scholarly journals Spike protein multiorgan tropism suppressed by antibodies targeting SARS-CoV-2

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Molly Brady ◽  
Conor McQuaid ◽  
Alexander Solorzano ◽  
Angelique Johnson ◽  
Abigail Combs ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Imaging System ◽  
Brain Parenchyma ◽  
Dynamic Imaging ◽  
Spike Protein ◽  
Tissue Analysis ◽  
Organ Uptake ◽  
Organ Specific ◽  
The Brain

AbstractWhile there is SARS-CoV-2 multiorgan tropism in severely infected COVID-19 patients, it’s unclear if this occurs in healthy young individuals. In addition, for antibodies that target the spike protein (SP), it’s unclear if these reduce SARS-CoV-2/SP multiorgan tropism equally. We used fluorescently labeled SP-NIRF to study viral behavior, using an in vivo dynamic imaging system and ex in vivo tissue analysis, in young mice. We found a SP body-wide biodistribution followed by a slow regional elimination, except for the liver, which showed an accumulation. SP uptake was highest for the lungs, and this was followed by kidney, heart and liver, but, unlike the choroid plexus, it was not detected in the brain parenchyma or CSF. Thus, the brain vascular barriers were effective in restricting the entry of SP into brain parenchyma in young healthy mice. While both anti-ACE2 and anti-SP antibodies suppressed SP biodistribution and organ uptake, anti-SP antibody was more effective. By extension, our data support the efficacy of these antibodies on SARS-CoV-2 multiorgan tropism, which could determine COVID-19 organ-specific outcomes.

scholarly journals Spike protein multiorgan tropism suppressed by antibodies targeting SARS-CoV-2

2021 ◽  
Author(s):  
Molly Brady ◽  
Abigail Combs ◽  
Chethana Venkatraman ◽  
Alexander Solorzano ◽  
Angelique Johnson ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Near Infrared ◽  
Imaging System ◽  
Protein Body ◽  
Brain Parenchyma ◽  
Dynamic Imaging ◽  
Spike Protein ◽  
Organ Uptake ◽  
The Brain

While there is clinical evidence of severe acute respiratory syndrome coronavirus 2 multiorgan tropism in severely infected coronavirus 19 patients, it is unclear if there is differential multiorgan biodistribution and organ uptake in healthy young individuals, a group that usually has asymptomatic to moderate coronavirus 19 symptoms. In addition, for antibody therapies and vaccines that target the spike protein, it is unclear if these reduce severe acute respiratory syndrome coronavirus 2 or spike protein multiorgan tropism equally. We used fluorescently labeled spike protein near infrared fluorescence to study viral behavior, using an in vivo dynamic imaging system, in young mice. We found a spike protein body-wide biodistribution followed by a slow regional elimination, except for the liver, which showed an accumulation. Spike protein uptake was highest for the lungs, and this was followed by kidney, heart and liver, but, unlike the choroid plexus, it was not detected in the brain parenchyma or cerebrospinal fluid. Thus, the brain vascular barriers were effective in restricting the entry of spike protein into brain parenchyma in young healthy mice. While both anti-angiotensin converting enzyme 2 and anti-spike protein antibodies suppressed spike protein biodistribution and organ uptake, anti-spike protein antibody was more effective. By extension, our data support the efficacy of these antibodies on severe acute respiratory syndrome coronavirus 2 biodistribution kinetics and multiorgan tropism that could determine coronavirus 19 organ-specific outcomes.

scholarly journals Kinetic Profile of the Transcriptome Changes Induced in the Choroid Plexus by Peripheral Inflammation

2009 ◽  
Vol 29 (5) ◽  
pp. 921-932 ◽  
Author(s):  
Fernanda Marques ◽  
João C Sousa ◽  
Giovanni Coppola ◽  
Ana M Falcao ◽  
Ana João Rodrigues ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Brain Parenchyma ◽  
Matrix Remodeling ◽  
Choroid Plexus Epithelial Cell ◽  
Blood Concentrations ◽  
The Brain

The choroid plexus, being part of the blood-brain barriers and responsible for the production of cerebrospinal fluid, is ideally positioned to transmit signals into and out of the brain. This study, using microarray analysis, shows that the mouse choroid plexus displays an acute-phase response after an inflammatory stimulus induced in the periphery by lipopolysaccharide (LPS). Remarkably, the response is specific to a restricted number of genes (out of a total of 24,000 genes analyzed, 252 are up-regulated and 173 are down-regulated) and transient, as it returns to basal conditions within 72 h. The up-regulated genes cluster into families implicated in immune-mediated cascades and in extracellular matrix remodeling, whereas those down-regulated participate in maintenance of the barrier function. Importantly, several acute-phase proteins, whose blood concentrations rise in response to inflammation, may contribute to the effects observed in vivo after LPS injection, as suggested by the differential response of primary choroid plexus epithelial cell cultures to LPS alone or to serum collected from animals exposed to LPS. By modulating the composition of the cerebrospinal fluid, which will ultimately influence the brain parenchyma, the choroid plexus response to inflammation may be of relevance in brain homeostasis in health and disease.

