Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
2.
Proc Natl Acad Sci U S A ; 119(30): e2122236119, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-1947759

ABSTRACT

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


Subject(s)
Astrocytes , Cerebral Cortex , SARS-CoV-2 , Viral Tropism , Angiotensin-Converting Enzyme 2/metabolism , Astrocytes/enzymology , Astrocytes/virology , Cerebral Cortex/virology , Humans , Organoids/virology , Primary Cell Culture , SARS-CoV-2/physiology
3.
Nat Med ; 27(9): 1600-1606, 2021 09.
Article in English | MEDLINE | ID: covidwho-1526089

ABSTRACT

Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral 'replication hubs', with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new 'assembloid' model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.


Subject(s)
Astrocytes/virology , Brain/virology , COVID-19/pathology , Pericytes/virology , Viral Tropism/physiology , Astrocytes/cytology , Brain/pathology , Cell Differentiation/physiology , Cells, Cultured , Humans , Interferon Type I/immunology , SARS-CoV-2 , Virus Replication/physiology
4.
J Neuroimmunol ; 361: 577728, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1440213

ABSTRACT

We herein report, by using confocal immunofluorescence, the colocalization of the SARS-CoV-2 nucleocapsid within neurons, astrocytes, oligodendrocytes and microglia in three deceased COVID-19 cases, of between 78 and 85 years of age at death. The viral nucleocapsid was detected together with its ACE2 cell entry receptor, as well as the NLRP3 inflammasome in cerebral cortical tissues. It is noteworthy that NLRP3 was colocalized with CD68 + macrophages in the brain and lung of the deceased, suggesting the critical role of this type of inflammasome in SARS-CoV-2 lesions of the nervous system/lungs and supporting its potential role as a therapeutic target.


Subject(s)
Brain/virology , COVID-19/virology , Inflammasomes/immunology , Microglia/virology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/pathogenicity , Aged , Aged, 80 and over , Astrocytes/virology , Autopsy , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Female , Humans , Male , Microglia/immunology , Neurons/virology , Nucleocapsid , Oligodendroglia/virology
6.
EBioMedicine ; 70: 103512, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1330766

ABSTRACT

BACKGROUND: Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19. METHODS: Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15). FINDINGS: One hundred patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID-19 were followed for a median (IQR) of 225 (187-262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r = 0·53, p < 0·001) and GFAp (r = 0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n = 40), "brain-fog" (n = 29), and changes in cognition (n = 25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase. INTERPRETATION: The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury. FUNDING: The Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.


Subject(s)
Astrocytes/pathology , Astrocytes/virology , COVID-19/pathology , COVID-19/virology , SARS-CoV-2/pathogenicity , Aged , Astrocytes/metabolism , Biomarkers/blood , Biomarkers/metabolism , COVID-19/blood , COVID-19/metabolism , Disease Progression , Female , Follow-Up Studies , Glial Fibrillary Acidic Protein/metabolism , Humans , Longitudinal Studies , Male , Middle Aged , Neurofilament Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Neurons/virology , Sweden
8.
Signal Transduct Target Ther ; 6(1): 169, 2021 04 24.
Article in English | MEDLINE | ID: covidwho-1199270

ABSTRACT

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.


Subject(s)
Brain Diseases/metabolism , Brain/metabolism , COVID-19/metabolism , Olfactory Bulb/metabolism , SARS-CoV-2/metabolism , Animals , Astrocytes/metabolism , Astrocytes/pathology , Astrocytes/virology , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , COVID-19/pathology , Disease Models, Animal , Humans , Macaca mulatta , Microglia/metabolism , Microglia/pathology , Microglia/virology , Neurons/metabolism , Neurons/pathology , Neurons/virology , Olfactory Bulb/pathology , Olfactory Bulb/virology
9.
Cell Stem Cell ; 28(2): 331-342.e5, 2021 02 04.
Article in English | MEDLINE | ID: covidwho-1009887

ABSTRACT

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.


Subject(s)
Apolipoproteins E/metabolism , Brain/pathology , Brain/virology , COVID-19/virology , Induced Pluripotent Stem Cells/virology , SARS-CoV-2/physiology , Tropism/physiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Antiviral Agents/pharmacology , Astrocytes/drug effects , Astrocytes/pathology , Astrocytes/virology , Cell Differentiation , Chlorocebus aethiops , Humans , Nerve Degeneration/pathology , Neurites/pathology , Neurons/drug effects , Neurons/pathology , Neurons/virology , Organoids/drug effects , Organoids/pathology , Organoids/virology , Protein Isoforms/metabolism , Synapses/pathology , Vero Cells
11.
Cell Stem Cell ; 27(6): 937-950.e9, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-779663

ABSTRACT

Neurological complications are common in patients with COVID-19. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function is not well understood. Here, we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found that neurons and astrocytes were sparsely infected, but choroid plexus epithelial cells underwent robust infection. We optimized a protocol to generate choroid plexus organoids from hiPSCs and showed that productive SARS-CoV-2 infection of these organoids is associated with increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our findings provide evidence for selective SARS-CoV-2 neurotropism and support the use of hiPSC-derived brain organoids as a platform to investigate SARS-CoV-2 infection susceptibility of brain cells, mechanisms of virus-induced brain dysfunction, and treatment strategies.


Subject(s)
Choroid Plexus/virology , Neural Stem Cells/virology , Organoids/virology , Pluripotent Stem Cells/virology , SARS-CoV-2/physiology , Viral Tropism , Animals , Astrocytes/virology , Brain/cytology , Brain/virology , COVID-19/genetics , COVID-19/virology , Cells, Cultured , Gene Expression Regulation , Humans , Neurons/virology
12.
ASN Neuro ; 12: 1759091420954960, 2020.
Article in English | MEDLINE | ID: covidwho-744949

ABSTRACT

With confirmed coronavirus disease 2019 (COVID-19) cases surpassing the 18 million mark around the globe, there is an imperative need to gain comprehensive understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are associated with respiratory or intestinal symptoms, reports of neurological signs and symptoms are increasing. The etiology of these neurological manifestations remains obscure, and probably involves several direct pathways, not excluding the direct entry of the virus to the central nervous system (CNS) through the olfactory epithelium, circumventricular organs, or disrupted blood-brain barrier. Furthermore, neuroinflammation might occur in response to the strong systemic cytokine storm described for COVID-19, or due to dysregulation of the CNS rennin-angiotensin system. Descriptions of neurological manifestations in patients in the previous coronavirus (CoV) outbreaks have been numerous for the SARS-CoV and lesser for Middle East respiratory syndrome coronavirus (MERS-CoV). Strong evidence from patients and experimental models suggests that some human variants of CoV have the ability to reach the CNS and that neurons, astrocytes, and/or microglia can be target cells for CoV. A growing body of evidence shows that astrocytes and microglia have a major role in neuroinflammation, responding to local CNS inflammation and/or to disbalanced peripheral inflammation. This is another potential mechanism for SARS-CoV-2 damage to the CNS. In this comprehensive review, we will summarize the known neurological manifestations of SARS-CoV-2, SARS-CoV and MERS-CoV; explore the potential role for astrocytes and microglia in the infection and neuroinflammation; and compare them with the previously described human and animal CoV that showed neurotropism to propose possible underlying mechanisms.


Subject(s)
Astrocytes/virology , Betacoronavirus , Central Nervous System/virology , Coronavirus Infections , Microglia/virology , Pandemics , Pneumonia, Viral , Animals , COVID-19 , Humans , Inflammation/virology , Middle East Respiratory Syndrome Coronavirus , SARS Virus , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL