scholarly journals Sublethal Enteroviral Infection Exacerbates Disease Progression in an ALS Mouse Model

2021 ◽  
Author(s):  
Honglin Luo ◽  
Yuan Chao Xue ◽  
Huitao Liu ◽  
Yasir Mohamud ◽  
Amirhossein Bahreyni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factor ◽  
Viral Infection ◽  
Motor Neurons ◽  
Immune Cell ◽  
Neuronal Damage ◽  
Motor Dysfunction ◽  
Sublethal Dose ◽  
Enteroviral Infection ◽  
Cvb3 Infection

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a fatalneurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors.Infection with enteroviruses, including poliovirus and coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALSdue to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathologicalphenotypes closely resembleALS. However, a causal relationship has not yet been affirmed.Methods:Wild-type C57BL/6J and SOD1G85R ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute and/or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting atweek 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression.Results: We found that sublethal infection (mimicking chronic infection) of SOD1G85R ALS mice with CVB3 resulted inearly onset and progressive motor dysfunction, andshortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1G85R mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeksPI).Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TDP-43 pathology and neuronal damage) in the CNS of both SOD1G85R and C57BL/6J mice. Finally, wediscovered that early (day 1) but not late (day 15) administration of ribavirincould rescue ALS-like neuropathology and symptoms induced by CVB3 infection.Conclusions: Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.

scholarly journals Sublethal enteroviral infection exacerbates disease progression in an ALS mouse model

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuan Chao Xue ◽  
Huitao Liu ◽  
Yasir Mohamud ◽  
Amirhossein Bahreyni ◽  
Jingchun Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factor ◽  
Viral Infection ◽  
Early Onset ◽  
Immune Cell ◽  
Neuronal Damage ◽  
Motor Dysfunction ◽  
Sublethal Dose ◽  
Enteroviral Infection ◽  
Cvb3 Infection

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neuron system associated with both genetic and environmental risk factors. Infection with enteroviruses, including poliovirus and coxsackievirus, such as coxsackievirus B3 (CVB3), has been proposed as a possible causal/risk factor for ALS due to the evidence that enteroviruses can target motor neurons and establish a persistent infection in the central nervous system (CNS), and recent findings that enteroviral infection-induced molecular and pathological phenotypes closely resemble ALS. However, a causal relationship has not yet been affirmed. Methods Wild-type C57BL/6J and G85R mutant superoxide dismutase 1 (SOD1G85R) ALS mice were intracerebroventricularly infected with a sublethal dose of CVB3 or sham-infected. For a subset of mice, ribavirin (a broad-spectrum anti-RNA viral drug) was given subcutaneously during the acute or chronic stage of infection. Following viral infection, general activity and survival were monitored daily for up to week 60. Starting at week 20 post-infection (PI), motor functions were measured weekly. Mouse brains and/or spinal cords were harvested at day 10, week 20 and week 60 PI for histopathological evaluation of neurotoxicity, immunohistochemical staining of viral protein, neuroinflammatory/immune and ALS pathology markers, and NanoString and RT-qPCR analysis of inflammatory gene expression. Results We found that sublethal infection (mimicking chronic infection) of SOD1G85R ALS mice with CVB3 resulted in early onset and progressive motor dysfunction, and shortened lifespan, while similar viral infection in C57BL/6J, the background strain of SOD1G85R mice, did not significantly affect motor function and mortality as compared to mock infection within the timeframe of the current study (60 weeks PI). Furthermore, we showed that CVB3 infection led to a significant increase in proinflammatory gene expression and immune cell infiltration and induced ALS-related pathologies (i.e., TAR DNA-binding protein 43 (TDP-43) pathology and neuronal damage) in the CNS of both SOD1G85R and C57BL/6J mice. Finally, we discovered that early (day 1) but not late (day 15) administration of ribavirin could rescue ALS-like neuropathology and symptoms induced by CVB3 infection. Conclusions Our study identifies a new risk factor that contributes to early onset and accelerated progression of ALS and offers opportunities for the development of novel targeted therapies.

