{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:16:29Z","timestamp":1785428189515,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,10]]},"group-title":"Immunology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["226817\/Z\/22\/Z"],"award-info":[{"award-number":["226817\/Z\/22\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CC2112"],"award-info":[{"award-number":["CC2112"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["214321\/Z\/18\/Z"],"award-info":[{"award-number":["214321\/Z\/18\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["203135\/Z\/16\/Z"],"award-info":[{"award-number":["203135\/Z\/16\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CC2112"],"award-info":[{"award-number":["CC2112"]}],"id":[{"id":"https:\/\/ror.org\/054225q67","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CC2112"],"award-info":[{"award-number":["CC2112"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01145436"],"award-info":[{"award-number":["R01145436"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["00"],"award-info":[{"award-number":["00"]}],"id":[{"id":"https:\/\/ror.org\/05vn9ks38","id-type":"ROR","asserted-by":"publisher"}]},{"name":"EDCTP2 Programme","award":["RIA2017T-2019"],"award-info":[{"award-number":["RIA2017T-2019"]}]},{"name":"NIHR Biomedical Research Centre of Imperial College Healthcare NHS Trust","award":["00"],"award-info":[{"award-number":["00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,23]]},"abstract":"<jats:p>Immune dysregulation contributes to death and disability in tuberculous meningitis. People living with HIV have the least evidence that anti-inflammatory therapy improves the poor outcome. Improving therapy relies on a more refined understanding of the host immune response. Single-cell RNA sequencing of 188,983 CSF cells from 25 adults with HIV-associated TBM revealed a predominance of cytotoxic CD8 T cells with low cytokine expression. In microbiologically-confirmed TBM, there was greater cytotoxicity in T, NK and \u03b3\u03b4 cells, and higher type 1 interferon stimulation in T and B lymphocytes. Neutrophils expressed markers suggesting heightened cytokine stimulation, enhanced effector function, and IL-8-mediated neutrophil recruitment. In a longitudinal cohort, type 1 interferon signaling increased in blood and CSF following treatment initiation. Overall, findings indicate a hyper-inflammatory immune response in the CSF of HIV-associated TBM patients characterised by an accumulation of granzyme-rich cytotoxic CD8 T cells, highly activated neutrophils and host-detrimental type 1 interferon signaling.<\/jats:p>","DOI":"10.64898\/2026.03.10.710544","type":"posted-content","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T15:22:49Z","timestamp":1773156169000},"source":"Crossref","is-referenced-by-count":1,"title":["Contribution of cytotoxic CD8 T cells, neutrophils and type 1 interferon signaling to hyperinflammation in HIV-associated TB meningitis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1316-6205","authenticated-orcid":false,"given":"James R","family":"Barnacle","sequence":"first","affiliation":[{"name":"Francis Crick Institute, London, NW1 1AT, UK"},{"name":"Department of Infectious Diseases, Imperial College London, W12 0NN, UK"},{"name":"Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonzwakazi","family":"Bangani","sequence":"additional","affiliation":[{"name":"Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Slawinski","sequence":"additional","affiliation":[{"name":"Genomics Science Technology Platform, Francis Crick Institute, London, NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Barrington","sequence":"additional","affiliation":[{"name":"Bioinformatics and Biostatistics Science Technology Platform, Francis Crick Institute, London, NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin A","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Francis Crick Institute, London, NW1 1AT, UK"},{"name":"Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cari J","family":"Stek","sequence":"additional","affiliation":[{"name":"Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Imperial College London, W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice","family":"Bonnet","sequence":"additional","affiliation":[{"name":"University of Bordeaux, National Institute for Health and Medical Research (INSERM) UMR 1219, Research Institute for Sustainable Development (IRD) EMR 271, Bordeaux Population Health Centre, Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Meintjes","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology and Infection, Blizard Institute, Queen Mary, University of London, London, E1 2AT, UK"},{"name":"Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Imperial College London, W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Gengenbacher","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, NJ 07110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angharad G","family":"Davis","sequence":"additional","affiliation":[{"name":"Francis Crick Institute, London, NW1 1AT, UK"},{"name":"Centre for Immunobiology and Infection, Blizard Institute, Queen Mary, University of London, London, E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7008-7509","authenticated-orcid":false,"given":"Daniel L","family":"Barber","sequence":"additional","affiliation":[{"name":"T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"O\u2019Garra","sequence":"additional","affiliation":[{"name":"Immunoregulation and Infection Laboratory, Francis Crick Institute, London, NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Francis Crick Institute, London, NW1 1AT, UK"},{"name":"Department of Infectious Diseases, Imperial College London, W12 0NN, UK"},{"name":"Wellcome Discovery Research Platforms in Infection, Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Republic of South Africa"},{"name":"Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, Observatory 7925, Republic of South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032506301029000_2026.03.10.710544v2.1","unstructured":"Global Tuberculosis Report 2024 (World Health Organization, Geneva, 1st ed., 2024)."