Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0770-9) contains supplementary material, which is available to authorized users.

Key Components of the Complement Lectin Pathway Are Not Only Required for the Development of Inflammatory Arthritis but Also Regulate the Transcription of Factor D

“…Overall, in this study, we have generated highly potent and specific MASP-1 and MASP-2 siRNA duplexes, especially targeting liver for a longer time with an excellent clinical therapeutic potential. These duplexes can be tested further in various mouse models of diseases involving MASP-1 and MASP-2 such as IgA Nephropathy (77) and experimental pneumococcal meningitis (78) to understand the contribution of liver MASP1 and MASP2 to disease pathology in conditions where LP activations has been implicated. Humanized MASP-2 duplexes can also be developed and tested.…”

Should MASP-2 Deficiency Be Considered a Primary Immunodeficiency? Relevance of the Lectin Pathway

“…Indeed, the LP, particularly MASP-2, may behave as a double-edged sword and be even detrimental in serious disease conditions such as myocardial infarction, stroke, renal ischemia-reperfusion injury, and rheumatoid arthritis [4,5,41,53]. Interestingly, increased levels of MASP-2 may contribute to poor disease outcome of pneumococcal meningitis [54]. Due to the low frequency of the studied variant, our study lacks statistical power to evaluate its association with outcome of CAP or IPD [7].…”

Characterization of a Listeria monocytogenes meningitis mouse model

“…The listerial meningitis mouse model provides an experimental setting of listerial meningitis with multiple outcome parameters. Similar model set up in pneumococcal meningitis has proven to be useful in exploring inflammatory hypotheses in pneumococcal meningitis [ 72 – 74 ]. Integration of these pathological features in a single model is a valuable tool in the further investigation of both pathophysiological and therapeutic intervention studies in listerial meningitis.…”