Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis

BACKGROUND: Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. METHODS: We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. RESULTS: Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. CONCLUSIONS: DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.