scholarly journals Influenza Viral Infection is a High-Risk Factor for Developing Coronavirus Disease 2019 (COVID-19)

2020 ◽  
Author(s):  
Lei Zhang ◽  
Youwei Zhang
Keyword(s):  
Gene Expression ◽  
Risk Factor ◽  
High Risk ◽  
Viral Infection ◽  
Respiratory System ◽  
Influenza A ◽  
Target Cells ◽  
High Risk Factor ◽  
Syncytial Virus ◽  
Influenza Viral Infection

Coronavirus disease 2019 (COVID-19) is caused by infection with the 2019 novel coronavirus 2 (2019-nCoV, now referred to as SARS-CoV-2). COVID-19 has become a global pandemic since its outbreak at the end of Dec 2019. COVID-19 could lead to severe acute respiratory disease, especially to those who have reduced immunity. Binding of the viral Spike protein (S) to its receptor ACE2 (Angiotensin Converting Enzyme 2) on the surface of target cells has been proven to be key for virus entry and infection. Although ACE2 expression in the respiratory system is necessary for pneumonia infection by SARS-CoV-2, the regulation of ACE2 gene expression remains poorly investigated, especially for patients that are in pre-pathological conditions. Here, by analyzing The Gene Expression Omnibus (GEO) database, we investigated the expression regulation of ACE2 in various kinds of primary epithelial cells from the respiratory system after influenza A or respiratory Syncytial Virus (RSV) infection. Our analyses reveal that infection of influenza A, RSV or influenza vaccines greatly increased ACE2 expression, suggesting that influenza viral infection could represent a high risk factor for developing COVID-19. We also found that the regulatory effect of influenza A virus on ACE2 expression is associated with activation of the interferon beta-induced pathway and viral RNA-activated host response. Together, our data provide a theoretical framework for clinical classification for SARS-CoV-2 infection susceptibility and could be used for future prevention and therapy treatment for COVID-19.

Calcitonin gene related peptide gene expression in collagen-induced arthritis

1995 ◽  
Vol 73 (7) ◽  
pp. 1015-1019 ◽  
Author(s):  
Eberhard Weihe ◽  
Donatus Nohr ◽  
Martin K.-H. Schäfer ◽  
Stefan Persson ◽  
Johanna Källström ◽  
...  
Keyword(s):  
Gene Expression ◽  
Motor Neurons ◽  
Calcitonin Gene Related Peptide ◽  
Motor Dysfunction ◽  
Mrna Levels ◽  
Related Peptide ◽  
Inflammatory Conditions ◽  
Systemic Corticosteroids ◽  
Calcitonin Gene ◽  
Peptide Gene

Changes in calcitonin gene related peptide (CGRP) gene expression in spinal motoneurons and dorsal root ganglia (DRG) of rats subjected to collagen II induced arthritis (CIA) were evaluated by semiquantitative in situ hybridization. The effects of systemic treatment with the corticosteroid budesonide on basal CGRP expression and on changes under inflammatory conditions were examined. CIA caused a significant increase in CGRP mRNA levels in DRG. Budesonide reduced the constitutive CGRP mRNA levels in DRG, compared with untreated control rats, and reversed the CIA-induced increase. In contrast, CIA caused a marked decrease of CGRP mRNA levels in motoneurons. Budesonide had no effect on constitutive CGRP mRNA levels in motoneurons and attenuated the decrease in CGRP mRNA levels in motoneurons of rats subjected to CIA. Thus, peripheral inflammation and systemic corticosteroids have differential effects on CGRP expression in sensory and motor neurons. This may be relevant for the pathophysiology and pharmacotherapy of chronic inflammatory pain and motor dysfunction in chronic arthritis.Key words: calcitonin gene related peptide, neuropeptides, sensory, spinal motoneuron, arthritis, glucocorticoids, pain.

