scholarly journals Endogenous α7 nAChR Agonist SLURP1 Facilitates Escherichia coli K1 Crossing the Blood-Brain Barrier

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaolong He ◽  
Lei Wang ◽  
Liqun Liu ◽  
Jie Gao ◽  
Beiguo Long ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Central Nervous System Infection ◽  
Brain Barrier ◽  
Transcriptional Analysis ◽  
E Coli ◽  
Blood Brain ◽  
Α7 Nachr ◽  
Alpha 7

Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is critical for the pathogenesis of Escherichia coli (E. coli) K1 meningitis, a severe central nervous system infection of the neonates. However, little is known about how E. coli K1 manipulates α7 nAChR signaling. Here, through employing immortalized cell lines, animal models, and human transcriptional analysis, we showed that E. coli K1 infection triggers releasing of secreted Ly6/Plaur domain containing 1 (SLURP1), an endogenous α7 nAChR ligand. Exogenous supplement of SLURP1, combined with SLURP1 knockdown or overexpression cell lines, showed that SLURP1 is required for E. coli K1 invasion and neutrophils migrating across the blood-brain barrier (BBB). Furthermore, we found that SLURP1 is required for E. coli K1-induced α7 nAChR activation. Finally, the promoting effects of SLURP1 on the pathogenesis of E. coli K1 meningitis was significantly abolished in the α7 nAChR knockout mice. These results reveal that E. coli K1 exploits SLURP1 to activate α7 nAChR and facilitate its pathogenesis, and blocking SLURP1-α7 nAChR interaction might represent a novel therapeutic strategy for E. coli K1 meningitis.

scholarly journals The Gene Locus yijP Contributes to Escherichia coli K1 Invasion of Brain Microvascular Endothelial Cells

1999 ◽  
Vol 67 (9) ◽  
pp. 4751-4756 ◽  
Author(s):  
Ying Wang ◽  
Sheng-He Huang ◽  
Carol A. Wass ◽  
Monique F. Stins ◽  
Kwang Sik Kim
Keyword(s):  
Escherichia Coli ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Parent Strain ◽  
Gene Locus ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
E Coli ◽  
Blood Brain

ABSTRACT Most cases of Escherichia coli meningitis develop as a result of hematogenous spread, but it is not clear how circulatingE. coli crosses the blood-brain barrier. A TnphoA mutant of E. coli K1 RS218 was shown to be significantly less invasive than its parent strain in bovine and human brain microvascular endothelial cells (BMEC), which constitute the blood-brain barrier. More importantly, traversal of the blood-brain barrier was significantly less with this mutant than with the parent strain in newborn rats with experimental hematogenous meningitis. A DNA segment containing the TnphoA insertion site was cloned from RS218, and the cloned DNA complemented the TnphoAmutant in invasion of BMEC. Nucleotide sequence revealed a near identity to that of a hypothetical yijP gene (also calledf577) in the E. coli K-12 genome. Sequence analysis indicated that the E. coli K1 yijPgene likely encodes a 66.6-kDa membrane protein. Deletion and complementation experiments indicated that the yijP gene was involved in E. coli K1 invasion of BMEC, i.e., the invasive ability of E. coli K1 was significantly reduced after yijP was deleted and was restored by complementation with a plasmid containing the yijP open reading frame. This is the first demonstration that the yijP gene locus plays a role in the pathogenesis of E. coli K1 meningitis.

scholarly journals Meningitic Escherichia coli Induction of ANGPTL4 in Brain Microvascular Endothelial Cells Contributes to Blood–Brain Barrier Disruption via ARHGAP5/RhoA/MYL5 Signaling Cascade

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 254 ◽  
Author(s):  
Lu Liu ◽  
Jixuan Li ◽  
Dong Huo ◽  
Zhong Peng ◽  
Ruicheng Yang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Endothelial Cells ◽  
Bacterial Meningitis ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Signaling Cascade ◽  
Brain Microvascular Endothelial Cells ◽  
E Coli ◽  
Blood Brain

Bacterial meningitis is currently recognized as one of the most important life-threatening infections of the central nervous system (CNS) with high morbidity and mortality, despite the advancements in antimicrobial treatment. The disruption of blood–brain barrier (BBB) induced by meningitis bacteria is crucial for the development of bacterial meningitis. However, the complete mechanisms involving in the BBB disruption remain to be elucidated. Here, we found meningitic Escherichia coli induction of angiopoietin-like 4 (ANGPTL4) in brain microvascular endothelial cells (BMECs) contributes to BBB disruption via ARHGAP5/RhoA/MYL5 signaling cascade, by the demonstration that ANGPTL4 was significantly upregulated in meningitis E. coli infection of BMECs as well as mice, and treatment of the recombinant ANGPTL4 protein led to an increased permeability of the BBB in vitro and in vivo. Moreover, we found that ANGPTL4 did not affect the expression of tight junction proteins involved in BBB disruption, but it increased the expression of MYL5, which was found to have a negative role on the regulation of barrier function during meningitic E. coli infection, through the activation of RhoA signaling pathway. To our knowledge, this is the first report demonstrating the disruption of BBB induced by ANGPTL4 through the ARHGAP5/RhoA/MYL5 pathway, which largely supports the involvement of ANGPTL4 during meningitic E. coli invasion and further expands the theoretical basis for the mechanism of bacterial meningitis.