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.

scholarly journals IMMU-28. INDUCTION OF TERTIARY LYMPHOID STRUCTURE-LIKE T-CELL CLUSTERS BY DELIVERY OF A NOVEL GENE COMBINATION INTO AN IMMUNOCOMPETENT MOUSE MODEL OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii110-ii111
Author(s):  
Kira Downey ◽  
Bindu Hegde ◽  
Zinal Chheda ◽  
Jason Zhang ◽  
Hideho Okada
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphatic Drainage ◽  
Lymphoid Follicle ◽  
Brain Parenchyma ◽  
Cell Therapies ◽  
Gene Combination ◽  
Cell Clustering ◽  
The Brain

Abstract The lack of conventional lymphatic drainage to and from the brain parenchyma restricts the capacity of the peripheral immune system to recognize and respond to glioma antigens. In some peripheral solid tumor types and central nervous system autoimmunity, the spontaneous development of tertiary lymphoid structures (TLS) with varying degrees of organization have been observed in human patients and mice following chronic inflammation. In the cancer setting, presence of TLS are generally associated with improved prognosis, especially when they are characterized by intratumoral infiltration of CD8+ T-cells. We aimed to induce the development of TLS in vivo, utilizing our SB28 glioblastoma model which is sparsely infiltrated by lymphocytes. As a proof-of-concept study, we stably transduced SB28 with a combination of several TLS-stimulating factors that we’ve identified and injected these cells into the brain parenchyma of syngeneic C57BL/6J mice. A combination of the chemoattractant and lymphoid follicle-stimulating cytokines LIGHT, CCL21, IL-7, and IL-17 produced substantial infiltration of CD8+CD3+ T-cells into the tumor and nearby parenchyma. However, this combination was also associated with accelerated tumor growth. A modified gene combination including LIGHT, CCL21, and IL-7 promoted CD8+CD3+ T-cell infiltration by flow cytometry, T-cell clustering by immunofluorescence analysis, and inhibited tumor burden compared with the control as measured by bioluminescent imaging. There was also evidence of increased lymphatic vasculature around the margins of T-cell clustering as demonstrated by LYVE-1 staining. Together, these analyses highlight a role for these factors in stimulating the recruitment and clustering of T-cell to the glioblastoma microenvironment in a TLS-like phenomenon. Future studies will evaluate whether the recruitment of other lymphocytes and stromal cells to these TLS-like clusters can promote T-cell memory and persistence. Ultimately, we aim to provide these factors utilizing a gene delivery method that will prove translatable to the clinic and complementary to existing T-cell therapies.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

Analysis of Changes in Signal Intensity of Choroid Plexus in MRI Using FLAIR-DW-EPI Pulse Sequence

2020 ◽  
Vol 3 (1) ◽  
pp. 9-15
Author(s):  
Jingyu Kim ◽  
◽  
Sang-Jin Im ◽  
Keyword(s):  
Choroid Plexus ◽  
Signal Intensity ◽  
Pulse Sequence ◽  
Signal Strength ◽  
Brain Parenchyma ◽  
Weighted Image ◽  
Diffusion Weighted ◽  
Water Signal ◽  
The Brain ◽  
Functional Problems

In this study, the signal intensity of choroid plexus, which is producing cerebrospinal fluid, is analyzed according to the FLAIR diffusion-weighted imaging technique. In the T2*-DW-EPI diffusion-weighted image, the FLAIR-DW-EPI technique, which suppressed the water signal, was additionally examined for subjects with high choroid plexus signals and compared and analyzed the signal intensity. As a result of the experiment, it was confirmed that the FLAIR-DW-EPI technique showed a signal strength equal to or lower than that of the brain parenchyma, and there was a difference in signal strength between the two techniques. As a result of this study, if the choroidal plexus signal is high in the T2 * -DW-EPI diffusionweighted image, additional examination of the FLAIR-DW-EPI technique is thought to be useful in distinguishing functional problems of the choroid plexus. In conclusion, if the choroidal plexus signal is high on the T2*-DW-EPI diffuse weighted image, it is thought that further examination of the FLAIR-DW-EPI technique will be useful in distinguishing functional problems of the choroidal plexus.

