Blood–Brain Barrier Integrity Damage in Bacterial Meningitis: The Underlying Link, Mechanisms, and Therapeutic Targets

Abstract

Despite advances in supportive care and antimicrobial treatment, bacterial meningitis remains the most serious infection of the central nervous system (CNS) that poses a serious risk to life. This clinical dilemma is largely due to our insufficient knowledge of the pathology behind this disease. By controlling the entry of molecules into the CNS microenvironment, the blood–brain barrier (BBB), a highly selective cellular monolayer that is specific to the CNS’s microvasculature, regulates communication between the CNS and the rest of the body. A defining feature of the pathogenesis of bacterial meningitis is the increase in BBB permeability. So far, several contributing factors for BBB disruption have been reported, including direct cellular damage brought on by bacterial virulence factors, as well as host-specific proteins or inflammatory pathways being activated. Recent studies have demonstrated that targeting pathological factors contributing to enhanced BBB permeability is an effective therapeutic complement to antimicrobial therapy for treating bacterial meningitis. Hence, understanding how these meningitis-causing pathogens affect the BBB permeability will provide novel perspectives for investigating bacterial meningitis’s pathogenesis, prevention, and therapies. Here, we summarized the recent research progress on meningitis-causing pathogens disrupting the barrier function of BBB. This review provides handy information on BBB disruption by meningitis-causing pathogens, and helps design future research as well as develop potential combination therapies.

C-X-C Motif Chemokine 3 Promotes the Inflammatory Response of Microglia after Escherichia coli-Induced Meningitis

“…In this study, we demonstrated that CXCL3 promotes microglia M1 polarization by binding to CXCR2, which ultimately induces the expression of pro-inflammatory cytokines (Figure 7). chemokines remain at high levels in the blood and brain for a long time [17,19]. In this study, we demonstrated that CXCL3 promotes microglia M1 polarization by binding to CXCR2, which ultimately induces the expression of pro-inflammatory cytokines (Figure 7).…”

Interleukin-22 Contributes to Blood–Brain Barrier Disruption via STAT3/VEGFA Activation in Escherichia coli Meningitis

“…In vitro and in vivo data showed that meningitic E. coli induced the upregulation of PDGFB, which dose-dependently increased BBB permeability by decreasing TJPs expression . A recent study found that meningitic E.…”

“…Intercellular junctions between BMECs play a critical role in maintaining vascular integrity and permeability for barrier functions . Several factors have been reported to contribute to BBB disruption in bacterial meningitis, including direct cellular damage caused by bacterial virulence factors (e.g., lipopolysaccharide, capsule, peptidoglycan, enolase, hyaluronidase, and hemolysin), as well as host-specific proteins [e.g., matrix metalloproteinases (MMP)-3, MMP-8, MMP-9, vascular endothelial growth factor A (VEGFA), and SNAI1] or proinflammatory cytokines [e.g., interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α]. − …”

Antibiotic susceptibility of Escherichia coli isolated from neonates admitted to neonatal intensive care units across China from 2015 to 2020

“…Several studies have found that E. coli strains containing all virulence genomes had a lower resistance phenotype than that observed in non-virulent E. coli strains, and this may be related to the regulation of the bacterial genome ( Čurová et al., 2020 ). As we know, meningitis-associated E. coli crosses the blood-brain barrier requiring a combination of virulence factors, such as OmpA , Ibe , CNF1 ( Yang et al., 2023 ). We therefore hypothesize that the reason why strains causing invasive infections were instead less resistant than those separated from sputum may be related to the complex regulation between virulence and drug resistance.…”