Abstract
Bacterial meningitis is a life-threatening infectious disease with severe neurological sequelae and a high mortality rate, in which Escherichia coli is one of the primary Gram-negative etiological bacteria. Meningitic E. coli infection is often accompanied by an elevated blood–brain barrier (BBB) permeability. BBB is the structural and functional barrier composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGFβ1 physiologically maintained the BBB permeability by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic E. coli infection could subvert this intercellular communication within BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we identified E. coli α-hemolysin as the critical determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction and triggering Ca2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG exhibited promising protection against the infection-caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism during meningitic E. coli-caused BBB disruption and suggested that activating hedgehog signaling within BBB could be a potential protective strategy for future therapy of bacterial meningitis.
Highlights
Bacterial meningitis is an important life-threatening infection in the central nervous system (CNS), especially in newborn infants, young teenagers, and the elder with low immunity [1,2,3]
We previously demonstrated that astrocytes-derived transforming growth factor-β1 (TGFβ1) enhanced the endothelial ZO-1 expression and maintained the blood–brain barrier (BBB) integrity by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs), indicating that the TGFβ1-mediated intercellular communication between astrocytes and BMECs is beneficial for BBB integrity maintaining [13], and exogenous TGFβ1 addition would exhibit a protective effect on BBB
The IF assay showed that the ZO-1 in BMECs of the infected mice was largely decreased compared to the control mice (Fig. 1A), and the BBB permeability was obviously increased in the challenged mice brain, evaluated by Evan’s blue dye infiltration (Fig. 1B)
Summary
Bacterial meningitis is an important life-threatening infection in the central nervous system (CNS), especially in newborn infants, young teenagers, and the elder with low immunity [1,2,3]. Escherichia coli is the most common Gram-negative bacillary organism that causes meningitis [4]. Most cases of E. coli meningitis initiate from the hematogenous spread and develop as circulating pathogenic bacteria penetrate and breakdown the blood–brain. BBB is a specialized structure composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes. This barrier separates the brain from the bloodstream and maintains the CNS homeostasis [6,7,8]. Among these component cells, BMECs act as the first and direct barrier unit to determine the BBB function [9, 10]. Ang1/ Tie and Flk were reported to promote the capillary
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