Exploration of beneficial and deleterious effects of inflammation in stroke: dynamics of inflammation cells

2009 ◽  
Vol 367 (1908) ◽  
pp. 4699-4716 ◽  
Author(s):  
Taïssia Lelekov-Boissard ◽  
Guillemette Chapuisat ◽  
Jean-Pierre Boissel ◽  
Emmanuel Grenier ◽  
Marie-Aimée Dronne
Keyword(s):  
Immune Cells ◽  
Blood Cells ◽  
Inflammatory Process ◽  
Living Cells ◽  
Therapeutic Strategies ◽  
Brain Parenchyma ◽  
Brain Cell ◽  
Cytokines And Chemokines ◽  
The Brain

The inflammatory process during stroke consists of activation of resident brain microglia and recruitment of leucocytes, namely neutrophils and monocytes/macrophages. During inflammation, microglial cells, neutrophils and macrophages secrete inflammatory cytokines and chemokines, and phagocytize dead cells. The recruitment of blood cells (neutrophils and macrophages) is mediated by the leucocyte–endothelium interactions and more specifically by cell adhesion molecules. A mathematical model is proposed to represent the dynamics of various brain cells and of immune cells (neutrophils and macrophages). This model is based on a set of six ordinary differential equations and explores the beneficial and deleterious effects of inflammation, respectively phagocytosis by immune cells and the release of pro-inflammatory mediators and nitric oxide (NO). The results of our simulations are qualitatively consistent with those observed in experiments in vivo and would suggest that the increase of phagocytosis could contribute to the increase of the percentage of living cells. The inhibition of the production of cytokines and NO and the blocking of neutrophil and macrophage infiltration into the brain parenchyma led also to the improvement of brain cell survival. This approach may help to explore the respective contributions of the beneficial and deleterious roles of the inflammatory process in stroke, and to study various therapeutic strategies in order to reduce stroke damage.

scholarly journals Vascular Dysfunction Induced by Mercury Exposure

2019 ◽  
Vol 20 (10) ◽  
pp. 2435 ◽  
Author(s):  
Tetsuya Takahashi ◽  
Takayoshi Shimohata
Keyword(s):  
Oxidative Stress ◽  
Vascular Dysfunction ◽  
Brain Parenchyma ◽  
Transport Systems ◽  
Mehg Exposure ◽  
In Vivo Models ◽  
The Central Nervous System ◽  
The Brain

Methylmercury (MeHg) causes severe damage to the central nervous system, and there is increasing evidence of the association between MeHg exposure and vascular dysfunction, hemorrhage, and edema in the brain, but not in other organs of patients with acute MeHg intoxication. These observations suggest that MeHg possibly causes blood–brain barrier (BBB) damage. MeHg penetrates the BBB into the brain parenchyma via active transport systems, mainly the l-type amino acid transporter 1, on endothelial cell membranes. Recently, exposure to mercury has significantly increased. Numerous reports suggest that long-term low-level MeHg exposure can impair endothelial function and increase the risks of cardiovascular disease. The most widely reported mechanism of MeHg toxicity is oxidative stress and related pathways, such as neuroinflammation. BBB dysfunction has been suggested by both in vitro and in vivo models of MeHg intoxication. Therapy targeted at both maintaining the BBB and suppressing oxidative stress may represent a promising therapeutic strategy for MeHg intoxication. This paper reviews studies on the relationship between MeHg exposure and vascular dysfunction, with a special emphasis on the BBB.

scholarly journals Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

2020 ◽  
Author(s):  
Andrés Fernández ◽  
Elena Quintana ◽  
Patricia Velasco ◽  
Belén de Andrés ◽  
Maria Luisa Gaspar ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Inflammatory Cytokines ◽  
Hippocampal Formation ◽  
Morphological Changes ◽  
Interleukin 1 ◽  
Brain Parenchyma ◽  
Age Related ◽  
Inflammatory Changes ◽  
Samp8 Mice ◽  
The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

scholarly journals Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus

2019 ◽  
Author(s):  
Felix C. Nebeling ◽  
Stefanie Poll ◽  
Lena C. Schmid ◽  
Manuel Mittag ◽  
Julia Steffen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Dendritic Spines ◽  
Synapse Formation ◽  
Brain Parenchyma ◽  
Two Photon ◽  
Contact Rates ◽  
Health And Disease ◽  
The Impact ◽  
The Brain

AbstractMicroglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

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