Table 2.
Evidence supporting the direct neurotropic effects of SARS-CoV-2.
| Models | Targets | Main findings | Methods | Immunostaining (colocalization with SARS-CoV-2 spike protein or nucleoprotein) | References |
|---|---|---|---|---|---|
| hPSC-derived neural progenitor cells, neurospheres, and brain organoids | Cortical neurons and neural progenitor cells | Human neural progenitor cells and neurospheres are permissive to SARS-CoV-2 infection and supported productive virus replication; SARS-CoV-2 can directly infect cortical neurons and neural progenitor cells in brain organoids | qRT-PCR; electron microscopy; immunofluorescence | Neuronal cell marker TUJ1, and proliferation neural progenitor cell marker NESTIN | Zhang et al., 2020 [96] |
| hPSC-derived monolayer brain cells, region-specific brain organoids, and choroid plexus organoids | Neurons, astrocytes, choroid plexus epithelial cells; cortical, hippocampal, hypothalamic, and midbrain regions | SARS-CoV-2 sparsely infects human neurons and astrocytes, but robustly infects choroid plexus epithelial cells; SARS-CoV-2 increases cell death in choroid plexus organoids | qRT-PCR; immunofluorescence; single-cell RNA-seq | Neuronal marker doublecortin, astrocyte marker GFAP, choroid plexus marker transthyretin | Jacob et al., 2020 [99] |
| hPSC-derived brain organoids | Choroid plexus epithelial cells | SARS-CoV-2 spike pseudovirus and live virus infects choroid plexus epithelial cells, but not neurons or glia; SARS-CoV-2 damages the choroid plexus epithelium and disrupts the blood–CSF barrier | qRT-PCR; immunofluorescence; single-cell RNA-seq | Choroid plexus marker transthyretin | Pellegrini et al., 2020 [101] |
| hPSC-derived neuroprogenitor cells and BrainSphere | Neuronal cell body and neurite structures | SARS-CoV-2 infects neuronal cell body and neurite structures with the replication of the virus | qRT-PCR; immunofluorescence | Neuronal marker MAP2 | Bullen et al., 2020 [105] |
| hPSC-derived brain organoids; mice overexpressing human ACE2; brain autopsy samples of deceased COVID-19 patients | Neurons; forebrain cortex, cerebellum, dentate gyrus, the globus pallidus | SARS-CoV-2 infects human brain organoids accompanying metabolic changes and induces cell death; SARS-CoV-2 neuroinvasion in vivo in mice; the presence of SARS-CoV-2 in cortical neurons of autopsy samples | qRT-PCR; electron microscopy; immunofluorescence; single-cell RNA-seq | Neuronal marker MAP2, vascular endothelium marker CD31, and podocalyxin | Song et al., 2021 [106] |
| hPSC-derived cortical neurons and brain organoids | Cortical neuron | SARS-CoV-2 preferably targets cortical neurons of brain organoids and causes aberrant Tau localization and neuronal death | qRT-PCR; immunofluorescence; ELISA | Neuronal cell marker TUJ1 | Ramani et al., 2020 [108] |
| hPSC-derived cells and organoids | Dopaminergic neurons | Dopaminergic neurons, but not cortical neurons or microglia, were permissive to SARS-CoV-2 infection | qRT-PCR; immunofluorescence; single-cell RNA-seq | Dopaminergic neuronal marker FOXA2 and MAP2, cortical neuronal marker beta III-tubulin, microglial marker Iba1 | Yang et al., 2020 [110] |
| Human embryonic stem cell-derived monolayer cortical neurons and dorsal forebrain organoids | Cortical neuron | SARS-CoV-2 pseudovirus infects only 10% of cortical neurons | Immunofluorescence | Neuronal cell marker TUJ1 | Yi et al., 2020 [107] |
| hPSC-derived neurons, astrocytes, and brain organoids | Neurons and astrocytes | SARS-CoV-2 infects hiPSC-derived neurons, astrocytes, and brain organoids; an increased rate of SARS-CoV-2 infection in ApoE4 neurons and astrocytes | qRT-PCR; immunofluorescence | Neuronal cell marker TUJ1 and MAP2; astrocyte marker SOX9 and GFAP | Wang et al., 2021 [97] |