},{"key":"2026032506301029000_2026.03.10.710544v2.2","doi-asserted-by":"crossref","first-page":"e0000069","DOI":"10.1371\/journal.pgph.0000069","article-title":"The global burden of tuberculous meningitis in adults: A modelling study","volume":"1","year":"2021","journal-title":"PLOS Global Public Health"},{"key":"2026032506301029000_2026.03.10.710544v2.3","first-page":"ofaa257","article-title":"Treatment Outcomes in Adult Tuberculous Meningitis: A Systematic Review and Meta-analysis","volume":"7","year":"2020","journal-title":"Open Forum Infect Dis"},{"key":"2026032506301029000_2026.03.10.710544v2.4","doi-asserted-by":"crossref","first-page":"ofaf503","DOI":"10.1093\/ofid\/ofaf503","article-title":"Intensified Treatment of Tuberculous Meningitis in Adults: A Systematic Review and Meta-analysis","volume":"12","year":"2025","journal-title":"Open Forum Infect Dis"},{"key":"2026032506301029000_2026.03.10.710544v2.5","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1056\/NEJMoa2502866","article-title":"Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis","volume":"393","year":"2025","journal-title":"New England Journal of Medicine"},{"key":"2026032506301029000_2026.03.10.710544v2.6","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1056\/NEJMoa2216218","article-title":"Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults","volume":"389","year":"2023","journal-title":"N Engl J Med"},{"key":"2026032506301029000_2026.03.10.710544v2.7","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy588"},{"key":"2026032506301029000_2026.03.10.710544v2.8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053420"},{"key":"2026032506301029000_2026.03.10.710544v2.9","doi-asserted-by":"crossref","unstructured":"M. S. Inkeles , R. M. B. Teles , D. Pouldar , P. R. Andrade , C. A. Madigan , D. Lopez , M. Ambrose , M. Noursadeghi , E. N. Sarno , T. H. Rea , M. T. Ochoa , M. L. Iruela-Arispe , W. R. Swindell , T. H. M. Ottenhoff , A. Geluk , B. R. Bloom , M. Pellegrini , R. L. Modlin , Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy. JCI Insight 1 (2016).","DOI":"10.1172\/jci.insight.88843"},{"key":"2026032506301029000_2026.03.10.710544v2.10","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix051"},{"key":"2026032506301029000_2026.03.10.710544v2.11","doi-asserted-by":"crossref","first-page":"8423","DOI":"10.1038\/s41467-023-44152-8","article-title":"Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy","volume":"14","year":"2023","journal-title":"Nat Commun"},{"key":"2026032506301029000_2026.03.10.710544v2.12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1387808"},{"key":"2026032506301029000_2026.03.10.710544v2.13","doi-asserted-by":"crossref","unstructured":"T. T. B. Tram , L. C. Garner , L. N. H. Thai , L. T. H. Nhat , D. D. A. Thu , H. D. T. Nghia , L. H. Van , G. E. Thwaites , V. T. N. Ha , P. Klenerman , N. T. T. Thuong , Single-cell profiling of blood and cerebrospinal fluid in tuberculous meningitis. J Immunol, vkaf186 (2025).","DOI":"10.1101\/2025.03.04.641394"},{"key":"2026032506301029000_2026.03.10.710544v2.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-093019-110159"},{"key":"2026032506301029000_2026.03.10.710544v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16889-z"},{"key":"2026032506301029000_2026.03.10.710544v2.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2216028120"},{"key":"2026032506301029000_2026.03.10.710544v2.17","doi-asserted-by":"crossref","unstructured":"C. Cantoni , R. A. Smirnov , M. Firulyova , P. S. Andhey , T. R. Bradstreet , E. Esaulova , M. Terekhova , E. A. Schwarzkopf , N. M. Abdalla , M. Kleverov , J. J. Sabatino , K. Liu , N. Schwab , G. M. zu H\u00f6rste , A. H. Cross , M. N. Artyomov , B. T. Edelson , G. F. Wu , A single-cell compendium of human cerebrospinal fluid identifies disease-associated immune cell populations. J Clin Invest 135 (2025).","DOI":"10.1172\/JCI177793"},{"key":"2026032506301029000_2026.03.10.710544v2.18","doi-asserted-by":"crossref","unstructured":"R. A. Pearson , K. N. Krish , W. E. Whatney , W. Jaoko , K. Mandaliya , J. Overbaugh , S. M. Graham , R. S. McClelland , S. L. Hicks , J. Maurer , C. D. Scharer , C. L. Day , Single-cell transcriptomics reveals depletion and dysregulation of Mycobacterium tuberculosis-specific Th1 and Th17 cells early after acquisition of HIV. J Infect Dis, jiaf354 (2025).","DOI":"10.1093\/infdis\/jiaf354"},{"key":"2026032506301029000_2026.03.10.710544v2.19","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141927"},{"key":"2026032506301029000_2026.03.10.710544v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2011.153"},{"key":"2026032506301029000_2026.03.10.710544v2.21","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo0686"},{"key":"2026032506301029000_2026.03.10.710544v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08713-9"},{"key":"2026032506301029000_2026.03.10.710544v2.