LacR and TrxB are key virulence factors involved in pneumococcal meningitis as identified by a genome-wide association study

Pneumococcal meningitis is the most common form of bacterial meningitis, with high case fatality rates. Bacterial genetics influence disease severity and patient outcome, but the mechanisms underlying pneumococcal meningitis pathogenesis remain poorly understood. Here, we evaluated top variants from a genome-wide association study (GWAS) linking Streptococcus pneumoniae genetic variation to disease outcome. Fifteen isogenic S. pneumoniae knockout mutants were tested for virulence in a zebrafish embryo meningitis model; six showed significantly reduced virulence compared to wild-type, but four were excluded following competitive index and growth assays. Deletion of SPV_1044 (lacR), encoding a lactose phosphotransferase system repressor involved in galactose metabolism, led to delayed growth in galactose and human cerebrospinal fluid in vitro. Deletion of SPV_1393 (trxB), encoding thioredoxin reductase, increased susceptibility to hydrogen peroxide. This proof-of-concept study, combining pathogen GWAS with in vivo validation, identifies two pneumococcal virulence genes linked to disease severity.