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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SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112189 - 112189

Published: Feb. 17, 2023

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or fragments released from cells during infection, reaching different tissues, including the CNS, irrespective of presence viral RNA. Here, we demonstrate brain infusion mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show neuroinflammation and hippocampal microgliosis mediate Spike-induced memory via complement-dependent engulfment synapses. Genetic pharmacological blockage Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination induced by infusion. Accordingly, cohort 86 who recovered mild COVID-19, genotype GG TLR4-2604G>A (rs10759931) associated poor outcome. These results identify TLR4 as key target to investigate long-term after COVID-19 infection humans rodents.

Language: Английский

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SARS-CoV-2 infection causes dopaminergic neuron senescence

Cell stem cell, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

COVID-19 patients commonly present with signs of central nervous system and/or peripheral dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection DA triggers an inflammatory cellular senescence response. High-throughput screening in hPSC-derived identified several FDA-approved drugs can rescue the phenotype by preventing We also signature low levels transcripts substantia nigra tissue patients. Furthermore, observed reduced numbers neuromelanin+ tyrosine-hydroxylase (TH)+ fibers a cohort Our findings demonstrate SARS-CoV-2, identify candidate neuroprotective for patients, suggest need careful, long-term monitoring neurological problems

Language: Английский

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Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 26, 2023

Abstract Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with emergence variants concern, clinical profile induced by SARS-CoV-2 infection has changed, anosmia being less frequent. Here, we assessed clinical, olfactory and neuroinflammatory conditions golden hamsters infected original Wuhan strain, its isogenic ORF7-deletion mutant three variants: Gamma, Delta, Omicron/BA.1. We show that animals develop variant-dependent disease including anosmia, ORF7 contributes to induction dysfunction. Conversely, all are neuroinvasive, regardless presentation they induce. Taken together, this confirms neuroinvasion independent phenomena upon infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, validate pathway major entry point into brain vivo demonstrate vitro travels retrogradely anterogradely along axons microfluidic neuron-epithelial networks.

Language: Английский

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Global Prevalence of Long COVID, its Subtypes and Risk factors: An Updated Systematic Review and Meta-Analysis

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Updated knowledge regarding the global prevalence of long COVID (or post-COVID-19 condition), its subtypes, risk factors, and variations across different follow-up durations geographical regions is necessary for informed public health recommendations healthcare delivery. The primary objective this systematic review to evaluate subtypes symptoms in individuals with confirmed COVID-19 diagnosis, while secondary assess factors same population. Studies on published from July 5, 2021, May 29, 2024, searched PubMed, Embase, Web Science were used review. Supplemental updates original search period made. There four inclusion criteria: (1) human study population diagnosis; (2) appropriate index diagnosis date; (3) outcome must include either prevalence, duration, or COVID; (4) time at least two months after date. exclusion criteria were: non-human population; case studies reviews; imaging, molecular, and/or cellular testing as results; specific populations such workers, residents nursing homes, those living long-term care facilities; that did not meet sample size threshold needed estimate overall margin error 0.05. Two screeners independently performed screenings data extraction, decision conflicts collectively resolved. pooled using a random-effects meta-analysis framework DerSimonian-Laird inverse variance weighted estimator. estimand (target parameter interest) was among diagnoses, effect sizes corresponding ten common A total 442 included mega-systematic review, 429 meta-analyzed various endpoints, avoiding duplicate estimates study. Of studies, 17.9% have high bias. Heterogeneity evident where I 2 statistic nearly 100% prevalence. Global estimated 36% positive (95% confidence interval [CI] 33%-40%) 144 studies. Geographical variation observed COVID: Asia 35% CI 25%-46%), Europe 39% 31%-48%), North America 30% 24%-38%), South 51% 35%-66%). Stratifying by longer periods 1 years (47% [95% 37%-57%]) compared times less than year (35% 31%-39%]) had overlapping therefore statistically distinguishable. Top five most prevalent cases respiratory 20% 14%-28%) 31 general fatigue 18%-23%) 121 psychological 18% 11%-28%) 10 neurological 16% 8%-30%) 23 dermatological 12% 8%-17%) symptom based memory problems 11% 7%-19%) 12 three strongest being unvaccinated COVID-19, pre-existing comorbidity, female sex. Individuals any these higher odds having ratios 2.34 1.49-3.67) 6 1.59 1.28-1.97) 13 1.55 1.25-1.92) 22 respectively. This shows globally highly varying estimates. persists over extended follow-up, burden post-infection. Our findings highlight continuing challenge worldwide. heterogeneity argues need carefully designed representative world. Question: What are patterns what COVID?Results: Meta-analysis 2021-2024 individuals. Variations showed highest CI: 35%-66%), does seem diminish (less year: 35%, 95% 31%-39% vs. years: 47%, 37%-57%). eight major (respiratory), (general fatigue), (psychological), (neurological), (dermatological), 10% (cardiovascular), 9% (musculoskeletal) 5% (gastrointestinal).Meaning: Quantitative evidence persistent globally, significant post-infection, underscoring accurate standardized diagnostic tests biomarkers COVID, better understanding physiology condition, treatment, potential needs workforce participation. wide range call samples well-designed

