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Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by <jats:italic>Streptococcus pneumoniae<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Three days prior to the induction of meningitis by intracerebral injection of <jats:italic>S. pneumoniae<\/jats:italic> D39, wild-type and Toll-like receptor (TLR9)<jats:sup>\u2212\/\u2212<\/jats:sup> mice received an intraperitoneal injection of 100\u2009\u03bcg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4\u2009days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24\u2009h and 36\u2009h after infection, were performed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Pre-treatment with 100\u2009\u03bcg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9<jats:sup>\u2212\/\u2212<\/jats:sup> mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12\/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12\/IL-23p40 and MIP-1\u03b1 correlated with lower bacterial concentrations in the blood and spleen during infection.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against <jats:italic>S. pneumoniae<\/jats:italic> meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-021-02077-3","type":"journal-article","created":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T12:27:00Z","timestamp":1612268820000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host"],"prefix":"10.1186","volume":"18","author":[{"given":"S.","family":"Ribes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Zacke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Nessler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Saiepour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Avenda\u00f1o-Guzm\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Ball\u00fcer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U. 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