HIF-1α is involved in blood-brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis.

Acta Neuropathologica
Gayatri DevrajVolkhard A J Kempf

Abstract

Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from blood to the brain across the blood-cerebrospinal fluid barrier or the blood-brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1α activation was observed by immunohistochemistry. S. pneumoniae infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluo...Continue Reading

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Datasets Mentioned

BETA
GSE122952

Methods Mentioned

BETA
electron microscopy
protein assay
electrophoresis
super-resolution microscopy
transfection
fluorescence microscopy
super resolution microscopy
RNAseq
PCA
super-resolution

Software Mentioned

Ensembl
NIS
NIS Elements
MS Office Excel
DESeq2
PANTHER
KOBAS
Subread
Adobe
Elements

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