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Brain injury and microglial activation are major determinants of outcome, yet the molecular mechanisms linking infection, inflammation, and neuronal injury remain poorly understood. Extracellular vesicles (EVs), critical mediators of cell-to-cell communication, have been investigated in pulmonary TB, but their role in TB meningitis remains unexplored. We used a young New Zealand White rabbit model of TB meningitis to isolate and characterize brain-derived EVs from infected and uninfected rabbits employing nanoflow cytometry, transmission electron microscopy, proteomic profiling by liquid chromatography-tandem mass spectrometry (LC-MS\/MS), and bioinformatic analysis of pathways, cell-type enrichment, and protein-protein interaction networks (DAVID, Enrichr, and STRING databases). EV recovery from flash-frozen brain tissue proved feasible, enabling future studies using biobanked samples. M. tuberculosis infection increased EV release in brain tissue and induced a selective proteomic shift characterized by enrichment of proteins associated with TB host defense, microglial activation, and stress-response pathways, coupled with a reduced representation of neuronal and neuroprotective EV-associated proteins. These findings suggest that infection reprograms the brain EV proteome toward inflammatory and injury-associated pathways. Collectively, this study provides the first comprehensive proteomic characterization of brain-derived EVs in TB meningitis and establishes a foundational atlas of EV-associated proteins altered during infection. These findings identify candidate proteins for future biomarker validation in accessible biofluids (e.g., plasma and CSF) and provide a framework for generating hypotheses about EV-mediated host\u2013pathogen interactions in the CNS during TB meningitis.<\/jats:p>","DOI":"10.3390\/cells15191749","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:09:02Z","timestamp":1790323742000},"page":"1749","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tuberculous Meningitis Alters the Proteomic Landscape of Brain-Derived Extracellular Vesicles"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5814-7190","authenticated-orcid":false,"given":"Blanca V.","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Nerketa N. L.","family":"Damiba","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Harshita","family":"Tak","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Nicole","family":"Beaubien","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1874-2351","authenticated-orcid":false,"given":"Daisy","family":"Puca","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9290-9590","authenticated-orcid":false,"given":"D. Brian","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4377-2823","authenticated-orcid":false,"given":"Samarjit","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-3635","authenticated-orcid":false,"given":"Elizabeth W.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"name":"Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref_1","first-page":"e684","article-title":"A clinical practice guideline for tuberculous meningitis","volume":"25","author":"Donovan","year":"2025","journal-title":"Lancet Infect. 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