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Bacterial induction of Snail1 contributes to blood-brain barrier disruption.
- 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.
- Subjects :
- Animals
Blood-Brain Barrier microbiology
Blood-Brain Barrier pathology
Cells, Cultured
Claudin-5 genetics
Claudin-5 metabolism
Gene Expression Regulation genetics
Humans
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 pathology
Tight Junctions genetics
Tight Junctions pathology
Transcription Factors genetics
Zebrafish genetics
Zebrafish metabolism
Zebrafish Proteins genetics
Zebrafish Proteins metabolism
Zonula Occludens-1 Protein genetics
Zonula Occludens-1 Protein metabolism
Blood-Brain Barrier metabolism
MAP Kinase Signaling System
Streptococcal Infections metabolism
Streptococcus agalactiae
Tight Junctions metabolism
Transcription Factors metabolism
Subjects
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