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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Long COVID, the Brain, Nerves, and Cognitive Function

Neurology International, Journal Year: 2023, Volume and Issue: 15(3), P. 821 - 841

Published: July 6, 2023

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are increasing issue in patients who have been infected with COVID-19 and may be result of viral-associated systemic central nervous system inflammation or arise from virus-induced hypercoagulable state. incite changes brain function wide range lingering symptoms. Patients often experience fatigue note fog, sensorimotor symptoms, sleep disturbances. Prolonged neurological neuropsychiatric symptoms prevalent can interfere substantially everyday life, leading to massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection sequelae important subject ongoing research. Inflammation- induced blood-brain barrier permeability viral neuro-invasion direct nerve damage involved. Though the mechanisms uncertain, resulting documented numerous patient reports studies. This review examines constellation spectrum seen long COVID incorporates information on prevalence these contributing factors, typical course. Although treatment options generally lacking, potential therapeutic approaches for alleviating improving quality life explored.

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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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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Mechanisms of SARS-CoV-2-associated anosmia

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(4), P. 2759 - 2766

Published: June 21, 2023

Anosmia, the loss of sense smell, is one main neurological manifestations COVID-19. Although SARS-CoV-2 virus targets nasal olfactory epithelium, current evidence suggests that neuronal infection extremely rare in both periphery and brain, prompting need for mechanistic models can explain widespread anosmia COVID-19 patients. Starting from work identifying non-neuronal cell types are infected by system, we review effects these supportive cells epithelium brain posit downstream mechanisms through which smell impaired We propose indirect contribute to altered system function COVID-19-associated anosmia, as opposed or neuroinvasion into brain. Such include tissue damage, inflammatory responses immune infiltration systemic circulation cytokines, downregulation odorant receptor genes sensory neurons response local signals. also highlight key unresolved questions raised recent findings.

Language: Английский

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A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(1), P. 97 - 116

Published: Jan. 1, 2023

Development of neuroprotective therapeutics for Parkinson's disease (PD) is facing a lack translation from pre-clinical to clinical trials. One strategy improvement increase predictive validity studies by using extensively characterized animal models with comprehensive set validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features sporadic PD, such as progressive loss striatal dopamine, pathology, deficits in motor and non-motor functions, elevation inflammatory markers. Extensive work this model multiple laboratories over past decade further increased confidence its robustness validity, especially analyzing pathomechanisms pathology down-stream pathways, drug testing. Interestingly, while postnatal transgene expression widespread central peripheral neurons, extent progression differs between brain regions, thereby replicating characteristic selective vulnerability neurodegenerative diseases. In-depth characterization these readouts conjunction behavioral has led more informative endpoints Each tested Thy1-aSyn 61 enhances knowledge on how molecular targets, functional are interconnected, optimizing platform towards Here, we present current state art target discovery, validation,

Language: Английский

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Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model

Brain, Journal Year: 2024, Volume and Issue: 147(5), P. 1636 - 1643

Published: Feb. 2, 2024

Abstract Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction following mild respiratory infection. To this end, we performed unbiased transcriptional analysis brain endothelial cell signalling pathways dysregulated by mouse adapted MA10 in aged immunocompetent C57Bl/6 mice vivo. This revealed significant suppression of Wnt/β-catenin signalling, a critical regulator blood–brain barrier (BBB) integrity. therefore hypothesized that enhancing activity would offer protection against BBB permeability, neuroinflammation, neurological signs acute Indeed, found delivery cerebrovascular-targeted, engineered Wnt7a ligands protected integrity, reduced T-cell infiltration brain, microglial activation Importantly, strategy also mitigated induced deficits novel object recognition assay for learning memory pole descent task bradykinesia. These observations suggest enhancement or its downstream effectors could be potential interventional strategies restoring health viral infections.

Language: Английский

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Neurological post‐acute sequelae of SARS‐CoV‐2 infection

Psychiatry and Clinical Neurosciences, Journal Year: 2022, Volume and Issue: 77(2), P. 72 - 83

Published: Sept. 23, 2022

The novel coronavirus disease 19 (COVID‐19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), can have two phases: (generally 4 weeks after onset) and chronic (>4 onset). Both phases include a wide variety of signs symptoms including neurological psychiatric symptoms. that are considered sequelae COVID‐19 termed post‐COVID condition, long COVID‐19, post‐acute SARS‐CoV‐2 infection (PASC). PASC fatigue, dyspnea, palpitation, dysosmia, subfever, hypertension, alopecia, sleep problems, loss concentration, amnesia, numbness, pain, gastrointestinal symptoms, depression, anxiety. Because the specific pathophysiology has not yet been clarified, there no definite criteria hence World Health Organization's definition is quite broad. Consequently, it difficult to correctly diagnose PASC. Approximately 50% patients may show at least one symptom up 12 months infection; however, exact prevalence determined. Despite extensive research in progress worldwide, currently clear diagnostic methodologies or treatments for In this review, we discuss available information on highlight infection. Furthermore, provide clinical suggestions diagnosing caring with based our outpatient clinic experience.

Language: Английский

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Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 13, 2023

The pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome 2 (SARS-CoV-2) and marked thromboembolic events an inflammatory response throughout the body, including brain. Employing machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells tested such respect their induce activation of human TLR7 TLR8 macrophages, as well iPSC-derived microglia, resident in We experimentally validated several sequence-specific fragment candidates out predicted silico activators Moreover, these ssRNAs induced cytokine release from macrophages microglia a sequence- species-specific fashion. Our findings determine key sensors SARS-CoV-2-derived may deepen our understanding mechanisms how this virus triggers, but also modulates through signaling.

Language: Английский

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COVID‐19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain

Annals of Neurology, Journal Year: 2023, Volume and Issue: 94(3), P. 531 - 546

Published: May 16, 2023

Objective Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection using a multiplatform strategy. Methods Brain tissues from disease 2019 (COVID‐19) (n = 12) other control (ODC) patients, as well primary human neural cells Syrian hamsters, infected with clinical variant of SARS‐CoV‐2, were by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT‐qPCR), immunodetection methods. Results SARS‐CoV‐2 RNA was detected CNS 4 patients COVID‐19 viral protein (NSP3 spike) brainstem. Olfactory bulb, brainstem, cerebrum showed induction pro‐inflammatory transcripts ( IL8, IL18, CXCL10, NOD2 ) cytokines (GM‐CSF IL‐18) compared to ODC p < 0.05). factor PEX3, PEX5L, PEX11β, PEX14 proteins (PEX3, PEX14, PMP70) suppressed hamsters revealed detection olfactory bulb at days 7 post‐infection while inflammatory gene expression upregulated animals day 14 Pex3 transcript levels together catalase PMP70 immunoreactivity Interpretation induced sustained neuroinflammatory suppression despite limited brainstem neurotropism humans. These observations offer insights into developing biomarkers therapies, also implicating persistent dysfunction contributor post‐acute sequelae COVID‐19. ANN NEUROL 2023;94:531–546

Language: Английский

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