mTORC1 inhibition by sirolimus as adjunctive treatment in experimental pneumococcal meningitis

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Abstract 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 h for disease severity until 72 h. In a time-point experiment, 48 mice were infected and terminated at 6 or 24 h 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 h after infection with a median of 10 (interquartile range 10–13) versus 7.5 (interquartile range 5–9) at 24 h after infection, P < 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 pg/ml versus 4804 pg/ml, P = 0.04), while interleukin 12 was elevated in both the brain (median 591 pg/ml versus 405 pg/ml, P = 0.03) and plasma (median 216 pg/ml versus 7 pg/ml, P < 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.