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

AbstractBacterial meningitis is a deadly disease most commonly caused byStreptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer ofS. 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, ne cessitating 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 (VE GF) 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-1 α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell–cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy , live-cell imaging). Hemat...

Source: Acta Neuropathologica - June 10, 2020 Category: Neurology Source Type: research