Bacterial Induction of Snail1 Contributes to Blood-Brain Barrier Disruption

J Clin Invest. 2015 Jun;125(6):2473-83. doi: 10.1172/JCI74159. Epub 2015 May 11.

Abstract

Bacterial meningitis is a serious infection of the CNS that results when blood-borne bacteria are able to cross the blood-brain barrier (BBB). Group B Streptococcus (GBS) is the leading cause of neonatal meningitis; however, the molecular mechanisms that regulate bacterial BBB disruption and penetration are not well understood. Here, we found that infection of human brain microvascular endothelial cells (hBMECs) with GBS and other meningeal pathogens results in the induction of host transcriptional repressor Snail1, which impedes expression of tight junction genes. Moreover, GBS infection also induced Snail1 expression in murine and zebrafish models. Tight junction components ZO-1, claudin 5, and occludin were decreased at both the transcript and protein levels in hBMECs following GBS infection, and this repression was dependent on Snail1 induction. Bacteria-independent Snail1 expression was sufficient to facilitate tight junction disruption, promoting BBB permeability to allow bacterial passage. GBS induction of Snail1 expression was dependent on the ERK1/2/MAPK signaling cascade and bacterial cell wall components. Finally, overexpression of a dominant-negative Snail1 homolog in zebrafish elevated transcription of tight junction protein-encoding genes and increased zebrafish survival in response to GBS challenge. Taken together, our data support a Snail1-dependent mechanism of BBB disruption and penetration by meningeal pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / microbiology
  • Blood-Brain Barrier / pathology
  • Cells, Cultured
  • Claudin-5 / genetics
  • Claudin-5 / metabolism
  • Gene Expression Regulation / genetics
  • Humans
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Snail Family Transcription Factors
  • Streptococcal Infections / genetics
  • Streptococcal Infections / metabolism*
  • Streptococcal Infections / pathology
  • Streptococcus agalactiae*
  • Tight Junctions / genetics
  • Tight Junctions / metabolism*
  • Tight Junctions / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism

Substances

  • CLDN5 protein, human
  • Claudin-5
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TJP1 protein, human
  • Transcription Factors
  • Zebrafish Proteins
  • Zonula Occludens-1 Protein
  • snai1a protein, zebrafish
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3