Global Gene Expression Analysis of Rodent Motor Neurons Following Spinal Cord Injury Associates Molecular Mechanisms With Development of Postinjury Spasticity

2010 ◽  
Vol 103 (2) ◽  
pp. 761-778 ◽  
Author(s):  
J. Wienecke ◽  
A-C. Westerdahl ◽  
H. Hultborn ◽  
O. Kiehn ◽  
J. Ryge
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Global Gene Expression ◽  
Motor Dysfunction ◽  
Plateau Potentials ◽  
Endogenous Expression ◽  
Cord Injury

Spinal cord injury leads to severe problems involving impaired motor, sensory, and autonomic functions. After spinal injury there is an initial phase of hyporeflexia followed by hyperreflexia, often referred to as spasticity. Previous studies have suggested a relationship between the reappearance of endogenous plateau potentials in motor neurons and the development of spasticity after spinalization. To unravel the molecular mechanisms underlying the increased excitability of motor neurons and the return of plateau potentials below a spinal cord injury we investigated changes in gene expression in this cell population. We adopted a rat tail-spasticity model with a caudal spinal transection that causes a progressive development of spasticity from its onset after 2 to 3 wk until 2 mo postinjury. Gene expression changes of fluorescently identified tail motor neurons were studied 21 and 60 days postinjury. The motor neurons undergo substantial transcriptional regulation in response to injury. The patterns of differential expression show similarities at both time points, although there are 20% more differentially expressed genes 60 days compared with 21 days postinjury. The study identifies targets of regulation relating to both ion channels and receptors implicated in the endogenous expression of plateaux. The regulation of excitatory and inhibitory signal transduction indicates a shift in the balance toward increased excitability, where the glutamatergic N-methyl-d-aspartate receptor complex together with cholinergic system is up-regulated and the γ-aminobutyric acid type A receptor system is down-regulated. The genes of the pore-forming proteins Cav1.3 and Nav1.6 were not up-regulated, whereas genes of proteins such as nonpore-forming subunits and intracellular pathways known to modulate receptor and channel trafficking, kinetics, and conductivity showed marked regulation. On the basis of the identified changes in global gene expression in motor neurons, the present investigation opens up for new potential targets for treatment of motor dysfunction following spinal cord injury.

Co-Culture of ES Cell-Derived Motor Neurons and Myotubes Show the Formation of Neuromuscular Junctions and Changes in Gene Expression

2006 ◽  
Vol 22 (06) ◽  
Author(s):  
Aleid Ruijs ◽  
Tateki Kubo ◽  
Jae Song ◽  
Milan Ranka ◽  
Mark Randolph ◽  
...  
Keyword(s):  
Gene Expression ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Es Cell

Prevention and Healing of Calcium Signaling Mediated Neuronal Damage on successive Administration of Flavonoid Enriched Pterocarpus Marsupium Roxb in Peripheral Neuropathy Model

2020 ◽  
Vol 16 (9) ◽  
pp. 1346-1355
Author(s):  
Neethi Shaju ◽  
Mrinmoy Gautam ◽  
Abdul Khayum ◽  
Gunasekaran Venkatesh
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Motor Neurons ◽  
Neuronal Damage ◽  
Interleukin 10 ◽  
Central Mechanism ◽  
Behavioral Models ◽  
Cell Hyperplasia ◽  
Pterocarpus Marsupium

