LacR and TrxB are key virulence factors involved in pneumococcal meningitis as identified by a genome-wide association study
9 affiliations
- 1Department of Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
- 2Department of Medical Microbiology and Infection Prevention, Amsterdam UMC location VU Universiteit Amsterdam, Amsterdam, The Netherlands
- 3Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- 4Department of Neurology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
- 5The Centre for Human Drug Research, Leiden, The Netherlands
- 6European Molecular Biology Laboratory, European Bioinformatics Institute EMBL-EBI, Hinxton, Cambridgeshire UK
- 7The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
- 8Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
- 9Department of Clinical Epidemiology, Infectious Diseases Surveillance and Epidemiology, Aarhus University, Aarhus, Denmark
Abstract
Pneumococcal meningitis is the most common form of bacterial meningitis, with high case fatality rates. Bacterial genetics influence disease severity, but the underlying mechanisms remain poorly understood. Here, we evaluated top variants from a genome-wide association study (GWAS) linking Streptococcus pneumoniae genetic variation to disease outcome. Fifteen S. pneumoniae knockout mutants were tested for virulence in a zebrafish embryo meningitis model; six showed reduced virulence compared to wild-type, but four were excluded following competitive index and growth assays. Loss of SPV_1044 (lacR) and SPV_1393 (trxB) resulted in lower bacterial loads, impaired neuroinvasion and a reduced inflammatory response. Furthermore, deletion of lacR, encoding a regulator of galactose metabolism, led to delayed growth in galactose and human cerebrospinal fluid. Deletion of trxB, encoding thioredoxin reductase, increased susceptibility to oxidative stress. This proof-of-concept study, combining pathogen GWAS with in vivo validation, identifies two pneumococcal virulence genes linked to disease severity.
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BibTeX
@article{koning2026lacr,
title = {{LacR and TrxB are key virulence factors involved in pneumococcal meningitis as identified by a genome-wide association study}},
author = {Rutger Koning and Kin Ki Jim and Philip H. C. Kremer and Hsueh-Chien Raymond Cheng and Valery Jaspers and Mans Perez and Bart Ferwerda and Bevika Sewgoolam and Roy Ummels and Maikel Boot and John A. Lees and Stephen D. Bentley and Jan-Willem Veening and Christina M.J.E. Vandenbroucke-Grauls and Matthijs C. Brouwer and Diederik van de Beek},
journal = {Communications Biology},
year = {2026},
month = jul,
doi = {10.1038/s42003-026-10638-6},
url = {https://doi.org/10.1038/s42003-026-10638-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - LacR and TrxB are key virulence factors involved in pneumococcal meningitis as identified by a genome-wide association study
AU - Rutger Koning
AU - Kin Ki Jim
AU - Philip H. C. Kremer
AU - Hsueh-Chien Raymond Cheng
AU - Valery Jaspers
AU - Mans Perez
AU - Bart Ferwerda
AU - Bevika Sewgoolam
AU - Roy Ummels
AU - Maikel Boot
AU - John A. Lees
AU - Stephen D. Bentley
AU - Jan-Willem Veening
AU - Christina M.J.E. Vandenbroucke-Grauls
AU - Matthijs C. Brouwer
AU - Diederik van de Beek
PY - 2026
DA - 2026/07/08
JO - Communications Biology
DO - 10.1038/s42003-026-10638-6
UR - https://doi.org/10.1038/s42003-026-10638-6
AB - Pneumococcal meningitis is the most common form of bacterial meningitis, with high case fatality rates. Bacterial genetics influence disease severity, but the underlying mechanisms remain poorly understood. Here, we evaluated top variants from a genome-wide association study (GWAS) linking Streptococcus pneumoniae genetic variation to disease outcome. Fifteen S. pneumoniae knockout mutants were tested for virulence in a zebrafish embryo meningitis model; six showed reduced virulence compared to wild-type, but four were excluded following competitive index and growth assays. Loss of SPV_1044 (lacR) and SPV_1393 (trxB) resulted in lower bacterial loads, impaired neuroinvasion and a reduced inflammatory response. Furthermore, deletion of lacR, encoding a regulator of galactose metabolism, led to delayed growth in galactose and human cerebrospinal fluid. Deletion of trxB, encoding thioredoxin reductase, increased susceptibility to oxidative stress. This proof-of-concept study, combining pathogen GWAS with in vivo validation, identifies two pneumococcal virulence genes linked to disease severity.
SN - 2399-3642
ER -