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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\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    genetic variation to disease outcome. Fifteen\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    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\n                    <jats:italic>SPV_1044 (lacR)<\/jats:italic>\n                    and\n                    <jats:italic>SPV_1393 (trxB)<\/jats:italic>\n                    resulted in lower bacterial loads, impaired neuroinvasion and a reduced inflammatory response. Furthermore, deletion of\n                    <jats:italic>lacR<\/jats:italic>\n                    , encoding a regulator of galactose metabolism, led to delayed growth in galactose and human cerebrospinal fluid. Deletion of\n                    <jats:italic>trxB<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10638-6","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:04:57Z","timestamp":1783512297000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LacR and TrxB are key virulence factors involved in pneumococcal meningitis as identified by a genome-wide association study"],"prefix":"10.1038","volume":"9","author":[{"given":"Rutger","family":"Koning","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin Ki","family":"Jim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip H. 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