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1.
Front Immunol ; 13: 826091, 2022.
Article in English | MEDLINE | ID: covidwho-1731778

ABSTRACT

Neural stem cells (NSCs) are multipotent stem cells that reside in the fetal and adult mammalian brain, which can self-renew and differentiate into neurons and supporting cells. Intrinsic and extrinsic cues, from cells in the local niche and from distant sites, stringently orchestrates the self-renewal and differentiation competence of NSCs. Ample evidence supports the important role of NSCs in neuroplasticity, aging, disease, and repair of the nervous system. Indeed, activation of NSCs or their transplantation into injured areas of the central nervous system can lead to regeneration in animal models. Viral invasion of NSCs can negatively affect neurogenesis and synaptogenesis, with consequent cell death, impairment of cell cycle progression, early differentiation, which cause neural progenitors depletion in the cortical layer of the brain. Herein, we will review the current understanding of Zika virus (ZIKV) infection of the fetal brain and the NSCs, which are the preferential population targeted by ZIKV. Furthermore, the potential neurotropic properties of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may cause direct neurological damage, will be discussed.


Subject(s)
Brain/virology , COVID-19/pathology , COVID-19/virology , Neurogenesis/physiology , Neurons/virology , Zika Virus Infection/pathology , Zika Virus Infection/virology , Animals , Humans , Neural Stem Cells/virology
2.
Stem Cell Reports ; 16(3): 437-445, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-1084274

ABSTRACT

COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.


Subject(s)
Brain/virology , COVID-19/virology , Induced Pluripotent Stem Cells/virology , Lung/virology , Neural Stem Cells/virology , Organoids/virology , SARS-CoV-2/pathogenicity , Apoptosis/physiology , Brain/metabolism , COVID-19/metabolism , Cells, Cultured , Complement System Proteins/metabolism , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Induced Pluripotent Stem Cells/metabolism , Inflammation/metabolism , Inflammation/virology , Lung/metabolism , Neural Stem Cells/metabolism , Neurons/metabolism , Neurons/virology , Organoids/metabolism , Serine Endopeptidases/metabolism , Signal Transduction/physiology , Stem Cells/metabolism , Stem Cells/virology
3.
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
4.
Viruses ; 12(9)2020 09 08.
Article in English | MEDLINE | ID: covidwho-760952

ABSTRACT

Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Neurons/virology , Organoids/virology , Prosencephalon/virology , Spike Glycoprotein, Coronavirus/physiology , Angiotensin-Converting Enzyme 2 , Axons/enzymology , Cell Differentiation , Cells, Cultured , Cerebral Cortex/cytology , Embryonic Stem Cells/virology , HEK293 Cells , Humans , Nerve Tissue Proteins/physiology , Neural Stem Cells/enzymology , Neural Stem Cells/virology , Neurons/enzymology , Peptidyl-Dipeptidase A/physiology , Prosencephalon/cytology , Receptors, Virus/physiology , SARS-CoV-2 , Viral Load , Viral Tropism , Virus Internalization
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