@article{b97ec390b42c4b87a28242003bdbc24a,
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 = "CP: Immunology, CP: Microbiology, Danio rerio, Streptococcus pneumoniae, competence, dual RNA-seq, host-pathogen interaction, meningitis, necroptosis",
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 Jan-Willem Veening",
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)",
year = "2022",
month = dec,
day = "20",
doi = "https://doi.org/10.1016/j.celrep.2022.111851",
language = "English",
volume = "41",
pages = "1--22",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}
