Astrocytes in human central nervous system diseases: a frontier for new therapies

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Окт. 13, 2023

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence the central nervous system (CNS). contribute pathophysiology all neurological neuropsychiatric disorders in ways that can be either beneficial or detrimental disorder outcome. Pathophysiological changes astroglia primary secondary result gain loss functions. respond external, non-cell autonomous signals associated with any form CNS pathology by undergoing complex variable their structure, molecular expression, function. In addition, internally driven, cell astroglial innate properties lead pathologies. Astroglial is complex, different pathophysiological states phenotypes context-specific vary disorder, disorder-stage, comorbidities, age, sex. Here, we classify into (i) reactive astrogliosis, (ii) atrophy function, (iii) degeneration death, (iv) astrocytopathies characterised aberrant forms drive disease. We review across spectrum human diseases disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack epilepsy, as well neurodevelopmental, neurodegenerative, metabolic disorders. Characterising cellular mechanisms represents new frontier identify novel therapeutic strategies.

Язык: Английский

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

Molecular Psychiatry, Год журнала: 2022, Номер 28(7), С. 2878 - 2893

Опубликована: Ноя. 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.

Язык: Английский

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Tropism of SARS-CoV-2 for human cortical astrocytes

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(30)

Опубликована: Июль 12, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function vital organ systems, with particularly impact on function. Neurological symptoms, which range in severity, accompany as many one-third COVID-19 cases, indicating potential vulnerability neural types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived organoids well primary tissue, both from developmental and adult stages. We find significant predominant infection astrocytes tissue organoid cultures, minimal other populations. Infected bystander have corresponding increase inflammatory gene expression, reactivity characteristics, increased cytokine growth factor signaling, cellular stress. Although cells, astrocytes, no observable ACE2 high levels coreceptors including CD147 DPP4. Decreasing coreceptor abundance activity reduces overall rate, increasing expression is sufficient to promote infection. Thus, tropism SARS-CoV-2 for resulting gliosis-type injury that dependent coreceptors.

Язык: Английский

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Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse

Viruses, Год журнала: 2022, Номер 14(5), С. 1020 - 1020

Опубликована: Май 11, 2022

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme (hACE2), we investigated spatiotemporal distribution pathomorphological features in CNS following intranasal infection with SARS-CoV-2 variants, well after prior influenza A virus infection. Apart from Omicron, found all variants to frequently spread within CNS. Infection was restricted neurons appeared olfactory bulb mainly basally oriented regions brain into spinal cord, independent ACE2 expression without evidence neuronal cell death, axonal damage demyelination. However, microglial activation, microgliosis a mild macrophage T dominated inflammatory response consistently observed, accompanied by apoptotic death endothelial, immune cells, their apparent Microgliosis apoptosis indicate potential role microglia for pathogenesis viral effect COVID-19 possible impairment functions, especially long COVID. These data may be informative selection therapeutic candidates broadly support investigation agents adequate penetration relevant

Язык: Английский

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New‐onset neurodegenerative diseases as long‐term sequelae of SARS‐CoV‐2 infection: A systematic review and meta‐analysis

Journal of Medical Virology, Год журнала: 2023, Номер 95(7)

Опубликована: Июль 1, 2023

Abstract The association between SARS‐CoV‐2 infection with increased risk for new‐onset neurodegenerative diseases remains unclear. Therefore, this meta‐analysis aims to elucidate whether are long‐term sequelae of infection. PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched articles published up January 10, 2023. A systematic review performed calculate the pooled effect size, expressed as hazard ratios (HR) corresponding 95% confidence interval (CI) each outcome. Twelve studies involving 33 146 809 individuals (2 688 417 post‐COVID‐19 cases 30 458 392 controls) included in present meta‐analysis. analyses compared control groups showed a significant Alzheimer's disease (HR = 1.50, CI 1.22–1.85, I 2 97%), dementia 1.66, 1.42–1.94, 91%), Parkinson's 1.44, 1.06–1.95, 86%) among COVID‐19 survivors. may be associated higher recovered patients. Future warranted determine biological mechanisms underlying consequences

Язык: Английский

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SARS-CoV-2 uses CD4 to infect T helper lymphocytes

eLife, Год журнала: 2023, Номер 12

Опубликована: Июль 31, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such lymphocytopenia cytokine storm, which are associated with severity predict mortality. mechanism by infection result in immune system dysfunction still not fully understood. Here, we show that human CD4+ T helper cells, but CD8+ present blood bronchoalveolar lavage cells COVID-19 patients. We demonstrated spike glycoprotein (S) directly binds to CD4 molecule, turn mediates entry SARS- CoV-2 cells. This leads impaired cell function death. SARS-CoV-2-infected express higher levels IL-10, viral persistence severity. Thus, CD4-mediated contribute poor response