| hPSC-derived neural progenitor cells, neurons, astrocytes, and cerebral organoids | Neurons and astrocytes | SARS-CoV-2 infects human cerebral organoids; SARS-CoV-2 infects neurons more efficiently than neural progenitor cells and astrocytes | qRT-PCR; immunofluorescence | Neuronal marker MAP2 and β-tubulin-III; astrocyte marker GFAP | Tiwari et al., 2021 [109] |
| hPSC-derived cortical organoids | Astrocytes | SARS-CoV-2 infects astrocytes in both primary human cortical tissue and human stem cell-derived cortical organoids | Immunofluorescence | Astrocyte marker GFAP; neuronal marker NeuN | Andrews et al., 2021 [111] |
| hPSC-derived cortical organoid and pericyte containing cortical organoids | Pericyte-like cells and astrocytes | SARS-CoV-2 infects pericyte-like cells and astrocytes | qRT-PCR, immunofluorescence, single-cell RNA-seq | Pericyte markers (NG2 and PDGFR-β) | Wang et al., 2021 [102] |
| hPSC-derived neural cultures | Neurons | SARS-CoV-2 does not replicate and only infects a minority of individual mature neurons but induces the production of type III interferons and interleukin-8 | Immunofluorescence | Neuronal marker (MAP2), astrocyte marker (GFAP), neural progenitor cell marker (SOX2) | Bauer et al., 2021 [103] |
| Human embryonic stem cell-derived cortical organoids | Neurons, astrocytes, choroid plexus cells | SARS-CoV-2 only minimally infected neurons, but preferentially infected astrocytes and choroid plexus cells | Immunofluorescence | Neuronal markers (DCX and MAP2), choroid plexus marker (5-HT2C), astrocytic marker (GFAP and ALDH1L1) | McMahon et al., 2021 [100] |
| Deer mouse model of SARS-CoV-2 infection | Neurons and microglia | The presence of SARS-CoV-2 in neurons and microglia of the afferent nerves (trigeminal nerve) and in the glomerular layer of the olfactory bulb | Immunofluorescence; ELISA | Neuronal marker MAP2, microglial marker Iba1 | Fagre et al., 2021 [131] |
| Rhesus monkey model of SARS-CoV-2 infection | Neurons, astrocytes, microglia, olfactory bulb, olfactory trigone, entorhinal area, hippocampus, thalamus, medulla oblongata, frontal lobe, occipital lobe | Intracranial inoculation with SARS-CoV-2 caused the distribution of viral antigen nucleoprotein in neurons, astrocytes, and microglial cells in multiple brain regions | qRT-PCR, immunofluorescence, single-cell RNA-seq | Neuronal marker (NeuN), astrocytic marker (GFAP_, microglial marker (Iba1) | Jiao et al., 2021 [132] |
| Brain autopsy samples of deceased COVID-19 patients | Neurons and cerebral vascular endothelial cells; medulla oblongata and cerebellum | the presence of SARS-CoV-2 RNA and protein in medulla oblongata and cerebellum; the presence of SARS-CoV-2 protein in the olfactory mucosa and its nervous tissues; the presence of SARS-CoV S protein in the endothelial cells of small brain vessels | qRT-PCR; electron microscopy; immunofluorescence | Neuronal marker TUJ1, NF200, and OMP | Meinhardt et al., 2020 [133] |
| Brain autopsy samples of deceased COVID-19 patients | Medulla oblongata and cranial nerves | The presence of SARS-CoV-2 viral proteins in cranial nerves originating from the lower brainstem and in isolated cells of the medulla oblongata | qRT-PCR; immunohistochemistry | — | Matschke et al., 2020 [134] |
hPSC human pluripotent stem cells, CSF cerebrospinal fluid, TuJ1 class III β-tubulin, GFAP glial fibrillary acidic protein, MAP2 microtubule-associated protein 2, Iba1 ionized calcium-binding adaptor molecule 1, NF200 neurofilament 200, OMP olfactory membrane protein.