Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

J Clin Invest. 2011 Oct;121(10):3943-53. doi: 10.1172/JCI57522. Epub 2011 Sep 19.

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 proinflammatory 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. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Arvicolinae
  • Brain / immunology
  • Brain / pathology
  • Cohort Studies
  • Complement C5 / antagonists & inhibitors
  • Complement C5 / cerebrospinal fluid
  • Complement C5 / genetics*
  • Disease Models, Animal
  • Female
  • Genetic Association Studies
  • Humans
  • Male
  • Meningitis, Pneumococcal / genetics*
  • Meningitis, Pneumococcal / immunology*
  • Meningitis, Pneumococcal / pathology
  • Meningitis, Pneumococcal / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Prospective Studies
  • Receptor, Anaphylatoxin C5a / deficiency
  • Receptor, Anaphylatoxin C5a / genetics

Substances

  • Antibodies, Monoclonal
  • Complement C5
  • Receptor, Anaphylatoxin C5a