SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(7), P. 2878 - 2893

Published: Nov. 1, 2022

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases probable Parkinson's disease. As microglial NLRP3 inflammasome activation major driver neurodegeneration, here we interrogated whether promote activation. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as COVID-19 pre-clinical model, established the presence virus in brain together with and upregulation comparison to uninfected mice. Next, utilising model monocyte-derived microglia, identified isolates bind enter microglia absence viral replication. This interaction directly induced robust activation, even another priming signal. Mechanistically, demonstrated purified spike glycoprotein activated LPS-primed ACE2-dependent manner. Spike protein could prime through NF-κB signalling, allowing for either ATP, nigericin or α-synuclein. Notably, protein-mediated was significantly enhanced α-synuclein fibrils entirely ablated by NLRP3-inhibition. Finally, demonstrate infected hACE2 treated orally post-infection inhibitory drug MCC950, have reduced increased survival untreated These results support possible mechanism innate immune SARS-CoV-2, which explain vulnerability developing symptoms akin disease individuals, potential therapeutic avenue intervention.

Language: Английский

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Innate immune sensors and regulators at the blood brain barrier: focus on toll-like receptors and inflammasomes as mediators of neuro-immune crosstalk and inflammation

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 15, 2025

Cerebral endothelial cells (CEC) that form the brain capillaries are principal constituents of blood barrier (BBB), main active interface between and which plays a protective role by restricting infiltration pathogens, harmful substances immune into while allowing entry essential nutrients. Aberrant CEC function often leads to increased permeability BBB altering bidirectional communication bloodstream facilitating extravasation brain. In addition their as gatekeepers BBB, exhibit cell properties they can receive transmit signals partly via release inflammatory effectors in pathological conditions. express innate receptors, including toll like receptors (TLRs) inflammasomes first sensors exogenous or endogenous dangers initiators responses drive neural dysfunction degeneration. Accumulating evidence indicates activation TLRs compromises integrity, promotes aberrant neuroimmune interactions modulates both systemic neuroinflammation, common features neurodegenerative psychiatric diseases central nervous system (CNS) infections injuries. The goal present review is provide an overview pivotal roles played discuss molecular cellular mechanisms contribute disruption neuroinflammation especially context traumatic ischemic injuries infections. We will focus on most recent advances literature reports field highlight knowledge gaps. future research directions advance our understanding contribution potential at promising therapeutic targets wide variety conditions

Language: Английский

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SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

Science Advances, Journal Year: 2022, Volume and Issue: 8(38)

Published: Sept. 21, 2022

In the initial process of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome 2 (SARS-CoV-2) infects epithelial cells and then transfers to other organs blood vessels. It is believed that SARS-CoV-2 can pass vascular wall by altering endothelial barrier using an unknown mechanism. this study, we investigated effect on airway-on-a-chip mimics found produced from infected disrupts decreasing Claudin-5 (CLDN5), a tight junction protein, disrupting cadherin–mediated adherens junctions. Consistently, gene protein expression levels CLDN5 in lungs patient with COVID-19 were decreased. overexpression or Fluvastatin treatment rescued SARS-CoV-2–induced disruption. We concluded down-regulation pivotal mechanism for disruption inducing therapeutic strategy against COVID-19.

Language: Английский

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Neurological complications associated with Covid‐19; molecular mechanisms and therapeutic approaches

Reviews in Medical Virology, Journal Year: 2022, Volume and Issue: 32(6)

Published: Feb. 9, 2022

Abstract With the progression of investigations on pathogenesis severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), neurological complications have emerged as a critical aspect ongoing disease 2019 (Covid‐19) pandemic. Besides well‐known symptoms, many manifestations such anosmia/ageusia, headaches, dizziness, seizures, and strokes been documented in hospitalised patients. The neurotropism background coronaviruses has led to speculation that are caused by direct invasion SARS‐CoV‐2 into nervous system. This is proposed occur through infection peripheral nerves or via systemic blood circulation, termed neuronal haematogenous routes invasion, respectively. On other hand, aberrant immune responses insufficiency associated with Covid‐19 suggested affect system indirectly. Deleterious roles cytokine storm hypoxic conditions blood‐brain barrier disruption, coagulation abnormalities, autoimmune neuropathies well investigated infections, Covid‐19. Here, we review latest discoveries focussing possible molecular mechanisms indirect impacts try elucidate link between some potential therapeutic strategies pathways.

Language: Английский

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Phenotyping Post-COVID Pain as a Nociceptive, Neuropathic, or Nociplastic Pain Condition

Biomedicines, Journal Year: 2022, Volume and Issue: 10(10), P. 2562 - 2562

Published: Oct. 13, 2022

Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to evidence-based method of grouping patients based on their diagnostic/symptom presentation then tailoring specific treatments accordingly. Evidence suggests that post-COVID pain can be categorized as nociceptive (i.e., attributable the activation peripheral receptive terminals primary afferent neurons in response noxious chemical, mechanical, or thermal stimuli), neuropathic associated with lesion somatosensory nervous system limited “neuroanatomically plausible” distribution system), nociplastic arising from altered nociception despite no clear evidence actual threatened tissue damage causing nociceptors for pain), mixed type (when two phenotypes co-exist). Each these may require different treatment approach maximize effectiveness. Accordingly, ability classify into one would likely critical producing successful outcomes. The 2021 International Association Study (IASP) clinical criteria grading provide framework classifying within precision approach. Here we present data supporting possibility phenotypes, using IASP classification criteria, focus pain, which probably mechanism involved pain. Nociplastic usually comorbid symptomology (e.g., poor sleep quality, fatigue, cognitive–emotional disturbances, etc.) considered more difficult treat than other types, nuanced multimodal achieve better

