Group B streptococcal beta-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis

J Clin Invest. 2003 Sep;112(5):736-44. doi: 10.1172/JCI17335.


Meningitis occurs when blood-borne pathogens cross the blood-brain barrier (BBB) in a complex interplay between endothelial cells and microbial gene products. We sought to understand the initial response of the BBB to the human meningeal pathogen group B Streptococcus (GBS) and the organism's major virulence factors, the exopolysaccharide capsule and the beta-hemolysin/cytolysin toxin (beta-h/c). Using oligonucleotide microarrays, we found that GBS infection of human brain microvascular endothelial cells (HBMEC) induced a highly specific and coordinate set of genes including IL-8, Groalpha, Grobeta, IL-6, GM-CSF, myeloid cell leukemia sequence-1 (Mcl-1), and ICAM-1, which act to orchestrate neutrophil recruitment, activation, and enhanced survival. Most strikingly, infection with a GBS strain lacking beta-h/c resulted in a marked reduction in expression of genes involved in the immune response, while the unencapsulated strain generally induced similar or greater expression levels for the same subset of genes. Cell-free bacterial supernatants containing beta-h/c activity induced IL-8 release, identifying this toxin as a principal provocative factor for BBB activation. These findings were further substantiated in vitro and in vivo. Neutrophil migration across polar HBMEC monolayers was stimulated by GBS and its beta-h/c through a process involving IL-8 and ICAM-1. In a murine model of hematogenous meningitis, mice infected with beta-h/c mutants exhibited lower mortality and decreased brain bacterial counts compared with mice infected with the corresponding WT GBS strains.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bacterial Proteins
  • Blood-Brain Barrier
  • Brain / blood supply
  • Brain / drug effects*
  • Brain / metabolism
  • Cell Movement
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling
  • Hemolysin Proteins / toxicity*
  • Humans
  • Interleukin-8 / biosynthesis
  • Meningitis, Bacterial / etiology*
  • Neutrophils / drug effects*
  • Neutrophils / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Streptococcus agalactiae / pathogenicity*


  • Bacterial Proteins
  • Hemolysin Proteins
  • Interleukin-8
  • streptococcal group B hemolysin