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We aimed to uncover genes and pathways associated with TBM pathogenesis and mortality, and determine the best predictors of death, utilizing whole-blood RNA sequencing from 281 Vietnamese adults with TBM, 295 pulmonary tuberculosis (PTB), and 30 healthy controls. Through weighted gene co-expression network analysis, we identified hub genes and pathways linked to TBM severity and mortality, with a consensus analysis revealing distinct patterns between HIV-positive and HIV-negative individuals. We employed multivariate elastic-net Cox regression to select candidate predictors of death, then logistic regression and internal bootstrap validation to choose best predictors. Increased neutrophil activation and decreased T and B cell activation pathways were associated with TBM mortality. Among HIV-positive individuals, mortality associated with increased angiogenesis, while HIV-negative individuals exhibited elevated TNF signaling and impaired extracellular matrix organization. Four hub genes\u2014\n                    <jats:italic>MCEMP1, NELL2, ZNF354C<\/jats:italic>\n                    , and\n                    <jats:italic>CD4<\/jats:italic>\n                    \u2014were strong TBM mortality predictors. These findings indicate that TBM induces a systemic inflammatory response similar to PTB, highlighting critical genes and pathways related to death, offering insights for potential therapeutic targets alongside a novel four-gene biomarker for predicting outcomes.\n                  <\/jats:p>","DOI":"10.7554\/elife.92344","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T14:25:41Z","timestamp":1706019941000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.92344","source":"Crossref","is-referenced-by-count":12,"title":["Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1809-5541","authenticated-orcid":true,"given":"Hoang Thanh","family":"Hai","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05rehad94","id-type":"ROR","asserted-by":"publisher"}],"name":"Oxford University Clinical Research Unit","place":["Ho Chi 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