Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier

Oncotarget. 2016 Sep 27;7(39):63839-63855. doi: 10.18632/oncotarget.11696.

Abstract

Escherichia coli is the most common Gram-negative bacterium that possesses the ability to cause neonatal meningitis, which develops as circulating bacteria penetrate the blood-brain barrier (BBB). However, whether meningitic E. coli could induce disruption of the BBB and the underlying mechanisms are poorly understood. Our current work highlight for the first time the participation of VEGFA and Snail-1, as well as the potential mechanisms, in meningitic E. coli induced disruption of the BBB. Here, we characterized a meningitis-causing E. coli PCN033, and demonstrated that PCN033 invasion could increase the BBB permeability through downregulating and remodeling the tight junction proteins (TJ proteins). This process required the PCN033 infection-induced upregulation of VEGFA and Snail-1, which involves the activation of TLR2-MAPK-ERK1/2 signaling cascade. Moreover, production of proinflammatory cytokines and chemokines in response to infection also promoted the upregulation of VEGFA and Snail-1, therefore further mediating the BBB disruption. Our observations reported here directly support the involvement of VEGFA and Snail-1 in meningitic E. coli induced BBB disruption, and VEGFA and Snail-1 would therefore represent the essential host targets for future prevention of clinical E. coli meningitis.

Keywords: Snail-1; bacterial meningitis; blood-brain barrier; tight junctions; vascular endothelial growth factor A.

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Escherichia coli
  • Escherichia coli Infections / prevention & control*
  • Humans
  • Inflammation
  • Meningitis / microbiology*
  • Meningitis / prevention & control*
  • Mice
  • Permeability
  • Signal Transduction
  • Snail Family Transcription Factors / metabolism*
  • Tight Junction Proteins / metabolism
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Cytokines
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Tight Junction Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A