scholarly journals Neurovirulent simian immunodeficiency virus replicates productively in endothelial cells of the central nervous system in vivo and in vitro.

1994 ◽  
Vol 68 (12) ◽  
pp. 8202-8208 ◽  
Author(s):  
J L Mankowski ◽  
J P Spelman ◽  
H G Ressetar ◽  
J D Strandberg ◽  
J Laterra ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Simian Immunodeficiency Virus ◽  
Immunodeficiency Virus ◽  
The Central Nervous System

scholarly journals Differential neurovirulence of Usutu virus lineages in mice and neuronal cells

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Marion Clé ◽  
Orianne Constant ◽  
Jonathan Barthelemy ◽  
Caroline Desmetz ◽  
Marie France Martin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Clinical Signs ◽  
Neuronal Cell ◽  
Brain Endothelial Cells ◽  
Usutu Virus ◽  
The Central Nervous System

Abstract Background Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location. Methods The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model). Results Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage. Conclusions Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection.

scholarly journals Expression of Simian Immunodeficiency Virus (SIV) Nef in Astrocytes during Acute and Terminal Infection and Requirement of Nef for Optimal Replication of Neurovirulent SIV In Vitro

2003 ◽  
Vol 77 (12) ◽  
pp. 6855-6866 ◽  
Author(s):  
Emily D. Overholser ◽  
Gary D. Coleman ◽  
Jennifer L. Bennett ◽  
Rebecca J. Casaday ◽  
M. Christine Zink ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Rhesus Macaque ◽  
Simian Immunodeficiency Virus ◽  
Critical Role ◽  
Productive Infection ◽  
Hiv Encephalitis ◽  
Immunodeficiency Virus

ABSTRACT As the most numerous cells in the brain, astrocytes play a critical role in maintaining central nervous system homeostasis, and therefore, infection of astrocytes by human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) in vivo could have important consequences for the development of HIV encephalitis. In this study, we establish that astrocytes are infected in macaques during acute SIV infection (10 days postinoculation) and during terminal infection when there is evidence of SIV-induced encephalitis. Additionally, with primary adult rhesus macaque astrocytes in vitro, we demonstrate that the macrophage-tropic, neurovirulent viruses SIV/17E-Br and SIV/17E-Fr replicate efficiently in astrocytes, while the lymphocyte-tropic, nonneurovirulent virus SIVmac239 open-nef does not establish productive infection. Furthermore, aminoxypentane-RANTES abolishes virus replication, suggesting that these SIV strains utilize the chemokine receptor CCR5 for entry into astrocytes. Importantly, we show that SIV Nef is required for optimal replication in primary rhesus macaque astrocytes and that normalizing input virus by particle number rather than by infectivity reveals a disparity between the ability of a Nef-deficient virus and a virus encoding a nonmyristoylated form of Nef to replicate in these central nervous system cells. Since the myristoylated form of Nef has been implicated in functions such as CD4 and major histocompatibility complex I downregulation, kinase association, and enhancement of virion infectivity, these data suggest that an as yet unidentified function of Nef may exist to facilitate SIV replication in astrocytes that may have important implications for in vivo pathogenesis.

scholarly journals A genome-wide view of the de-differentiation of central nervous system endothelial cells in culture

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mark F Sabbagh ◽  
Jeremy Nathans
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
In Vitro Culture ◽  
Vascular Endothelial Cells ◽  
Beta Catenin ◽  
A Genome ◽  
Accessible Chromatin

Vascular endothelial cells (ECs) derived from the central nervous system (CNS) variably lose their unique barrier properties during in vitro culture, hindering the development of robust assays for blood-brain barrier (BBB) function, including drug permeability and extrusion assays. In previous work (Sabbagh et al., 2018) we characterized transcriptional and accessible chromatin landscapes of acutely isolated mouse CNS ECs. In this report, we compare transcriptional and accessible chromatin landscapes of acutely isolated mouse CNS ECs versus mouse CNS ECs in short-term in vitro culture. We observe that standard culture conditions are associated with a rapid and selective loss of BBB transcripts and chromatin features, as well as a greatly reduced level of beta-catenin signaling. Interestingly, forced expression of a stabilized derivative of beta-catenin, which in vivo leads to a partial conversion of non-BBB CNS ECs to a BBB-like state, has little or no effect on gene expression or chromatin accessibility in vitro.

Design, fabrication, and testing of a bioprinted nerve graft

2016 ◽  
Author(s):  
◽  
Christopher M. Owens
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Nerve Graft ◽  
Loss Of Function ◽  
Vitro Assay ◽  
Central Nervous System Damage ◽  
In Vivo Animal Model ◽  
The Central Nervous System

Injuries to nerves vary in their consequences, from weakened sensation and motor function to partial or complete paralysis. In the latter case, affecting about twenty thousand Americans yearly, the injury is debilitating and results in a significant decrease in quality of life. Currently there is no effective treatment for damage to the central nervous system, in particular the spinal cord. Compared to the injuries to the central nervous system, damage in the peripheral nerves, is more common, with about sixty thousand occurrences annually. The cost of associated surgical procedures and due to loss of function is in the billions. In this thesis we present work towards the construction and testing of a fully cellular, patented nerve graft, one amongst the first of its kind. For the fabrication of the graft we are the first to employ bioprinting (either implemented through a special purpose 3D bioprinter or manually), a novel tissue engineering method rapidly gaining acceptance and utility. We first review the status of bioprinting. We then detail the fabrication process. Next we report on the testing of the graft in an in vivo animal model through electrophysiology and histology. This is followed by the introduction of a novel in vitro model, aimed at providing a fast, inexpensive and reliable method to test engineered nerve grafts. We describe our work on the optimization of the in vitro assay and then the testing of the graft using the optimized assay. We conclude with a summary of our accomplishments and make suggestions for some exciting future applications of our approach.

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 Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate

2020 ◽  
Vol 17 (3) ◽  
pp. 1142-1152 ◽  
Author(s):  
Karl E. Carlström ◽  
Praveen K. Chinthakindi ◽  
Belén Espinosa ◽  
Faiez Al Nimer ◽  
Elias S. J. Arnér ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
De Novo ◽  
Dimethyl Fumarate ◽  
The Novel ◽  
The Central Nervous System ◽  
Demyelinating Disorders ◽  
Target Effects

Abstract The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1–CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NFκB, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.

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