antimicrobial Resistance	40AR40_185533, 51NF40_180541

Keywords

competence
CP: Immunology
CP: Microbiology
Danio rerio
dual RNA-seq
host-pathogen interaction
meningitis
necroptosis
Streptococcus pneumoniae

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2022.111851

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Cite this

Jim, K. K., Aprianto, R., Koning, R., Domenech, A., Kurushima, J., van de Beek, D., Vandenbroucke-Grauls, C. M. J. E., Bitter, W., & Veening, J. W. (2022). Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq. Cell Reports, 41(12), 1-22. Article 111851. https://doi.org/10.1016/j.celrep.2022.111851

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title = "Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq",

abstract = "Pneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole-animal in vivo dual RNA sequencing (RNA-seq) approach, we identify pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis, we identify host pathways known to be activated by pneumolysin and discover the importance of necroptosis for host survival. Inhibition of this pathway using the drug GSK′872 increases host mortality during pneumococcal meningitis. On the pathogen's side, we show that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis.",

keywords = "competence, CP: Immunology, CP: Microbiology, Danio rerio, dual RNA-seq, host-pathogen interaction, meningitis, necroptosis, Streptococcus pneumoniae",

author = "Jim, {Kin Ki} and Rieza Aprianto and Rutger Koning and Arnau Domenech and Jun Kurushima and {van de Beek}, Diederik and Vandenbroucke-Grauls, {Christina M.J.E.} and Wilbert Bitter and Veening, {Jan Willem}",

note = "Funding Information: We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792); a JPIAMR grant (40AR40_185533) from SNSF; NCCR “AntiResist” from SNSF (51NF40_180541); and ERC consolidator grant 771534-PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant (Vici 91819627). Conceptualization and methodology, K.K.J. R.A. W.B. and J.-W.V.; investigation, K.K.J. R.A. R.K. A.D. and J.K.; writing – original draft, K.K.J. R.A. W.B. and J.-W.V.; resources, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V.; writing – review & editing, K.K.J. R.A. D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. with input from all authors; funding acquisition, D.v.d.B. W.B. and J.-W.V.; supervision, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. The authors declare no competing interests. Funding Information: We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792 ); a JPIAMR grant ( 40AR40_185533 ) from SNSF; NCCR “AntiResist” from SNSF ( 51NF40_180541 ); and ERC consolidator grant 771534 -PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant ( Vici 91819627 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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T1 - Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq

AU - Jim, Kin Ki

AU - Aprianto, Rieza

AU - Koning, Rutger

AU - Domenech, Arnau

AU - Kurushima, Jun

AU - van de Beek, Diederik

AU - Vandenbroucke-Grauls, Christina M.J.E.

AU - Bitter, Wilbert

AU - Veening, Jan Willem

N1 - Funding Information: We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792); a JPIAMR grant (40AR40_185533) from SNSF; NCCR “AntiResist” from SNSF (51NF40_180541); and ERC consolidator grant 771534-PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant (Vici 91819627). Conceptualization and methodology, K.K.J. R.A. W.B. and J.-W.V.; investigation, K.K.J. R.A. R.K. A.D. and J.K.; writing – original draft, K.K.J. R.A. W.B. and J.-W.V.; resources, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V.; writing – review & editing, K.K.J. R.A. D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. with input from all authors; funding acquisition, D.v.d.B. W.B. and J.-W.V.; supervision, D.v.d.B. C.M.J.E.V.-G. W.B. and J.-W.V. The authors declare no competing interests. Funding Information: We thank Vladimir Benes (GeneCore, EMBL, Heidelberg) for his continuing support in library preparation and sequencing. We would like to acknowledge the Center for Information Technology of the University of Groningen for their support and for providing access to the Peregrine High-Performance Computing cluster. We thank Petr Broz (Immunology, University of Lausanne), Coen Kuijl (Medical Microbiology and Infection Prevention, Amsterdam UMC), and Astrid van der Sar (Medical Microbiology and Infection Prevention, Amsterdam UMC) for valuable discussions. We thank Annemarie Meijer (Institute of Biology, Leiden University) for providing the Tg(cxcl18b:EGFP) transgenic zebrafish line and Theo Verboom (Medical Microbiology and Infection Prevention, Amsterdam UMC) and Jeroen Kole (Confocal.nl) for technical support. We thank Doran Pauka for building the dual-danio website. Work in the Veening lab is supported by the Swiss National Science Foundation (SNSF) (project grants 310030_192517 and 310030_200792 ); a JPIAMR grant ( 40AR40_185533 ) from SNSF; NCCR “AntiResist” from SNSF ( 51NF40_180541 ); and ERC consolidator grant 771534 -PneumoCaTChER. D.v.d.B. is supported by a ZonMw Vici grant ( Vici 91819627 ). Publisher Copyright: © 2022 The Author(s)

PY - 2022/12/20

Y1 - 2022/12/20

N2 - Pneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole-animal in vivo dual RNA sequencing (RNA-seq) approach, we identify pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis, we identify host pathways known to be activated by pneumolysin and discover the importance of necroptosis for host survival. Inhibition of this pathway using the drug GSK′872 increases host mortality during pneumococcal meningitis. On the pathogen's side, we show that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis.

AB - Pneumolysin is a major virulence factor of Streptococcus pneumoniae that plays a key role in interaction with the host during invasive disease. How pneumolysin influences these dynamics between host and pathogen interaction during early phase of central nervous system infection in pneumococcal meningitis remains unclear. Using a whole-animal in vivo dual RNA sequencing (RNA-seq) approach, we identify pneumolysin-specific transcriptional responses in both S. pneumoniae and zebrafish (Danio rerio) during early pneumococcal meningitis. By functional enrichment analysis, we identify host pathways known to be activated by pneumolysin and discover the importance of necroptosis for host survival. Inhibition of this pathway using the drug GSK′872 increases host mortality during pneumococcal meningitis. On the pathogen's side, we show that pneumolysin-dependent competence activation is crucial for intra-host replication and virulence. Altogether, this study provides new insights into pneumolysin-specific transcriptional responses and identifies key pathways involved in pneumococcal meningitis.

KW - competence

KW - CP: Immunology

KW - CP: Microbiology

KW - Danio rerio

KW - dual RNA-seq

KW - host-pathogen interaction

KW - meningitis

KW - necroptosis

KW - Streptococcus pneumoniae

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U2 - 10.1016/j.celrep.2022.111851

DO - 10.1016/j.celrep.2022.111851

M3 - Article

C2 - 36543127

AN - SCOPUS:85144370608

SN - 2211-1247

VL - 41

SP - 1

EP - 22

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 111851

ER -

Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq

Abstract

Bibliographical note

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Keywords

UN SDGs

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