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1711853115"},{"key":"2026032506301029000_2026.03.10.710544v2.24","doi-asserted-by":"crossref","first-page":"16084","DOI":"10.1038\/cddiscovery.2016.84","article-title":"Granzymes A and K differentially potentiate LPS-induced cytokine response","volume":"2","year":"2016","journal-title":"Cell Death Discovery"},{"key":"2026032506301029000_2026.03.10.710544v2.25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101122"},{"key":"2026032506301029000_2026.03.10.710544v2.26","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2299"},{"key":"2026032506301029000_2026.03.10.710544v2.27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200419930"},{"key":"2026032506301029000_2026.03.10.710544v2.28","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1093\/jleuko\/qiae090","article-title":"Regulation of ICAM-1 in human neutrophils","volume":"116","year":"2024","journal-title":"J Leukoc Biol"},{"key":"2026032506301029000_2026.03.10.710544v2.29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-664995"},{"key":"2026032506301029000_2026.03.10.710544v2.30","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(04)00022-6"},{"key":"2026032506301029000_2026.03.10.710544v2.31","doi-asserted-by":"crossref","first-page":"60.07","DOI":"10.4049\/jimmunol.206.Supp.60.07","article-title":"Neutrophil-specific Socs3 deficiency induces brain-targeted experimental autoimmune encephalomyelitis with increased cerebellar neutrophils","volume":"206","year":"2021","journal-title":"J Immunol"},{"key":"2026032506301029000_2026.03.10.710544v2.32","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20180325"},{"key":"2026032506301029000_2026.03.10.710544v2.33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401088"},{"key":"2026032506301029000_2026.03.10.710544v2.34","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201344219"},{"key":"2026032506301029000_2026.03.10.710544v2.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.002"},{"key":"2026032506301029000_2026.03.10.710544v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2016.12.006"},{"key":"2026032506301029000_2026.03.10.710544v2.37","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40817"},{"key":"2026032506301029000_2026.03.10.710544v2.38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091096998"},{"key":"2026032506301029000_2026.03.10.710544v2.39","doi-asserted-by":"publisher","DOI":"10.1038\/nature13489"},{"key":"2026032506301029000_2026.03.10.710544v2.40","doi-asserted-by":"crossref","first-page":"e20210915","DOI":"10.1084\/jem.20210915","article-title":"Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis","volume":"218","year":"2021","journal-title":"Journal of Experimental Medicine"},{"key":"2026032506301029000_2026.03.10.710544v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/nature09247"},{"key":"2026032506301029000_2026.03.10.710544v2.42","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1186\/s13063-022-06772-1","article-title":"Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial","volume":"23","year":"2022","journal-title":"Trials"},{"key":"2026032506301029000_2026.03.10.710544v2.43","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-1950-6"},{"key":"2026032506301029000_2026.03.10.710544v2.44","doi-asserted-by":"crossref","first-page":"979","DOI":"10.12688\/f1000research.73600.2","article-title":"Doublet identification in single-cell sequencing data using scDblFinder","volume":"10","year":"2022","journal-title":"F1000Res"},{"key":"2026032506301029000_2026.03.10.710544v2.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0276-y"},{"key":"2026032506301029000_2026.03.10.710544v2.46","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl5197"},{"key":"2026032506301029000_2026.03.10.710544v2.47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203828120"},{"key":"2026032506301029000_2026.03.10.710544v2.48","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v076.i01"},{"key":"2026032506301029000_2026.03.10.710544v2.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19894-4"},{"key":"2026032506301029000_2026.03.10.710544v2.50","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac932"},{"key":"2026032506301029000_2026.03.10.710544v2.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0439-x"},{"key":"2026032506301029000_2026.03.10.710544v2.52","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3820"},{"key":"2026032506301029000_2026.03.10.710544v2.53","unstructured":"R Core Team, R: A language and environment for statistical computing., Foundation for Statistical Computing (2022); https:\/\/www.R-project.org\/."},{"key":"2026032506301029000_2026.03.10.710544v2.54","doi-asserted-by":"crossref","unstructured":"M. I. Love , W. Huber , S. Anders , Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology 15, 550 (2014).","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026032506301029000_2026.03.10.710544v2.55","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty895"},{"key":"2026032506301029000_2026.03.10.710544v2.56","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.10.710544","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T13:30:24Z","timestamp":1774445424000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.10.710544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":56,"URL":"https:\/\/doi.org\/10.64898\/2026.03.10.710544","relation":{},"subject":[],"published":{"date-parts":[[2026,3,10]]},"subtype":"preprint"}}