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Bacterial induction of Snail1 contributes to blood-brain barrier disruption.

Authors :
Kim BJ
Hancock BM
Bermudez A
Del Cid N
Reyes E
van Sorge NM
Lauth X
Smurthwaite CA
Hilton BJ
Stotland A
Banerjee A
Buchanan J
Wolkowicz R
Traver D
Doran KS
Source :
The Journal of clinical investigation [J Clin Invest] 2015 Jun; Vol. 125 (6), pp. 2473-83. Date of Electronic Publication: 2015 May 11.
Publication Year :
2015

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.

Details

Language :
English
ISSN :
1558-8238
Volume :
125
Issue :
6
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
25961453
Full Text :
https://doi.org/10.1172/JCI74159