Language: Английский

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Differential effects of SARS-CoV-2 variants on central nervous system cells and blood–brain barrier functions

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Aug. 3, 2023

Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects brain and mutations carried by different variants modulate those remain unclear.We used primary human pericytes, foetal astrocytes, endothelial cells microglial cell line to investigate effect several concern or interest on their functional activities. Cells 3D blood-brain barrier model were infected with wild-type form SARS-CoV-2, Alpha, Beta, Delta, Eta, Omicron (BA.1) at various MOI. supernatant evaluate susceptibility using microscopic assay as well effects infection (i) metabolic activity colorimetric MTS assay; (ii) viral cytopathogenicity xCELLigence system; (iii) extracellular glutamate concentration fluorometric (iv) modulation permeability.We demonstrate that productive is variant dependent all induce stress CNS cells. The was cytopathic types except whilst Alpha Beta only for pericytes. Lastly increases permeability variants, concentration, which can lead excitotoxicity altered neurotransmission.These results suggest neurotropic, deleterious consequences integrity central nervous system cells, could underlie disorders

Language: Английский

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Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

Viruses, Journal Year: 2023, Volume and Issue: 15(3), P. 745 - 745

Published: March 14, 2023

Neurological effects of COVID-19 and long-COVID-19, as well neuroinvasion by SARS-CoV-2, still pose several questions are both clinical scientific relevance. We described the cellular molecular human brain microvascular endothelial cells (HBMECs) in vitro exposure SARS-CoV-2 to understand underlying mechanisms viral transmigration through blood–brain barrier. Despite low non-productive replication, SARS-CoV-2-exposed cultures displayed increased immunoreactivity for cleaved caspase-3, an indicator apoptotic cell death, tight junction protein expression, immunolocalization. Transcriptomic profiling SARS-CoV-2-challenged revealed activation via NF-κB non-canonical pathway, including RELB overexpression mitochondrial dysfunction. Additionally, led altered secretion key angiogenic factors significant changes dynamics, with mitofusin-2 expression networks. Endothelial remodeling can further contribute neuroinflammatory processes lead BBB permeability COVID-19.

Language: Английский

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COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions

The Neuroscientist, Journal Year: 2023, Volume and Issue: 30(4), P. 421 - 439

Published: Sept. 11, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of disease 2019 (COVID-19), could affect brain structure and function. SARS-CoV-2 can enter through different routes, including olfactory, trigeminal, vagus nerves, blood immunocytes. may also from peripheral a disrupted blood-brain barrier (BBB). The neurovascular unit in brain, composed neurons, astrocytes, endothelial cells, pericytes, protects parenchyma by regulating entry substances blood. astrocytes highly express angiotensin converting enzyme (ACE2), indicating that BBB be disturbed lead to derangements tight junction adherens proteins. This leads increased permeability, leakage components, movement immune cells into parenchyma. cross microvascular an ACE2 receptor–associated pathway. exact mechanism dysregulation COVID-19/neuro-COVID is not clearly known, nor development long COVID. Various biomarkers indicate severity neurologic complications COVID-19 help objectively diagnose those developing review highlights importance disruption, as well some potentially useful COVID-19, COVID/neuro-COVID.

Language: Английский

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Prevalence of Neuropathic Component in Post-COVID Pain Symptoms in Previously Hospitalized COVID-19 Survivors

International Journal of Clinical Practice, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 6

Published: March 16, 2022

To investigate the prevalence of neuropathic pain symptoms and to analyze correlation between with pain-related, psychological, cognitive variables in COVID-19 survivors exhibiting "de novo" post-COVID pain.Seventy-seven (n = 77) previously hospitalized presenting completed demographic (such as age, height, weight), pain-related (the duration intensity pain), psychological (depressive/anxiety levels), (catastrophizing kinesiophobia) variables. The Self-Report Leeds Assessment Neuropathic Symptoms Signs (S-LANSS) questionnaire was also assessed. After conducting multivariable analyses, a stepwise multiple linear regression model performed identify S-LANSS predictors.Participants were assessed mean 6.0 (SD 0.8) months after hospital discharge. Nineteen (24.6%) exhibited (S-LANSS score≥12 points). score positively associated (r: 0.262), anxiety levels 0.275), kinesiophobia level 0.291) (all, P < 0.05). analysis revealed that 12.8% variance just explained by kinesiophobia.This study found almost 25% reported component. presence symptomatology more kinesiophobia, but only significantly explaining score.

Language: Английский

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COVID-19 Anosmia: High Prevalence, Plural Neuropathogenic Mechanisms, and Scarce Neurotropism of SARS-CoV-2?

Viruses, Journal Year: 2021, Volume and Issue: 13(11), P. 2225 - 2225

Published: Nov. 4, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of disease 2019 (COVID-19). It known as a virus, but SARS-CoV-2 appears equally, or even more, infectious for olfactory epithelium (OE) than in nasal cavity. In light small area OE relative to epithelium, high prevalence dysfunctions (ODs) COVID-19 has been bewildering and attracted much attention. This review aims first examine cytological molecular biological characteristics OE, especially microvillous apical surfaces sustentacular cells abundant receptor molecules thereof, that may underlie susceptibility this neuroepithelium infection damages. The possibility neurotropism, lack it, then analyzed with regard expression (angiotensin-converting enzyme 2) priming protease (transmembrane serine 2), cellular targets infection. Neuropathology bulb, other related neural structures are also reviewed. Toward end, we present our perspectives regarding possible mechanisms neuropathogenesis ODs, absence substantial viral neurons. Plausible causes persistent ODs some convalescents examined.

Language: Английский

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