Язык: Английский

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Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 19, 2024

Abstract Although some studies have shown neuroimaging and neuropsychological alterations in post-COVID-19 patients, fewer combined neuropsychology evaluations of individuals who presented a mild acute infection. Here we investigated cognitive dysfunction brain changes group mildly infected individuals. We conducted cross-sectional study 97 consecutive subjects (median age 41 years) without current or history psychiatric symptoms (including anxiety depression) after infection, with median 79 days (and mean days) diagnosis COVID-19. performed semi-structured interviews, neurological examinations, 3T-MRI scans, assessments. For MRI analyses, included non-infected 77 controls. The white matter (WM) investigation diffusion tensor images (DTI) functional connectivity resting-state (RS-fMRI). patients reported memory loss (36%), fatigue (31%) headache (29%). quantitative analyses confirmed (83% participants), excessive somnolence (35%), impaired phonemic verbal fluency (21%), categorical (13%) logical immediate recall (16%). WM DTI revealed higher axial diffusivity values post-infected compared to Compared controls, there were no significant differences the posterior cingulum cortex. There correlations between scores features RS-fMRI). Our results suggest persistent impairment subtle abnormalities depression symptoms. longitudinal will clarify whether these are temporary permanent.

Язык: Английский

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Mucosal immune response in biology, disease prevention and treatment

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 7, 2025

Abstract The mucosal immune system, as the most extensive peripheral network, serves frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion establishing tolerance. A comprehensive understanding immunity essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing overall impact on body. Despite its importance, our knowledge remains incomplete, necessitating further research. outbreak severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored critical role disease prevention treatment. This systematic review focuses dynamic interactions between mucosa-associated lymphoid structures related diseases. We delve into basic functions these tissues during processes explore intricate regulatory networks mechanisms involved. Additionally, we summarize novel therapies clinical research advances immunity-related also addresses challenges vaccines, which aim to induce specific responses while maintaining tolerance non-pathogenic microbes. Innovative therapies, such nanoparticle vaccines inhalable antibodies, show promise enhancing offer potential improved

Язык: Английский

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Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems

Biomedicines, Год журнала: 2022, Номер 10(12), С. 3113 - 3113

Опубликована: Дек. 2, 2022

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as "brain fog", fatigue and clotting problems. Explanations for "long COVID" include immune imbalance, incomplete viral clearance potentially, mitochondrial dysfunction. As conditions sub-optimal function are associated initial severity of disease, their prior health could be key in resistance to long COVID recovery. The SARs virus redirects host metabolism towards replication; response, can metabolically react control virus. Resolution is normally achieved after stress activates a hormetic negative feedback mechanism. It therefore possible that, some individuals function, "tip" into chronic inflammatory cycle. This might explain main including platelet Long thus described virally induced self-perpetuating imbalanced non-resolving state characterised by dysfunction, where reactive oxygen species continually drive inflammation shift glycolysis. would suggest that sufferer's needs "tipped" back using stimulus, physical activity, calorie restriction, or chemical compounds mimic these enhancing perhaps combination inhibitors quell response.

Язык: Английский

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COVID-19 severity is related to poor executive function in people with post-COVID conditions

Journal of Neurology, Год журнала: 2023, Номер 270(5), С. 2392 - 2408

Опубликована: Март 20, 2023

Patients with post-coronavirus disease 2019 (COVID-19) conditions typically experience cognitive problems. Some studies have linked COVID-19 severity long-term damage, while others did not observe such associations. This discrepancy can be attributed to methodological and sample variations. We aimed clarify the relationship between outcomes determine whether initial symptomatology predict Cognitive evaluations were performed on 109 healthy controls 319 post-COVID individuals categorized into three groups according WHO clinical progression scale: severe-critical (n = 77), moderate-hospitalized 73), outpatients 169). Principal component analysis was used identify factors associated symptoms in acute-phase domains. Analyses of variance regression linear models study intergroup differences The group significantly worse than control general cognition (Montreal Assessment), executive function (Digit symbol, Trail Making Test B, phonetic fluency), social (Reading Mind Eyes test). Five components emerged from principal analysis: "Neurologic/Pain/Dermatologic" "Digestive/Headache", "Respiratory/Fever/Fatigue/Psychiatric" "Smell/ Taste" predictors Montreal Assessment scores; predicted attention working memory; verbal memory, "Respiratory/Fever/Fatigue/Psychiatric," "Neurologic/Pain/Dermatologic," "Digestive/Headache" function. severe exhibited persistent deficits Several sequelae, indicating role systemic inflammation neuroinflammation COVID-19." Study Registration: www.ClinicalTrials.gov , identifier NCT05307549 NCT05307575.

Язык: Английский

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