scholarly journals An original model of brain infection identifies the hijacking of host lipoprotein import as a bacterial strategy for blood-brain barrier crossing

2020 ◽  
Author(s):  
Billel Benmimoun ◽  
Florentia Papastefanaki ◽  
Bruno Périchon ◽  
Katerina Segklia ◽  
Nicolas Roby ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Group B Streptococcus ◽  
Ldl Receptor ◽  
Systemic Infection ◽  
Brain Barrier ◽  
Brain Infection ◽  
Blood Brain ◽  
Drosophila Brain ◽  
Group B

AbstractPathogens able to cross the blood-brain barrier (BBB) induce long-term neurological sequelae and death. Understanding how neurotropic pathogens bypass this strong physiological barrier is a prerequisite to devise therapeutic strategies. Here we propose an innovative model of infection in the developing Drosophila brain, combining whole brain explants with in vivo systemic infection. We identified several mammalian pathogens able to cross the Drosophila BBB, including Group B Streptococcus (GBS). Amongst GBS surface components, lipoproteins, and in particular the B leucin-rich Blr, were important for BBB crossing and virulence in Drosophila. Further, we identified (V)LDL receptor LpR2, expressed in the BBB, as a host receptor for Blr, allowing GBS translocation through endocytosis. Finally, we demonstrated that Blr is required for BBB crossing and pathogenicity in a murine model of infection. Our results support the relevance of Drosophila for studying host-pathogen interactions and identify a new mechanism by which pathogens exploit host barriers to generate brain infection.

scholarly journals An original infection model identifies host lipoprotein import as a route for blood-brain barrier crossing

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Billel Benmimoun ◽  
Florentia Papastefanaki ◽  
Bruno Périchon ◽  
Katerina Segklia ◽  
Nicolas Roby ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ldl Receptor ◽  
Systemic Infection ◽  
Brain Barrier ◽  
Infection Model ◽  
Brain Infection ◽  
Blood Brain ◽  
Group B

AbstractPathogens able to cross the blood-brain barrier (BBB) induce long-term neurological sequelae and death. Understanding how neurotropic pathogens bypass this strong physiological barrier is a prerequisite to devise therapeutic strategies. Here we propose an innovative model of infection in the developing Drosophila brain, combining whole brain explants with in vivo systemic infection. We find that several mammalian pathogens are able to cross the Drosophila BBB, including Group B Streptococcus (GBS). Amongst GBS surface components, lipoproteins, and in particular the B leucine-rich Blr, are important for BBB crossing and virulence in Drosophila. Further, we identify (V)LDL receptor LpR2, expressed in the BBB, as a host receptor for Blr, allowing GBS translocation through endocytosis. Finally, we show that Blr is required for BBB crossing and pathogenicity in a murine model of infection. Our results demonstrate the potential of Drosophila for studying BBB crossing by pathogens and identify a new mechanism by which pathogens exploit the machinery of host barriers to generate brain infection.

scholarly journals Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Marko Brankatschk ◽  
Sebastian Dunst ◽  
Linda Nemetschke ◽  
Suzanne Eaton
Keyword(s):  
Blood Brain Barrier ◽  
Insulin Signaling ◽  
Ldl Receptor ◽  
Dietary Lipid ◽  
Brain Barrier ◽  
Free Calcium ◽  
Blood Brain ◽  
Nutritional Conditions ◽  
Drosophila Brain ◽  
Related Proteins

The Insulin signaling pathway couples growth, development and lifespan to nutritional conditions. Here, we demonstrate a function for the Drosophila lipoprotein LTP in conveying information about dietary lipid composition to the brain to regulate Insulin signaling. When yeast lipids are present in the diet, free calcium levels rise in Blood Brain Barrier glial cells. This induces transport of LTP across the Blood Brain Barrier by two LDL receptor-related proteins: LRP1 and Megalin. LTP accumulates on specific neurons that connect to cells that produce Insulin-like peptides, and induces their release into the circulation. This increases systemic Insulin signaling and the rate of larval development on yeast-containing food compared with a plant-based food of similar nutritional content.

scholarly journals Regulation of CovR expression in Group B Streptococcus impacts blood-brain barrier penetration

2010 ◽  
Vol 77 (2) ◽  
pp. 431-443 ◽  
Author(s):  
Annalisa Lembo ◽  
Michael A. Gurney ◽  
Kellie Burnside ◽  
Anirban Banerjee ◽  
Melissa De Los Reyes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Group B Streptococcus ◽  
Brain Barrier ◽  
Blood Brain ◽  
Barrier Penetration ◽  
Group B

scholarly journals Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

2005 ◽  
Vol 115 (9) ◽  
pp. 2499-2507 ◽  
Author(s):  
Kelly S. Doran ◽  
Erin J. Engelson ◽  
Arya Khosravi ◽  
Heather C. Maisey ◽  
Iris Fedtke ◽  
...  
Keyword(s):  
Cell Surface ◽  
Blood Brain Barrier ◽  
Group B Streptococcus ◽  
Lipoteichoic Acid ◽  
Brain Barrier ◽  
Surface Anchoring ◽  
Blood Brain ◽  
Group B

scholarly journals Penetration of the Blood-Brain Barrier by Bacillus anthracis Requires the pXO1-Encoded BslA Protein

