The structural basis of accelerated host cell entry by SARS‐CoV‐2†

FEBS Journal, Год журнала: 2020, Номер 288(17), С. 5010 - 5020

Опубликована: Дек. 2, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of pandemic disease 2019 (COVID-19) that exhibits an overwhelming contagious capacity over other human coronaviruses (HCoVs). This structural snapshot describes bases underlying SARS-CoV-2 and explains its fast motion epithelia allow rapid cellular entry. Based on notable viral spike (S) protein features, we propose flat sialic acid-binding domain at N-terminal (NTD) S1 subunit leads to more effective first contact interaction with acid layer epithelium, this, in turn, allows faster 'surfing' epithelium receptor scanning by SARS-CoV-2. Angiotensin-converting enzyme (ACE-2) epithelial surface primary entry for SARS-CoV-2, protein-protein assays demonstrate high-affinity binding (S protein) ACE-2. To date, no high-frequency mutations were detected C-terminal S protein, where receptor-binding (RBD) located. Tight ACE-2 a conserved RBD suggests ACE2-RBD likely optimal. Moreover, contains cleavage site furin proteases, which accelerates cell The model proposed here basis accelerated host relative HCoVs also discusses emerging hypotheses are contribute development antiviral strategies combat

Язык: Английский

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Dopamine, Immunity, and Disease

Pharmacological Reviews, Год журнала: 2022, Номер 75(1), С. 62 - 158

Опубликована: Дек. 8, 2022

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions peripheral organs, such as blood pressure, renal activity, intestinal motility. Beyond these functions, growing body of evidence indicates that an important immunoregulatory factor. Most types immune cells express receptors other dopaminergic proteins, take up, produce, store, and/or release dopamine, suggesting immunomodulation for function. Targeting pathways could be promising avenue the treatment inflammation disease, but despite increasing research this area, data on specific effects disease remain inconsistent poorly understood. Therefore, review integrates current knowledge role cell function inflammatory signaling across systems. We discuss understanding regulation CNS tissues, highlighting diseases Parkinson’s several neuropsychiatric conditions, neurologic human immunodeficiency virus, bowel rheumatoid arthritis, others. Careful consideration given to influence experimental design results, we note number areas need further research. Overall, our immunology at cellular, tissue, level prompts development therapeutics strategies targeted toward ameliorating through immunity.

Significance Statement

Canonically, recognized involved cognition, reward. However, acts modulator periphery. This comprehensively assesses pathogenesis cellular tissue level. will provide broad access information fields, identify investigation, drive therapeutic strategies.

Язык: Английский

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Astrocytes are HIV reservoirs in the brain: A cell type with poor HIV infectivity and replication but efficient cell‐to‐cell viral transfer

Journal of Neurochemistry, Год журнала: 2021, Номер 158(2), С. 429 - 443

Опубликована: Март 3, 2021

The major barrier to eradicating Human immunodeficiency virus-1 (HIV) infection is the generation of tissue-associated quiescent long-lasting viral reservoirs refractory therapy. Upon interruption anti-retroviral therapy (ART), HIV replication can be reactivated. Within brain, microglia/macrophages and a small population astrocytes are infected with HIV. However, role as potential reservoir becoming more recognized because improved detection quantification reservoirs. In this report, we examined infectivity human primary in vivo vitro, their capacity maintain infection, become latently infected, reactivated, transfer new virions into neighboring cells. Analysis brain tissue sections obtained from HIV-infected individuals under effective prolonged ART indicates that has integrated HIV-DNA. vitro experiments using astrocyte cultures confirmed low percentage had HIV-DNA, poor undetectable replication. Even absence ART, long-term culture results latency could transiently reactivated histone deacetylase inhibitor, tumor necrosis factor-alpha (TNF-α), or methamphetamine. Reactivation resulted production but efficient cell-to-cell cells support high Together, our data provide understanding astrocytes' within central nervous system (CNS).

Язык: Английский

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The reservoir of latent HIV

Frontiers in Cellular and Infection Microbiology, Год журнала: 2022, Номер 12

Опубликована: Июль 28, 2022

The persistence of latent reservoir the human immunodeficiency virus (HIV) is currently major challenge in curing HIV infection. After infects body, unable to be recognized by body’s immune system. Currently, widely adopted antiretroviral therapy (ART) also unble eliminate it, thus hindering progress treatment. This review discusses existence vault for treatment, its formation and factors affecting formation, cell, tissue localization, methods detection removing reservoir, provide a comprehensive understanding vault, order assist future research play potential role achieving

Язык: Английский

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Intact HIV Proviruses Persist in the Brain Despite Viral Suppression with ART

Annals of Neurology, Год журнала: 2022, Номер 92(4), С. 532 - 544

Опубликована: Июль 22, 2022

Human immunodeficiency virus (HIV) persistence in blood and tissue reservoirs, including the brain, is a major barrier to HIV cure possible cause of comorbid disease. However, size replication competent nature central nervous system (CNS) reservoir unclear. Here, we used intact proviral DNA assay (IPDA) provide first quantitative assessment defective brain people with (PWH).Total, intact, proviruses were measured autopsy frontal lobe from viremic (n = 18) or virologically suppressed 12) PWH. Total intact/defective by detection pol IPDA, respectively, through use droplet digital polymerase chain reaction (ddPCR). HIV-seronegative individuals included as controls 6).Total was present at similar levels tissues untreated antiretroviral (ART)-suppressed (median 22.3 vs 26.2 copies/106 cells), reflecting stable CNS that persists despite therapy. Furthermore, 8 10 6 9 virally PWH also harbored (4.63 12.7 cells). Viral reservoirs matched lymphoid composition and/or proviruses, albeit lower brain. Importantly, resident CD68+ myeloid cells DNA, directly showing presence reservoir.Our results demonstrate evidence for an potentially ANN NEUROL 2022;92:532-544.

