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We aimed to develop an integrated and representative pneumococcal meningitis mouse model resembling the human situation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adult mice (C57BL\/6) were inoculated in the cisterna magna with increasing doses of<jats:italic>S. pneumoniae<\/jats:italic>serotype 3 colony forming units (CFU; n = 24, 10<jats:sup>4<\/jats:sup>, 10<jats:sup>5<\/jats:sup>, 10<jats:sup>6<\/jats:sup>and 10<jats:sup>7<\/jats:sup>CFU) and survival studies were performed. Cerebrospinal fluid (CSF), brain, blood, spleen, and lungs were collected. Subsequently, mice were inoculated with 10<jats:sup>4<\/jats:sup>CFU<jats:italic>S. pneumoniae<\/jats:italic>serotype 3 and sacrificed at 6 (n = 6) and 30 hours (n = 6). Outcome parameters were bacterial outgrowth, clinical score, and cytokine and chemokine levels (using Luminex<jats:sup>\u00ae<\/jats:sup>) in CSF, blood and brain. Meningeal inflammation, neutrophil infiltration, parenchymal and subarachnoidal hemorrhages, microglial activation and hippocampal apoptosis were assessed in histopathological studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lower doses of bacteria delayed onset of illness and time of death (median survival CFU 10<jats:sup>4<\/jats:sup>, 56 hrs; 10<jats:sup>5<\/jats:sup>, 38 hrs, 10<jats:sup>6<\/jats:sup>, 28 hrs. 10<jats:sup>7<\/jats:sup>, 24 hrs). Bacterial titers in brain and CSF were similar in all mice at the end-stage of disease independent of inoculation dose, though bacterial outgrowth in the systemic compartment was less at lower inoculation doses. At 30 hours after inoculation with 10<jats:sup>4<\/jats:sup>CFU of<jats:italic>S. pneumoniae<\/jats:italic>, blood levels of KC, IL6, MIP-2 and IFN- \u03b3 were elevated, as were brain homogenate levels of KC, MIP-2, IL-6, IL-1\u03b2 and RANTES. Brain histology uniformly showed meningeal inflammation at 6 hours, and, neutrophil infiltration, microglial activation, and hippocampal apoptosis at 30 hours. Parenchymal and subarachnoidal and cortical hemorrhages were seen in 5 of 6 and 3 of 6 mice at 6 and 30 hours, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We have developed and validated a murine model of pneumococcal meningitis.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2334-12-71","type":"journal-article","created":{"date-parts":[[2012,3,28]],"date-time":"2012-03-28T10:45:10Z","timestamp":1332931510000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Characterization of a pneumococcal meningitis mouse model"],"prefix":"10.1186","volume":"12","author":[{"given":"Barry","family":"Mook-Kanamori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelijn","family":"Geldhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Troost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"van der Poll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diederik","family":"van de Beek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,3,28]]},"reference":[{"issue":"18","key":"1903_CR1","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1056\/NEJMoa040845","volume":"351","author":"D van de Beek","year":"2004","unstructured":"van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M: Clinical features and prognostic factors in adults with bacterial meningitis. 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