2009 ◽  
Vol 191 (23) ◽  
pp. 7165-7173 ◽  
Author(s):  
Celia M. Ebrahimi ◽  
Justin W. Kern ◽  
Tamsin R. Sheen ◽  
Mohammad A. Ebrahimi-Fardooee ◽  
Nina M. van Sorge ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Human Infection ◽  
Brain Barrier ◽  
Brain Infection ◽  
Blood Brain ◽  
Junction Protein

ABSTRACT Anthrax is a zoonotic disease caused by the gram-positive spore-forming bacterium Bacillus anthracis. Human infection occurs after the ingestion, inhalation, or cutaneous inoculation of B. anthracis spores. The subsequent progression of the disease is largely mediated by two native virulence plasmids, pXO1 and pXO2, and is characterized by septicemia, toxemia, and meningitis. In order to produce meningitis, blood-borne bacteria must interact with and breach the blood-brain barrier (BBB) that is composed of a specialized layer of brain microvascular endothelial cells (BMEC). We have recently shown that B. anthracis Sterne is capable of penetrating the BBB in vitro and in vivo, establishing the classic signs of meningitis; however, the molecular mechanisms underlying the central nervous system (CNS) tropism are not known. Here, we show that attachment to and invasion of human BMEC by B. anthracis Sterne is mediated by the pXO1 plasmid and an encoded envelope factor, BslA. The results of studies using complementation analysis, recombinant BslA protein, and heterologous expression demonstrate that BslA is both necessary and sufficient to promote adherence to brain endothelium. Furthermore, mice injected with the BslA-deficient strain exhibited a significant decrease in the frequency of brain infection compared to mice injected with the parental strain. In addition, BslA contributed to BBB breakdown by disrupting tight junction protein ZO-1. Our results identify the pXO1-encoded BslA adhesin as a critical mediator of CNS entry and offer new insights into the pathogenesis of anthrax meningitis.

Use of LDL receptor—targeting peptide vectors for in vitro and in vivo cargo transport across the blood‐brain barrier

2017 ◽  
Vol 31 (5) ◽  
pp. 1807-1827 ◽  
Author(s):  
Yves Molino ◽  
Marion David ◽  
Karine Varini ◽  
Françoise Jabès ◽  
Nicolas Gaudin ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ldl Receptor ◽  
Brain Barrier ◽  
Receptor Targeting ◽  
Cargo Transport ◽  
Blood Brain ◽  
Targeting Peptide

Hyperosmolar blood-brain barrier disruption in baboons: an in vivo study using positron emission tomography and rubidium-82

1996 ◽  
Vol 84 (3) ◽  
pp. 494-502 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeffrey Olson ◽  
Ronald G. Blasberg ◽  
Mary Girton ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Blood Brain ◽  
Positron Emission ◽  
The Mean ◽  
Rubidium 82

✓ Hyperosmolar blood-brain barrier (BBB) disruption remains controversial as an adjuvant therapy to increase delivery of water-soluble compounds to extracellular space in the brain in patients with malignant brain tumors. To understand the physiological effects of BBB disruption more clearly, the authors used positron emission tomography (PET) to study the time course of BBB permeability in response to the potassium analog rubidium-82 (82Rb, halflife 75 seconds) following BBB disruption in anesthetized adult baboons. Mannitol (25%) was injected into the carotid artery and PET scans were performed before and serially at 8- to 15-minute intervals after BBB disruption. The mean influx constant (K1), a measure of permeability-surface area product, in ipsilateral, mannitol-perfused mixed gray- and white-matter brain regions was 4.9 ± 2.4 µl/min/ml (± standard deviation) at baseline and increased more than 100% (ΔK1 = 9.4 ± 5.1 µl/min/ml, 18 baboons) in brain perfused by mannitol. The effect of BBB disruption on K1 correlated directly with the total amount of mannitol administered (p < 0.005). Vascular permeability returned to baseline with a halftime of 24.0 ± 14.3 minutes. The mean brain plasma volume rose by 0.57 ± 0.34 ml/100 ml in ipsilateral perfused brain following BBB disruption. This work provides a basis for the in vivo study of permeability changes induced by BBB disruption in human brain and brain tumors.

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