Staphylococcus aureus-mediated blood-brain barrier injury: anin vitrohuman brain microvascular endothelial cell model

Abstract

Blood-brain barrier (BBB) disruption constitutes a hallmark event during pathogen-mediated neurological disorders such as bacterial meningitis. As a prevalent opportunistic pathogen, Staphylococcus aureus (SA) is of particular interest in this context, although our fundamental understanding of how SA disrupts the BBB is very limited. This paper employs in vitro infection models to address this. Human brain microvascular endothelial cells (HBMvECs) were infected with formaldehyde-fixed (multiplicity of infection [MOI] 0-250, 0-48 hr) and live (MOI 0-100, 0-3 hr) SA cultures. Both Fixed-SA and Live-SA could adhere to HBMvECs with equal efficacy and cause elevated paracellular permeability. In further studies employing Fixed-SA, infection of HBMvECs caused dose-dependent release of cytokines/chemokines (TNF-α, IL-6, MCP-1, IP-10, and thrombomodulin), reduced expression of interendothelial junction proteins (VE-Cadherin, claudin-5, and ZO-1), and activation of both canonical and non-canonical NF-κB pathways. Using N-acetylcysteine, we determined that these events were coupled to the SA-mediated induction of reactive oxygen species (ROS) within HBMvECs. Finally, treatment of HBMvECs with Fixed-ΔSpA (MOI 0-250, 48 hr), a gene deletion mutant of Staphylococcal protein A associated with bacterial infectivity, had relatively similar effects to Newman WT Fixed-SA. In conclusion, these findings provide insight into how SA infection may activate proinflammatory mechanisms within the brain microvascular endothelium to elicit BBB failure.

Transcriptome profiling of avian pathogenicEscherichia coliand the mouse microvascular endothelial cell line bEnd.3 during interaction

“…Conversely, Cldn5 highly expressed in ECs in the CNS (Daneman et al, 2010;Ohtsuki et al, 2008), which plays a key role in the paracellular barrier and forms mechanical links to maintain the structural integrity and high electrical resistance of vasculature (Abbott et al, 2010). The changes in Cdh5 and Cldn5 expression observed in the present study are consistent with the previous findings reported in a Staphylococcus aureus and group B Streptococcus model of meningitis (Kim et al, 2015;McLoughlin et al, 2017). In addition, Cdh5 controls Cldn5 by triggering its transcriptional repression via FoxO1 and β-catenin (Taddei et al, 2008).…”

Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier

“…BBB paracellular permeability may be modulated by different pathological conditions including subarachnoid hemorrhage, autoimmune encephalomyelitis, bacterial meningitis, HIV infection among others [25-28], as well as by therapeutic treatments such as hyperbaric oxygen intervention [26]; highlighting the need for more studies investigating whether TRL-3 activation disrupts BBB paracellular permeability in the developing and adult brains.…”

SadA-Expressing Staphylococci in the Human Gut Show Increased Cell Adherence and Internalization

“…However, to successfully colonize and infect the CNS, the blood-brain barrier (BBB) has to be crossed. The BBB is a very strong protection against pathogens, nevertheless, S. aureus transmigration through the endothelial tight junctions of the BBB has been shown recently (McLoughlin et al, 2017). With this in mind, TAs might not only contribute to neurological effects in the course of infection, but may also support infection of the CNS by their capability of enhancing adherence and infection of the bacteria.…”