Background: Modern research on peripheral neuropathy circumstance utter that treatments with Vincristine (VCR) disturb the microtubular cells in sensory and motor neurons due to calcium over- load in sciatic nerve, unfortunately, VCR triggering the release of Tumor necrosis factor-α (TNFα) in central neurons causes excitotoxicity as well. Although ethnomedical information specifies that Pterocarpus marsupium Roxb (PM) is widely used for various nervous disorders, not yet justified on VCR induced peripheral neuropathy and in relation to central mechanism. Objective: This study is aimed to explore the possible central and peripheral mechanism of flavonoid enriched PM in VCR induced neuropathy model. Methods: Neuropathic pain was induced in female Wistar rats by VCR (75μg/ kg/day, i.p) for 10 days. Nociceptive thresholds were assessed by subjecting them to behavioral and biochemical estimation, proinflammatory cytokines along with morphological evaluation. Results: PM significantly increased the nociceptive threshold evident from various behavioral models in comparison to VCR group. More importantly, PM significantly reversed the VCR induced calcium elevation, glutamate and aspartate release in the brain. Discussion: It was also observed that the raised TNF-α, Interleukin-1β were controlled and interleukin- 10 was elevated in sciatic nerve after PM treatment. Evident from histology, PM markedly reversed the VCR induced axonal degeneration, Schwann cell hyperplasia, and myelin fibrosis. Conclusion: Flavonoid enriched PM both 100 & 200mg/kg post and co-administration exerted a preventive and curative effect in VCR induced neuropathic pain by controlling calcium-mediated excitotoxicity through peripheral and central mechanism.

scholarly journals Gene expression and immunohistochemical analyses identify SOX2 as major risk factor for overall survival and relapse in Ewing sarcoma patients

EBioMedicine ◽  
2019 ◽  
Vol 47 ◽  
pp. 156-162 ◽  
Author(s):  
Giuseppina Sannino ◽  
Aruna Marchetto ◽  
Andreas Ranft ◽  
Susanne Jabar ◽  
Constanze Zacherl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Risk Factor ◽  
Ewing Sarcoma ◽  
Major Risk Factor ◽  
Immunohistochemical Analyses

scholarly journals Inflamm-Aging Is Associated with Lower Plasma PTX3 Concentrations and an Impaired Capacity of PBMCs to Express hTERT following LPS Stimulation

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Aaron L. Slusher ◽  
Tiffany M. Zúñiga ◽  
Edmund O. Acevedo
Keyword(s):  
Gene Expression ◽  
Young Adults ◽  
Telomere Length ◽  
Immune Cell ◽  
Ex Vivo ◽  
Middle Aged ◽  
Human Telomerase Reverse Transcriptase ◽  
Negatively Associated ◽  
Htert Gene ◽  
Age Related

Age-related elevations in proinflammatory cytokines, known as inflamm-aging, are associated with shorter immune cell telomere lengths. Purpose. This study examined the relationship of plasma PTX3 concentrations, a biomarker of appropriate immune function, with telomere length in 15 middle-aged (40-64 years) and 15 young adults (20-31 years). In addition, PBMCs were isolated from middle-aged and young adults to examine their capacity to express a key mechanistic component of telomere length maintenance, human telomerase reverse transcriptase (hTERT), following ex vivo cellular stimulation. Methods. Plasma PTX3 and inflammatory cytokines (i.e., IL-6, IL-10, TGF-β, and TNF-α), PBMC telomere lengths, and PBMC hTERT gene expression and inflammatory protein secretion following exposure to LPS, PTX3, and PTX3+LPS were measured. Results. Aging was accompanied by the accumulation of centrally located visceral adipose tissue, without changes in body weight and BMI, and alterations in the systemic inflammatory milieu (decreased plasma PTX3 and TGF-β; increased TNF-α (p≤0.050)). In addition, shorter telomere lengths in middle-aged compared to young adults (p=0.011) were negatively associated with age, body fat percentages, and plasma TNF-α (r=−0.404, p=0.027; r=−0.427, p=0.019; and r=−0.323, p=0.041, respectively). Finally, the capacity of PBMCs to increase hTERT gene expression following ex vivo stimulation was impaired in middle-aged compared to young adults (p=0.033) and negatively associated with telomere lengths (r=0.353, p=0.028). Conclusions. Proinflammation and the impaired hTERT gene expression capacity of PBMCs may contribute to age-related telomere attrition and disease.

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

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