Abstract
BackgroundPneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies.MethodsWe investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2−/− mice and evaluated the potential of adjuvant treatment with MASP-2-specific monoclonal antibodies in wild-type (WT) mice.ResultsMASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity.ConclusionsMASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis.
Highlights
Pneumococcal meningitis is the most common and severe form of bacterial meningitis
We investigated Mannose-binding lectinassociated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes (39%)
We found that pneumococcal meningitis patients had increased levels of MASP-2 in their CSF compared to controls
Summary
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Acute community-acquired bacterial meningitis is a lifethreatening disease associated with substantial morbidity and mortality and ranks among the top ten infectious causes of death [1]. Experimental studies in pneumococcal meningitis showed that the host inflammatory response . Genetic variants in complement system, TLR and IL-1R signaling pathways, and the M-TOR pathway have been identified to be associated with outcome in pneumococcal meningitis [7, 9, 12,13,14,15]. Inhibition of the final common pathway in the complement cascade has been identified as target for adjunctive treatment for experimental pneumococcal meningitis. Inhibition of the upstream activation pathways of the complement system may result in a more complete reduction of complement-mediated inflammation
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