Language: Английский

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iPSC‐derived human cortical organoids display profound alterations of cellular homeostasis following SARS‐CoV‐2 infection and Spike protein exposure

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(4)

Published: Feb. 14, 2025

Abstract COVID‐19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting detrimental impact SARS‐CoV‐2 or the viral Spike protein on central nervous system. Nonetheless, molecular pathway behind pathology and presumed neurotropism remains largely unexplored. We generated human cortical organoids (HCOs) derived from induced pluripotent stem cells (hiPSC) assess: (1) expression main entry factors; (2) their vulnerability infection; (3) infection exposure transcriptome. Results proved that HCOs express receptors co‐receptors; may be productively infected by SARS‐CoV‐2; particles released SARS‐CoV‐2‐infected are able re‐infect another cellular line; (4) resulted in activation apoptotic stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when exposed alone. The data obtained demonstrate likely infects probably through binding ACE2, CD147, NRP1 factors. Furthermore, alone sufficient disrupt homeostasis induce neurotoxic effects, potentially contributing onset long‐COVID symptoms.

Language: Английский

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Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice

Antiviral Research, Journal Year: 2022, Volume and Issue: 208, P. 105430 - 105430

Published: Oct. 6, 2022

As the SARS-CoV-2 pandemic remains uncontrolled owing to continuous emergence of variants concern, there is an immediate need implement most effective antiviral treatment strategies, especially for risk groups. Here, we evaluated therapeutic potency nirmatrelvir, remdesivir and molnupiravir, their combinations in infected K18-hACE2 transgenic mice. Systemic mice with each drug (20 mg/kg) resulted slightly enhanced efficacy yielded increased life expectancy only about 20-40% survival. However, combination therapy nirmatrelvir molnupiravir lethally showed profound inhibition replication both lung brain synergistically improved survival rates up 80% compared those (36%, P < 0.001) (43%, administered alone. This effectively reduced clinical severity score, virus-induced tissue damage, viral distribution animals treated these monotherapies. Furthermore, all assessments associated this were also significantly higher than that receiving monotherapy (P 0.001), underscored significance combination. By contrast, less efficacy, lower due insufficient plasma exposure remdesivir, demonstrating inefficient effect mouse model. The contributes alleviated morbidity mortality, which can serve as a basis design studies COVID-19 patients.

Language: Английский

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Investigating the possible mechanisms of autonomic dysfunction post-COVID-19

Autonomic Neuroscience, Journal Year: 2022, Volume and Issue: 245, P. 103071 - 103071

Published: Dec. 24, 2022

Language: Английский

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In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants

Acta Neuropathologica Communications, Journal Year: 2022, Volume and Issue: 10(1)

Published: Sept. 4, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism not fully understood, several studies have shown that neuroinflammation occurs in and post-acute phase. As these predominantly been performed isolates from 2020, it unknown if there are differences among SARS-CoV-2 variants their ability to cause neuroinflammation. Here, we compared neuroinvasiveness, neurotropism neurovirulence of ancestral strain D614G, Delta (B.1.617.2) Omicron BA.1 (B.1.1.529) using vitro vivo models. The variant showed reduced D614G human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured astrocytes. Similar were obtained Syrian hamsters inoculated 5 days post infection. Replication olfactory mucosa was observed all hamsters, but most prominently hamsters. Furthermore, neuroinvasion into CNS via nerve or bulb D614G. Altogether, our findings suggest neuroinvasive, neurotropic neurovirulent potential between hiPSC-derived neural cultures during phase

Language: Английский

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Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients

Neuron, Journal Year: 2022, Volume and Issue: 110(23), P. 3919 - 3935.e6

Published: Nov. 10, 2022

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct short route from nose into brain? We reasoned that neurotropic or neuroinvasive capacity of virus, if it exists, should be most easily detectable in individuals who died an acute phase infection. Here, we applied postmortem bedside surgical procedure for rapid procurement tissue, blood, cerebrospinal fluid samples deceased COVID-19 patients infected with Delta, Omicron BA.1, BA.2 variants. Confocal imaging sections stained fluorescence RNAscope immunohistochemistry afforded light-microscopic visualization extracellular virions tissues. failed to find evidence viral invasion parenchyma bulb frontal lobe brain. Instead, identified anatomical barriers at vulnerable interfaces, exemplified by perineurial nerve fibroblasts enwrapping axon fascicles lamina propria mucosa.

Language: Английский

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