title: Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis.
abstract: 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.
  
  
  
  We 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.
  
  
  
  MASP-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.
  
  
  
  MASP-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.
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: E Soemirien
authors.initials: ES
authors.lastname: Kasanmoentalib
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Valls Seron
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.affiliation: Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.affiliation: Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Medical Microbiology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.|The Netherlands Reference Laboratory for Bacterial Meningitis, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
authors.forename: William J
authors.initials: WJ
authors.lastname: Schwaeble
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: Department of Neurology, Academic Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands. d.vandebeek@amc.nl.|Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam Neuroscience, PO Box 22660, 1100 DD, Amsterdam, The Netherlands. d.vandebeek@amc.nl.
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
mesh_terms: D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000906:Antibodies / Q000009:adverse effects; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D023261:Glasgow Outcome Scale; D006801:Humans; D008297:Male; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000134:cerebrospinal fluid* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D000906:Antibodies; D016207:Cytokines; D002443:Ceftriaxone; D005620:Freund's Adjuvant; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases