scholarly journals Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

2019 ◽  
Author(s):  
Jihye Kim ◽  
Michal Hetman ◽  
Eyas M. Hattab ◽  
Joshua Joiner ◽  
Brian Alejandro ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Zika Virus ◽  
Neurological Complications ◽  
Brain Infection ◽  
The Central Nervous System ◽  
The Brain ◽  
Host Brain

ABSTRACTZika virus (ZIKV) can infect and cause microcephaly and Zika-associated neurological complications in the developing fetal and adult brains. In terms of pathogenesis, a critical question is how ZIKV overcomes the barriers separating the brain from the circulation and gains access to the central nervous system (CNS). Despite the importance of ZIKV pathogenesis, the route ZIKV utilizes to cross CNS barriers remains unclear.Here we show that in mouse models, ZIKV-infected cells initially appeared in the periventricular regions of the brain, including the choroid plexus and the meninges, prior to infection of the cortex. The appearance of ZIKV in cerebrospinal fluid (CSF) preceded infection of the brain parenchyma. We show that ZIKV infects pericytes in the choroid plexus, and that ZIKV infection of pericytes is dependent on AXL receptor tyrosine kinase. Using an in vitro Transwell system, we highlight the possibility of ZIKV to move from the blood side to CSF side, across the choroid plexus epithelial layers, via a nondestructive pathway (e.g., transcytosis). Finally, we demonstrate that brain infection is significantly attenuated by neutralization of the virus in the CSF, indicating that ZIKV in the CSF at the early stage of infection might be responsible for establishing a lethal infection of the brain. Taken together, our results suggest that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.AUTHOR SUMMARYZika virus invades the human brains and causes Zika-associated neurological complications; however, the mechanism(s) by which Zika virus accesses the central nerves system remain unclear. Understanding of the cellular and molecular mechanisms will shed light on development of novel therapeutic and prophylactic targets for Zika virus and other neurotropic viruses. Here we use in vivo and in vitro models to understand how Zika virus enters the brain. In mouse models, we found that Zika virus infects pericytes in the choroid plexus at very early stages of infection and neutralization of Zika virus in the cerebrospinal fluid significantly attenuate the brain infection. Further we show evidence that Zika virus can cross the epithelial cell layers in the choroid plexus from the blood side. Our research highlights that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.

Myo-inositol transport in the central nervous system

1975 ◽  
Vol 228 (5) ◽  
pp. 1510-1518 ◽  
Author(s):  
R Spector ◽  
AV Lorenzo
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Choroid Plexus ◽  
Intraventricular Injection ◽  
Affinity Constant ◽  
Rapid Injection ◽  
The Central Nervous System

Free myo-inositol (inositol) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the cerebrospinal fluid was measured in rabbits. In vivo, inositol transport from blood into choroid plexus, CSF, and brain was saturable with an apparent affinity constant (K-t) of approximately 0.1 mM. The relative turnover of free inositol in choroid plexus (16 percent/h) was higher than in CSF 4percent/h) and brain (0.3percent/h) when meausred by tissue penetration of tracer [3-H]-labeled inositol injected into blood. However, the passage of tracer inositol was not greater than the passage of mannitol into brain when measured 15 s after a rapid injection of inositol and mannitol into the left common carotid artery. From the CSF, the clearance of inositol relative to inulin was saturable after the intraventricular injection of various concentrations of inositol and inulin. Moreover, a portion of the inositol cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [3-H-labeled myo-inositol against a concentration gradient by a specific, active, saturable process with a K-t of 0.2 mM inositol. These results were interpreted as showing that the entry of inositol into the central nervous system from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.

scholarly journals Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

2020 ◽  
Vol 16 (5) ◽  
pp. e1008204 ◽  
Author(s):  
Jihye Kim ◽  
Brian Alejandro ◽  
Michal Hetman ◽  
Eyas M. Hattab ◽  
Joshua Joiner ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Choroid Plexus ◽  
Zika Virus ◽  
The Central Nervous System

Abstract 245: Intravenously Injected Human Apolipoprotein A-I Rapidly Enters the Central Nervous System via the Choroid Plexus in Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sophie Stukas ◽  
Jerome Robert ◽  
Michael Lee ◽  
Iva Kulic ◽  
Nicole DeValle ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Choroid Plexus ◽  
Lipoprotein Metabolism ◽  
High Density Lipoproteins ◽  
Dependent Manner ◽  
Apo E ◽  
The Central Nervous System ◽  
The Brain

Background: Lipoprotein metabolism in the brain is based on particles that resemble high-density lipoproteins (HDL) that use apolipoprotein (apo) E as opposed to apoA-I as their primary protein component. Although apoA-I is not synthesized by astrocytes or microglia, which secrete apoE, it is abundant in cerebrospinal fluid (CSF) and is readily detectable in brain tissue lysates.However, the mechanisms by which plasma apoA-I enters and is metabolized within the central nervous system (CNS) are unknown. Methods and Results: Western blot analysis shows that steady state levels of endogenous apoA-I in CSF and brain are approximately 0.01% and 10-15% of its levels in plasma and liver, respectively. Recombinant, fluorescently tagged, lipid-free human (h) apoA-I injected into the tail vein of wild-type mice localizes to the choroid plexus within 0.5h and accumulates in a saturable, dose-dependent manner in brain. hApoA-I accumulates in the brain for up to 2h, after which it is turned over with a half life of ~133 minutes, 3 times longer than the relatively quick turnover 40-45 minutes found in plasma, liver, and kidney. In vitro, hApoA-I is taken up and actively transported across confluent monolayers of primary human choroid epithelial cells. Conclusions: Following intravenous injection, hApoA-I rapidly and strongly localizes to the choroid plexus, suggesting it gains access to the CNS primarily via the blood CSF barrier. Further, apoA-I found in the CNS of mice is exclusively derived from the circulation as apoA-I mRNA is not detectable in murine brain. These results suggest that apoA-I based HDL may primarily play a role in CSF lipoprotein metabolism in addition to potentially impacting cerebrovasculature health and function from the lumen of the vessel.

scholarly journals Transport across the choroid plexus epithelium

2017 ◽  
Vol 312 (6) ◽  
pp. C673-C686 ◽  
Author(s):  
Jeppe Praetorius ◽  
Helle Hasager Damkier
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Choroid Plexus ◽  
System Development ◽  
Nervous System Development ◽  
Ionic Balance ◽  
Choroid Plexus Epithelium ◽  
The Central Nervous System ◽  
The Brain

The choroid plexus epithelium is a secretory epithelium par excellence. However, this is perhaps not the most prominent reason for the massive interest in this modest-sized tissue residing inside the brain ventricles. Most likely, the dominant reason for extensive studies of the choroid plexus is the identification of this epithelium as the source of the majority of intraventricular cerebrospinal fluid. This finding has direct relevance for studies of diseases and conditions with deranged central fluid volume or ionic balance. While the concept is supported by the vast majority of the literature, the implication of the choroid plexus in secretion of the cerebrospinal fluid was recently challenged once again. Three newer and promising areas of current choroid plexus-related investigations are as follows: 1) the choroid plexus epithelium as the source of mediators necessary for central nervous system development, 2) the choroid plexus as a route for microorganisms and immune cells into the central nervous system, and 3) the choroid plexus as a potential route for drug delivery into the central nervous system, bypassing the blood-brain barrier. Thus, the purpose of this review is to highlight current active areas of research in the choroid plexus physiology and a few matters of continuous controversy.

scholarly journals Beyond Oncological Hyperthermia: Physically Drivable Magnetic Nanobubbles as Novel Multipurpose Theranostic Carriers in the Central Nervous System

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2104 ◽  
Author(s):  
Eleonora Ficiarà ◽  
Shoeb Anwar Ansari ◽  
Monica Argenziano ◽  
Luigi Cangemi ◽  
Chiara Monge ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Ad Hoc ◽  
Superparamagnetic Iron Oxide ◽  
Conventional Radiotherapy ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain

Magnetic Oxygen-Loaded Nanobubbles (MOLNBs), manufactured by adding Superparamagnetic Iron Oxide Nanoparticles (SPIONs) on the surface of polymeric nanobubbles, are investigated as theranostic carriers for delivering oxygen and chemotherapy to brain tumors. Physicochemical and cyto-toxicological properties and in vitro internalization by human brain microvascular endothelial cells as well as the motion of MOLNBs in a static magnetic field were investigated. MOLNBs are safe oxygen-loaded vectors able to overcome the brain membranes and drivable through the Central Nervous System (CNS) to deliver their cargoes to specific sites of interest. In addition, MOLNBs are monitorable either via Magnetic Resonance Imaging (MRI) or Ultrasound (US) sonography. MOLNBs can find application in targeting brain tumors since they can enhance conventional radiotherapy and deliver chemotherapy being driven by ad hoc tailored magnetic fields under MRI and/or US monitoring.

