# mTORC1 inhibition by sirolimus as adjunctive treatment in experimental pneumococcal meningitis

## TL;DR

Sirolimus, an mTORC1 inhibitor, was tested in a mouse model of pneumococcal meningitis but worsened symptoms and increased inflammation, suggesting it is not an effective treatment.

## Contribution

This study is the first to investigate mTORC1 inhibition as an adjunctive treatment for pneumococcal meningitis in a mouse model.

## Key findings

- Sirolimus treatment increased clinical severity and inflammation in mice with pneumococcal meningitis.
- Interleukin 6 and 12 levels were significantly elevated in the brains and plasma of sirolimus-treated mice.
- mTORC1 signaling appears to play a regulatory role in inflammation during pneumococcal meningitis.

## 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.

Sirolimus, an mTORC1 inhibitor, was tested as adjunctive treatment in a mouse model of pneumococcal meningitis. Sirolimus worsened clinical severity and increased inflammation, elevating IL-6 and IL-12 levels. Findings highlight mTORC1’s role in inflammation but suggest sirolimus is ineffective for treating pneumococcal meningitis.

Graphical Abstract