scholarly journals Arachidonic Acid Metabolism Regulates Escherichia coli Penetration of the Blood-Brain Barrier

2010 ◽  
Vol 78 (10) ◽  
pp. 4302-4310 ◽  
Author(s):  
Longkun Zhu ◽  
Ravi Maruvada ◽  
Adam Sapirstein ◽  
Kafait U. Malik ◽  
Marc Peters-Golden ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Arachidonic Acid ◽  
Blood Brain Barrier ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Brain Barrier ◽  
Membrane Phospholipids ◽  
E Coli ◽  
Blood Brain ◽  
Underlying Mechanisms

ABSTRACT Escherichia coli K1 meningitis occurs following penetration of the blood-brain barrier, but the underlying mechanisms involved in E. coli penetration of the blood-brain barrier remain incompletely understood. We have previously shown that host cytosolic phospholipase A2α (cPLA2α) contributes to E. coli invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier, but the underlying mechanisms remain unclear. cPLA2α selectively liberates arachidonic acid from membrane phospholipids. Here, we provide the first direct evidence that host 5-lipoxygenase and lipoxygenase products of arachidonic acid, cysteinyl leukotrienes (LTs), contribute to E. coli K1 invasion of HBMEC and penetration into the brain, and their contributions involve protein kinase C alpha (PKCα). These findings demonstrate that arachidonic acid metabolism regulates E. coli penetration of the blood-brain barrier, and studies are needed to further elucidate the mechanisms involved with metabolic products of arachidonic acid for their contribution to E. coli invasion of the blood-brain barrier.

scholarly journals Escherichia coli K1 aslAContributes to Invasion of Brain Microvascular Endothelial Cells In Vitro and In Vivo

2000 ◽  
Vol 68 (9) ◽  
pp. 5062-5067 ◽  
Author(s):  
Jill A. Hoffman ◽  
Julie L. Badger ◽  
Yan Zhang ◽  
Sheng-He Huang ◽  
Kwang Sik Kim
Keyword(s):  
Escherichia Coli ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
E Coli ◽  
Blood Brain ◽  
Microvascular Endothelial

ABSTRACT Neonatal Escherichia coli meningitis remains a devastating disease, with unacceptably high morbidity and mortality despite advances in supportive care measures and bactericidal antibiotics. To further our ability to improve the outcome of affected neonates, a better understanding of the pathogenesis of the disease is necessary. To identify potential bacterial genes which contribute toE. coli invasion of the blood-brain barrier, a cerebrospinal fluid isolate of E. coli K1 was mutagenized with TnphoA. TnphoA mutant 27A-6 was found to have a significantly decreased ability to invade brain microvascular endothelial cells compared to the wild type. In vivo, 32% of the animals infected with mutant 27A-6 developed meningitis, compared to 82% of those infected with the parent strain, despite similar levels of bacteremia. The DNA flanking the TnphoA insertion in 27A-6 was cloned and sequenced and determined to be homologous toE. coli K-12 aslA (arylsulfatase-like gene). The deduced amino acid sequence of the E. coli K1aslA gene product shows homology to a well-characterized arylsulfatase family of enzymes found in eukaryotes, as well as prokaryotes. Two additional aslA mutants were constructed by targeted gene disruption and internal gene deletion. Both of these mutants demonstrated decreased invasion phenotypes, similar to that of TnphoA mutant 27A-6. Complementation of the decreased-invasion phenotypes of these mutants was achieved whenaslA was supplied in trans. This is the first demonstration that this locus contributes to invasion of the blood-brain barrier by E. coli K1.

scholarly journals Meningitic Escherichia coli α-hemolysin aggravates blood–brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jiyang Fu ◽  
Liang Li ◽  
Dong Huo ◽  
Ruicheng Yang ◽  
Bo Yang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Endothelial Cells ◽  
Bacterial Meningitis ◽  
Blood Brain Barrier ◽  
Hedgehog Signaling ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
E Coli ◽  
Blood Brain

AbstractBacterial 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.