Thiamine transport in the central nervous system

1976 ◽  
Vol 230 (4) ◽  
pp. 1101-1107 ◽  
Author(s):  
R Spector
Keyword(s):  
Choroid Plexus ◽  
Intraventricular Injection ◽  
Simple Diffusion ◽  
Thiamine Transport ◽  
Choroid Plexuses ◽  
The Central Nervous System ◽  
The Brain ◽  
Thiamine Phosphates

Total thiamine (free thiamine and thiamine phosphates) transport into the cerebrospinal fluid (CSF), brain, and choroid plexus and out of the CSF was measured in rabbits. In vivo, total thiamine transport into CSF, choroid plexus, and brain was saturable. At the normal plasma total thiamine concentration, less than 5% of total thiamine entry into CSF, choroid plexus, and brain was by simple diffusion. The relative turnovers of total thiamine in choroid plexus, whole brain, and CSF were 5, 2, and 14% per h, respectively, when measured by the penetration of 35S-labeled thiamine injected into blood. From the CSF, clearance of [35S]thiamine relative to mannitol was not saturable after the intraventricular injection of various concentrations of thiamine. However, a portion of the [35S]thiamine cleared from the CSF entered brain by a saturable mechanism. In vitro, choroid plexuses, isolated from rabbits and incubated in artificial CSF, accumulated [35S]thiamine against a concentration gradient by an active saturable process that did not depend on pyrophosphorylation of the [35S]thiamine. The [35S]thiamine accumulated within the choroid plexus in vitro was readily released. These results were interpreted as showing that the entry of total thiamine into the brain and CSF from blood is regulated by a saturable transport system, and that the locus of this system may be, in part, in the choroid plexus.

Developmental Overview of Central Neuroanatomy

2017 ◽  
Author(s):  
Peggy Mason
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Cerebral Cortex ◽  
Neural Tube ◽  
The Central Nervous System ◽  
Dorsal Telencephalon ◽  
Adult Spinal Cord ◽  
The Brain

The central nervous system develops from a proliferating tube of cells and retains a tubular organization in the adult spinal cord and brain, including the forebrain. Failure of the neural tube to close at the front is lethal, whereas failure to close the tube at the back end produces spina bifida, a serious neural tube defect. Swellings in the neural tube develop into the hindbrain, midbrain, diencephalon, and telencephalon. The diencephalon sends an outpouching out of the cranium to form the retina, providing an accessible window onto the brain. The dorsal telencephalon forms the cerebral cortex, which in humans is enormously expanded by growth in every direction. Running through the embryonic neural tube is an internal lumen that becomes the cerebrospinal fluid–containing ventricular system. The effects of damage to the spinal cord and forebrain are compared with respect to impact on self and potential for improvement.

The area postrema plays no role in the pressor action of angiotensin in the rat

1980 ◽  
Vol 239 (1) ◽  
pp. H108-H113 ◽  
Author(s):  
J. R. Haywood ◽  
G. D. Fink ◽  
J. Buggy ◽  
M. I. Phillips ◽  
M. J. Brody
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Carotid Arteries ◽  
Area Postrema ◽  
Renal Hypertension ◽  
Conscious Rat ◽  
The Central Nervous System ◽  
Pressor Activity ◽  
The Brain

The area postrema has been shown to have a major role in mediating the pressor effects of peripheral angiotensin in the dog, cat, and rabbit. The purpose of this study was to ascertain the function of the medullary circumventricular structure in the conscious rat. The pressor potency of angiotensin administered into the vertebral and carotid arteries was compared with intra-aortic infusions of angiotensin. Although no difference in pressor activity of angiotensin could be detected between intraaortic and intravertebral administration, greater sensitivity was observed during intracarotid infusion. No difference in the course of one-kidney renal hypertension was observed between sham-lesioned rats and animals with an area postrema lesion. In addition, lesioned and sham-lesioned animals showed equivalent responses to graded doses of angiotensin administered either intravenously or into the lateral ventricle. It was concluded that in the rat the area postrema plays no role in mediating the central nervous system actions of angiotensin whether the peptide reaches the brain via the blood or the cerebrospinal fluid.

scholarly journals Infectious Progression of Canine Distemper Virus from Circulating Cerebrospinal Fluid into the Central Nervous System