Язык: Английский

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The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder

Trends in Immunology, Год журнала: 2022, Номер 43(8), С. 630 - 639

Опубликована: Июль 12, 2022

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% HIV-1-infected patients receiving ART exhibit neuroinflammation symptoms HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that emergence from latency microglia underlies both CNS progression HAND. Recent molecular studies cellular silencing mechanisms show can be reversed proinflammatory cytokines signals damaged neurons, potentially creating intermittent cycles reactivation brain. posit anti-inflammatory agents also block reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for treatment

Язык: Английский

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Characterization of HIV-1 Infection in Microglia-Containing Human Cerebral Organoids

Viruses, Год журнала: 2022, Номер 14(4), С. 829 - 829

Опубликована: Апрель 16, 2022

The achievement of an HIV cure is dependent on the eradication or permanent silencing HIV-latent viral reservoirs, including understudied central nervous system (CNS) reservoir. This requires a deep understanding molecular mechanisms HIV's entry into CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect intercellular dynamics pathophysiology human brain are urgently needed in order to study reservoir HIV-induced neuropathogenesis. In this study, we characterized cerebral organoid model which microglia grow intrinsically as infection CNS. We demonstrated both organoids isolated organoid-derived (oMG), infected with replication-competent HIVbal reporter viruses, support productive via CCR5 co-receptor. Productive was only observed microglial cells. Fluorescence analysis revealed target cell. Susceptibility co-expression microglia-specific markers CD4 receptors. Altogether, will be valuable tool within research community HIV-CNS interactions, underlying HIV-associated neurological disorders (HAND), efficacy new therapeutic curative strategies

Язык: Английский

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HIV infection of non-classical cells in the brain

Retrovirology, Год журнала: 2023, Номер 20(1)

Опубликована: Янв. 13, 2023

Abstract HIV-associated neurological disorders (HAND) affect up to 50% of people living with HIV (PLWH), even in the era combination antiretroviral therapy (cART). HIV-DNA can be detected cerebral spinal fluid (CSF) approximately half aviremic ART-suppressed PLWH and its presence is associated poorer neurocognitive performance. DNA + RNA cells have also been observed postmortem brain tissue individuals sustained cART suppression. In this review, we provide an overview how invades infection resident glial (astrocytes microglia). We discuss role persistent neuroinflammation HAND their potential contribution reservoir. eradication strategies that target persistently infected glia will likely needed achieve cure.

Язык: Английский

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Immune Functions of Astrocytes in Viral Neuroinfections

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3514 - 3514

Опубликована: Фев. 9, 2023

Neuroinfections of the central nervous system (CNS) can be triggered by various pathogens. Viruses are most widespread and have potential to induce long-term neurologic symptoms with potentially lethal outcomes. In addition directly affecting their host cells inducing immediate changes in a plethora cellular processes, viral infections CNS also trigger an intense immune response. Regulation innate response depends not only on microglia, which fundamental CNS, but astrocytes. These align blood vessels ventricle cavities, consequently, they one first cell types become infected after virus breaches CNS. Moreover, astrocytes increasingly recognized as reservoir CNS; therefore, initiated presence intracellular particles may profound effect tissue physiology morphology. should addressed terms persisting because contribute recurring sequelae. To date, different viruses originating from genetically distinct families, including Flaviviridae, Coronaviridae, Retroviridae, Togaviridae, Paramyxoviridae, Picomaviridae, Rhabdoviridae, Herpesviridae, been confirmed. Astrocytes express receptors that detect signaling cascades, leading this review, we summarize current knowledge initiate release inflammatory cytokines depict involvement functions

Язык: Английский

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Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 10, 2025

Cerebral organoids (COs) are valuable tools for studying the intricate interplay between glial cells and neurons in brain development disease, including HIV-associated neuroinflammation. We developed a novel approach to generate microglia containing COs (CO-iMs) by co-culturing hematopoietic progenitors inducing pluripotent stem cells. This allowed differentiation of within concomitantly with neuronal progenitors. Compared conventional COs, CO-iMs were more efficient at generating CD45+/CD11b+/Iba-1+ presented physiologically relevant proportion (~ 7%). substantially increased expression microglial homeostatic sensome markers as well complement cascade. susceptible HIV infection, resulting significant increase several pro-inflammatory cytokines/chemokines, which abrogated addition antiretrovirals. Thus, CO-iM is robust model deciphering neuropathogenesis, neuroinflammation, viral infections 3D culture system.

Язык: Английский

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