{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T13:10:40Z","timestamp":1767964240382,"version":"3.49.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["918.19.627"],"award-info":[{"award-number":["918.19.627"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sirolimus, an inhibitor of mammalian target of rapamycin complex (mTORC) 1, a regulatory protein involved in seizures and a modulator of inflammation, represents a potential new treatment strategy for pneumococcal meningitis. This study investigates the effects of mTORC1 inhibition using sirolimus in a mouse model of experimental pneumococcal meningitis. In a prospective, investigator-blinded and randomized trial, 96 mice were infected intracisternally with Streptococcus pneumoniae serotype 2. Mice were randomized for treatment with sirolimus and all mice received antibiotic treatment. In a clinical severity experiment, 48 mice were infected and scored every 4\u2005h for disease severity until 72\u2005h. In a time-point experiment, 48 mice were infected and terminated at 6 or 24\u2005h after infection for evaluation. In the clinical severity experiment, sirolimus treatment did not improve survival, although seizures tended to occur less in treated mice [3 of 24 (13%) versus 5 of 24 (21%), P = 0.7]. In the time point experiment, clinical severity scores were increased in sirolimus-treated mice [maximum difference at 24\u2005h after infection with a median of 10 (interquartile range 10\u201313) versus 7.5 (interquartile range 5\u20139) at 24\u2005h after infection, P &amp;lt; 0.01]. While bacterial loads were similar across groups, sirolimus treatment increased inflammation. In the brain of treated mice, interleukin 6 was increased (median 8900\u2005pg\/ml versus 4804\u2005pg\/ml, P = 0.04), while interleukin 12 was elevated in both the brain (median 591\u2005pg\/ml versus 405\u2005pg\/ml, P = 0.03) and plasma (median 216\u2005pg\/ml versus 7\u2005pg\/ml, P &amp;lt; 0.01). Our findings illustrate the importance of mTORC1 signalling during pneumococcal meningitis in regulating inflammation. However, our results indicate that sirolimus is unlikely to be an effective treatment for this condition.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf460","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T13:15:28Z","timestamp":1763730928000},"source":"Crossref","is-referenced-by-count":0,"title":["mTORC1 inhibition by sirolimus as adjunctive treatment in experimental pneumococcal meningitis"],"prefix":"10.1093","volume":"8","author":[{"given":"Rutger","family":"Koning","sequence":"first","affiliation":[{"name":"Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dixie","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian A","family":"van Roon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valery","family":"Jaspers","sequence":"additional","affiliation":[{"name":"Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthijs C","family":"Brouwer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4571-044X","authenticated-orcid":false,"given":"Diederik","family":"van de Beek","sequence":"additional","affiliation":[{"name":"Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"issue":"5","key":"2026010906114913700_fcaf460-B1","doi-asserted-by":"crossref","first-page":"e1099","DOI":"10.1093\/cid\/ciaa1774","article-title":"Changing epidemiology of bacterial meningitis since introduction of conjugate vaccines: 3 decades of national meningitis surveillance in The Netherlands","volume":"73","author":"Koelman","year":"2021","journal-title":"Clin Infect Dis"},{"issue":"9854","key":"2026010906114913700_fcaf460-B2","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/S0140-6736(12)61186-6","article-title":"Advances in treatment of bacterial meningitis","volume":"380","author":"van de Beek","year":"2012","journal-title":"Lancet"},{"issue":"10","key":"2026010906114913700_fcaf460-B3","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1136\/jnnp.2006.110023","article-title":"Cognitive outcome in adults after bacterial meningitis","volume":"78","author":"Hoogman","year":"2007","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"3","key":"2026010906114913700_fcaf460-B4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S1473-3099(15)00430-2","article-title":"Community-acquired bacterial meningitis in adults in The Netherlands, 2006\u201314: A prospective cohort study","volume":"16","author":"Bijlsma","year":"2016","journal-title":"Lancet Infect Dis"},{"issue":"8","key":"2026010906114913700_fcaf460-B5","doi-asserted-by":"crossref","first-page":"e2424802","DOI":"10.1001\/jamanetworkopen.2024.24802","article-title":"Global case fatality of bacterial meningitis during an 80-year period: A systematic review and meta-analysis","volume":"7","author":"van Ettekoven","year":"2024","journal-title":"JAMA Netw Open."},{"issue":"22 Pt 2","key":"2026010906114913700_fcaf460-B6","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1212\/01.wnl.0000288178.91614.5d","article-title":"Seizures in adults with bacterial meningitis","volume":"70","author":"Zoons","year":"2008","journal-title":"Neurology"},{"issue":"9","key":"2026010906114913700_fcaf460-B7","first-page":"CD004405","article-title":"Corticosteroids for acute bacterial meningitis","volume":"2015","author":"Brouwer","year":"2015","journal-title":"Cochrane Database Syst Rev"},{"issue":"20","key":"2026010906114913700_fcaf460-B8","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1056\/NEJMoa021334","article-title":"European dexamethasone in adulthood bacterial meningitis study I. 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