2016 ◽  
Vol 90 (20) ◽  
pp. 9285-9292 ◽  
Author(s):  
Akiko Takenaka ◽  
Hiroki Sato ◽  
Fusako Ikeda ◽  
Misako Yoneda ◽  
Chieko Kai
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Hippocampal Formation ◽  
Target Cells ◽  
Canine Distemper ◽  
P Gene ◽  
The Central Nervous System ◽  
The Brain ◽  
Parental Mouse

ABSTRACTIn the current study, we generated recombinant chimeric canine distemper viruses (CDVs) by replacing the hemagglutinin (H) and/or phosphoprotein (P) gene in an avirulent strain expressing enhanced green fluorescent protein (EGFP) with those of a mouse-adapted neurovirulent strain. Anin vitroexperimental infection indicated that the chimeric CDVs possessing the H gene derived from the mouse-adapted CDV acquired infectivity for neural cells. These cells lack the CDV receptors that have been identified to date (SLAM and nectin-4), indicating that the H protein defines infectivity in various cell lines. The recombinant viruses were administered intracerebrally to 1-week-old mice. Fatal neurological signs of disease were observed only with a recombinant CDV that possessed both the H and P genes of the mouse-adapted strain, similar to the parental mouse-adapted strain, suggesting that both genes are important to drive virulence of CDV in mice. Using this recombinant CDV, we traced the intracerebral propagation of CDV by detecting EGFP. Widespread infection was observed in the cerebral hemispheres and brainstems of the infected mice. In addition, EGFP fluorescence in the brain slices demonstrated a sequential infectious progression in the central nervous system: CDV primarily infected the neuroependymal cells lining the ventricular wall and the neurons of the hippocampus and cortex adjacent to the ventricle, and it then progressed to an extensive infection of the brain surface, followed by the parenchyma and cortex. In the hippocampal formation, CDV spread in a unidirectional retrograde pattern along neuronal processes in the hippocampal formation from the CA1 region to the CA3 region and the dentate gyrus. Our mouse model demonstrated that the main target cells of CDV are neurons in the acute phase and that the virus spreads via neuronal transmission pathways in the hippocampal formation.IMPORTANCECDV is the etiological agent of distemper in dogs and other carnivores, and in many respects, the pathogenesis of CDV infection in animals resembles that of measles virus infection in humans. We successfully generated a recombinant CDV containing the H and P genes from a mouse-adapted neurovirulent strain and expressing EGFP. The recombinant CDV exhibited severe neurovirulence with high mortality, comparable to the parental mouse-adapted strain. The mouse-infectious model could become a useful tool for analyzing CDV infection of the central nervous system subsequent to passing through the blood-cerebrospinal fluid barrier and infectious progression in the target cells in acute disease.

scholarly journals ACCUMULATION OF ANTIBODIES IN THE CENTRAL NERVOUS SYSTEM

1930 ◽  
Vol 51 (6) ◽  
pp. 889-902 ◽  
Author(s):  
Jules Freund
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Slow Rate ◽  
Immune Serum ◽  
Brain Extract ◽  
Rapid Rate ◽  
The Central Nervous System ◽  
Brain And Spinal Cord ◽  
The Brain

1. Antibodies can be extracted from the brain and spinal cord of rabbits actively or passively immunized with typhoid bacilli. 2. The titers of the antibodies in the extracts of brain and cord depend upon the titer of the blood serum. In actively immunized rabbits the following numerical relationships exist between the titers of the serum and of these organ extracts: The ratio of the titer of the serum is to the titers of extract of brain and of the spinal cord about as 100 is to 0.8; the titer of the serum is to the titer of the cerebrospinal fluid as 100 is to 0.3. In passively immunized rabbits the titer of the serum is to the titer of brain and spinal-cord extract as 100 is to 0.7. 3. The antibodies recovered from the brain are not due to the presence of blood in it for perfusion of the brain does not reduce its antibody content appreciably. 4. Antibodies penetrate into the spinal fluid from the blood even in the absence of inflammation of the meninges. When the penetration is completed the following numerical relationship exists between the titer of the serum and that of the cerebrospinal fluid: 100 to 0.25. 5. The penetration into the cerebrospinal fluid of antibodies injected intravenously proceeds at a slow rate, being completed only several hours after the immune serum has been injected. The penetration of antibodies into the tissue of the brain occurs at a very rapid rate. It is completed within 15 minutes. 6. It is very unlikely that when the immune serum is injected intravenously the antibodies reach the brain tissue by way of the cerebrospinal fluid, for (1) the antibody titer of the cerebrospinal fluid is lower than that of the brain extract, and (2) antibodies penetrate faster into the tissue of the brain than into the cerebrospinal fluid.

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