CNS-infecting pathogens Escherichia coli and Cryptococcus neoformans exploit the host Pdlim2 for intracellular traversal and exocytosis in the blood-brain barrier

2021 ◽  
Author(s):  
Zhongming Li ◽  
Vincent M. Bruno ◽  
Kwang Sik Kim
Keyword(s):  
Escherichia Coli ◽  
Cryptococcus Neoformans ◽  
Blood Brain Barrier ◽  
Calcium Ionophore ◽  
Brain Barrier ◽  
Cns Infection ◽  
Knockdown Cell ◽  
E Coli ◽  
Microbial Invasion ◽  
Blood Brain

Microbial penetration of the blood–brain barrier, a prerequisite for development of the central nervous system (CNS) infection, involves microbial invasion, intracellular traversal and exocytosis. Microbial invasion of the blood-brain barrier has been investigated, but the molecular basis for microbial traversal and exit from the blood-brain barrier remains unknown. We performed transcriptome analysis of the human brain microvascular endothelial cell (HBMEC) infected with Escherichia coli and Cryptococcus neoformans , representative bacterial and fungal pathogens common in CNS infection. Among the upregulated targets in response to E. coli and C. neoformans infection, PDLIM2 was knocked down by shRNA in HBMEC for further investigation. We demonstrated that Pdlim2 specifically regulated the microbial traversal and exit from HBMEC by assessing microbial invasion, transcytosis, intracellular multiplication and egression. Additionally, the defective exocytosis of internalized E. coli from the PDLIM2 shRNA knockdown cell was restored by treatment with a calcium ionophore (ionomycin). Moreover, we performed the proximity-dependent biotin labeling with the biotin ligase BioID2 and identified 210 potential Pdlim2-interactors. Among the nine enriched Pdlim2-interactors in response to both E. coli and C. neoformans infection, we selected MPRIP and showed that HBMEC with knockdown of MPRIP mimicked the phenotype of PDLIM2 knockdown cell. These results suggest that the CNS-infecting microbes hijack Pdlim2 and Mprip for intracellular traversal and exocytosis in the blood-brain barrier.

scholarly journals IbeA and OmpA of Escherichia coli K1 Exploit Rac1 Activation for Invasion of Human Brain Microvascular Endothelial Cells

2012 ◽  
Vol 80 (6) ◽  
pp. 2035-2041 ◽  
Author(s):  
Ravi Maruvada ◽  
Kwang Sik Kim
Keyword(s):  
Escherichia Coli ◽  
Endothelial Cells ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Content Type ◽  
E Coli ◽  
Blood Brain

ABSTRACTMeningitis-causingEscherichia coliK1 internalization of the blood-brain barrier is required for penetration into the brain, but the host-microbial interactions involved inE. colientry of the blood-brain barrier remain incompletely understood. We show here that a meningitis-causingE. coliK1 strain RS218 activates Rac1 (GTP-Rac1) of human brain microvascular endothelial cells (HBMEC) in a time-dependent manner. Both activation and bacterial invasion were significantly inhibited in the presence of a Rac1 inhibitor. We further showed that the guanine nucleotide exchange factor Vav2, not β-Pix, was involved inE. coliK1-mediated Rac1 activation. Since activated STAT3 is known to bind GTP-Rac1, the relationship between STAT3 and Rac1 was examined inE. coliK1 invasion of HBMEC. Downregulation of STAT3 resulted in significantly decreasedE. coliinvasion compared to control HBMEC, as well as a corresponding decrease in GTP-Rac1, suggesting that Rac1 activation in response toE. coliis under the control of STAT3. More importantly, twoE. colideterminants contributing to HBMEC invasion, IbeA and OmpA, were shown to affect both Rac1 activation and their association with STAT3. These findings demonstrate for the first time that specificE. colideterminants regulate a novel mechanism of STAT3 cross talk with Rac1 inE. coliK1 invasion of HBMEC.

scholarly journals Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier

Oncotarget ◽  
2016 ◽  
Vol 7 (39) ◽  
pp. 63839-63855 ◽  
Author(s):  
Ruicheng Yang ◽  
Wentong Liu ◽  
Ling Miao ◽  
Xiaopei Yang ◽  
Jiyang Fu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals In Vitro Blood-Brain-Barrier Permeability and Cytotoxicity of Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

2019 ◽  
Author(s):  
Michael M Lübtow ◽  
Sabrina Oertner ◽  
Sabina Quader ◽  
Elisabeth Jeanclos ◽  
Alevtina Cubukova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Oral Administration ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Drug Loading ◽  
3D Models ◽  
Physicochemical Characteristics ◽  
Brain Barrier ◽  
Blood Brain

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with potential to cross the blood-brain-barrier, however, the concentrations necessary for a cytotoxic effect against cancer cells exceeds the concentration achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the 3D models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain-barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration, however, if transport across the blood-brain-barrier is sufficient to reach therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.<br>

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