Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(35)

Опубликована: Авг. 11, 2022

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum cerebral impact acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranging from alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to damage confirmed brain tissue samples extracted orbitofrontal region (via endonasal transethmoidal access) who died COVID-19. In an independent cohort 26 COVID-19, we used histopathological signs a guide for possible SARS-CoV-2 infection found that among 5 exhibited those signs, all them had genetic material virus brain. Brain these five patients also foci replication, particularly astrocytes. Supporting hypothesis astrocyte neural stem cell-derived human astrocytes vitro are susceptible through noncanonical mechanism involves spike-NRP1 interaction. SARS-CoV-2-infected manifested changes energy metabolism key proteins metabolites fuel neurons, well biogenesis neurotransmitters. Moreover, elicits secretory phenotype reduces neuronal viability. Our data support model which reaches brain, infects astrocytes, consequently, leads death or dysfunction. These deregulated processes could contribute structural functional seen brains patients.

Язык: Английский

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The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2

Trends in Neurosciences, Год журнала: 2022, Номер 45(5), С. 358 - 368

Опубликована: Март 3, 2022

Язык: Английский

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Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 65(4), С. 2940 - 2955

Опубликована: Окт. 19, 2021

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination protein substrates. PLpro is a promising therapeutic target, albeit challenging owing featureless P1 P2 sites recognizing glycine. To overcome this challenge, we leveraged cooperativity multiple shallow on surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed ligand induces new interactions PLpro: closing BL2 loop forming "BL2 groove" mimicking interaction ubiquitin Glu167 PLpro. Together, translates most potent inhibitors reported date, slow off-rates, improved affinities, low micromolar antiviral potency in SARS-CoV-2-infected human cells.

Язык: Английский

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Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations

Cells, Год журнала: 2021, Номер 10(2), С. 386 - 386

Опубликована: Фев. 13, 2021

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological are unknown and need be identified. Plasma from 24 individuals recovering at 1 3 months after initial infection were collected for cytokine antibody levels neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. IL-4 was increased in all participants. Volunteers with self-reported problems (nCoV, n = 8) had a positive correlation of IL6 age or severity sequalae, least one co-morbidity compared those without issues (CoV, 16). Protein markers neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, p-T181-tau significantly nEVs participants historic controls. This study suggests ongoing peripheral neuroinflammation that may influence by altering nEV proteins. Individuals occult neural damage while demonstrative symptoms additionally more severe infection. Longitudinal studies monitor plasma biomarkers warranted assess persistent neurodegeneration systemic effects.

Язык: Английский

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Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Alzheimer s Research & Therapy, Год журнала: 2021, Номер 13(1)

Опубликована: Июнь 9, 2021

Abstract Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this remain unclear. A better understanding causative processes by which COVID-19 may lead to essential developing preventive and therapeutic interventions. Methods In study, we conducted a network-based, multimodal omics comparison neurologic complications. We constructed virus-host interactome from protein-protein interaction assay CRISPR-Cas9-based genetic results compared network-based relationships therein with those known neurological manifestations using network proximity measures. also investigated transcriptomic profiles (including single-cell/nuclei RNA-sequencing) Alzheimer’s disease (AD) marker genes patients infected COVID-19, as well prevalence entry factors in brains AD not SARS-CoV-2. Results found significant between neuroinflammation brain microvascular injury pathways are implicated AD. detected aberrant expression biomarkers cerebrospinal fluid blood COVID-19. While analyses showed relatively low human brain, neuroinflammatory changes were pronounced. addition, single-nucleus that host ( BSG FURIN ) antiviral defense LY6E , IFITM2 IFITM3 IFNAR1 was elevated endothelial cells healthy controls relative neurons other cell types, suggesting possible role COVID-19-mediated impairment. Overall, individuals risk allele APOE E4/E4 displayed reduced E3/E3 individuals. Conclusion Our suggest mechanistic overlap centered on injury. These help improve our COVID-19-associated provide guidance future development or treatment interventions, although causal relationship need investigations.

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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Cerebral dysfunctions caused by sepsis during ageing

Nature reviews. Immunology, Год журнала: 2021, Номер 22(7), С. 444 - 458

Опубликована: Ноя. 11, 2021

Язык: Английский

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Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis

Nature Cancer, Год журнала: 2021, Номер 2(9), С. 932 - 949

Опубликована: Авг. 16, 2021

Язык: Английский

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Human organoid models to study SARS-CoV-2 infection

Nature Methods, Год журнала: 2022, Номер 19(4), С. 418 - 428

Опубликована: Апрель 1, 2022

Язык: Английский

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SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

Molecular Psychiatry, Год журнала: 2022, Номер 27(10), С. 3939 - 3950

Опубликована: Окт. 1, 2022

Abstract Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but mechanisms these effects unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that infection initiate neuronal cell death cause loss post-synaptic termini. Despite limited neurotropism decelerating viral replication, observe threefold increase microglial engulfment postsynaptic termini after exposure. We define responses to by single transcriptomic profiling an upregulation interferon-responsive genes as well promoting migration synapse engulfment. To large extent, exposed microglia adopt profile overlapping neurodegenerative disorders display early increased incident risk infection. Our results reveal organoids infected disruption circuit integrity via microglia-mediated elimination identifies potential novel mechanism contributing cognitive impairments patients recovering from COVID-19.

Язык: Английский

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