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The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys.

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.

SUBMITTER: Jiao L

PROVIDER: S-EPMC8065334 | biostudies-literature |

REPOSITORIES: biostudies-literature

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SARS-CoV-2 Invades the Central Nervous System via the Olfactory Route in Rhesus Monkeys

Project description:Purpose: Neurological manifestations are frequently reported in the Coronavirus Disease 2019 (COVID-19) patients. However, the neuroinvasion mechanism of SARS-CoV-2 remains to be determined. In this study, we explored the neuroinvasion of SARS-CoV-2 via our established non-human primate (NHP) model of COVID-19. Single-cell sequencing was conducted to comprehensively determine effects of SARS-CoV-2 infection on the CNS in consideration of the its cellular heterogeneity. Methods: Rhesus monkeys (3-5 kg, 3-5years old) were used for this study. One monkey were intranasally infected with 1x 10^7 PFU of SARS-CoV-2 in 1mL of PBS, and another monkey was intracranially injected with 1x10^6 of SARS-CoV-2 in 200 µl of PBS. One monkey was intranasally and intracranially treated with PBS as a control. We analyzed the tissues collected on the 4 dpi and 7dpi following intranasal inoculation and on the 9 dpi following intracranial inoculation. Two thousand cells were used to create 5 different clusters, including microglia, mature neurons, oligodendrocytes, endothelial vascular cells, and astrocytes. Single-cell sequencing of were sequenced by an Illumina Novaseq6000 sequencer, the sequencing depth of each cell was at least 100,000 reads, and the paired-end 150 bp (PE150) reading strategy was adopted. Results and Conclusions: Single-cell sequencing data showed that mitochondrial-related genes ND3, ATP6 and COX3 were down-regulated in mature neurons, oligodendrocytes, endothelial vascular cells and microglia in the hippocampus, primary olfactory cortex, and cerebral cortex infected with SARS-CoV-2.

2021-04-14 | GSE167319 | GEO

SARS-CoV-2 Invades the Central Nervous System via the Olfactory Route in Rhesus Monkeys

Project description:SARS-CoV-2 Invades the Central Nervous System via the Olfactory Route in Rhesus Monkeys

| PRJNA704283 | ENA

Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys.

Project description:Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. ZIKV-specific neutralizing antibodies correlated with rapid clearance of virus in peripheral blood but remained undetectable in CSF for the duration of the study. Viral persistence in both CSF and LN correlated with upregulation of mechanistic target of rapamycin (mTOR), proinflammatory, and anti-apoptotic signaling pathways, as well as downregulation of extracellular matrix signaling pathways. These data raise the possibility that persistent or occult neurologic and lymphoid disease may occur following clearance of peripheral virus in ZIKV-infected individuals.

| S-EPMC5426912 | biostudies-literature

Rapid Nipah virus entry into the central nervous system of hamsters via the olfactory route.

Project description:Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication.

| S-EPMC3471094 | biostudies-literature

Leukaemia hijacks a neural mechanism to invade the central nervous system.

Project description:Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

| S-EPMC10257142 | biostudies-literature

Leukemia hijacks a neural mechanism to invade the central nervous system

Project description:Acute lymphoblastic leukemia (ALL) has a striking propensity to metastasize to the central nervous system (CNS).1 In contrast to solid tumor brain metastases, ALL seldom involves the parenchyma but is isolated to the leptomeninges, an infrequent site for carcinomatous invasion.2,3 While CNS metastasis is characteristic across ALL subtypes, a unifying mechanism for invasion has not been determined. Here we show that ALL cells in circulation are unable to breach the blood brain barrier; instead they migrate into the CNS along vessels that passage directly between vertebral or calvarial bone marrow (BM) and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, known to coordinate neuronal progenitor cell pathfinding in the CNS.4-6 The laminin receptor a6 integrin is expressed by most ALL.7,8 We found that a6/laminin mediated ALL migration toward cerebrospinal fluid (CSF) in vitro. ALL-xenografted mice treated with either a PI3Kd inhibitor that decreased ALL a6 expression or specific a6 neutralizing antibodies showed significantly less ALL transit along bridging vessels, CSF blast counts and CNS disease symptoms despite minimally decreased BM disease burden. Our data suggest that a6 integrin expression, common in ALL, allows cells to coopt neural migratory pathways to invade the CNS.

2018-07-12 | GSE114627 | GEO

Olfactory bulb SARS-CoV-2 infection is not paralleled by the presence of virus in other central nervous system areas.

Project description: Not available

| S-EPMC8447476 | biostudies-literature

Enterovirus-A71 exploits peripherin and Rac1 to invade the central nervous system.

Project description:Enterovirus-A71 (EV-A71) has been associated with severe neurological forms of hand, foot, and mouth disease (HFMD). EV-A71 infects motor neurons at neuromuscular junctions (NMJs) to invade the central nervous system (CNS). Here, we investigate the role of peripherin (PRPH) during EV-A71 infection, a type III intermediate neurofilament involved in neurodegenerative conditions. In mice infected with EV-A71, PRPH co-localizes with viral particles in the muscles at NMJs and in the spinal cord. In motor neuron-like and neuroblastoma cell lines, surface-expressed PRPH facilitates viral entry, while intracellular PRPH influences viral genome replication through interactions with structural and non-structural viral components. Importantly, PRPH does not play a role during infection with coxsackievirus A16, another causative agent of HFMD rarely associated with neurological complications, suggesting that EV-A71 ability to exploit PRPH represents a unique attribute for successful CNS invasion. Finally, we show that EV-A71 also exploits some of the many PRPH-interacting partners. Of these, small GTP-binding protein Rac1 represents a potential druggable host target to limit neuroinvasion of EV-A71.

| S-EPMC8183415 | biostudies-literature

Enterovirus-A71 exploits peripherin and Rac1 to invade the central nervous system

Project description:Enterovirus-A71 (EV-A71) has been associated with severe neurological forms of Hand, Foot and Mouth Disease (HFMD). EV-A71 infects motorneurons at neuromuscular junctions (NMJs) to invade the central nervous system (CNS). Here, we investigate the role of peripherin (PRPH) during EV-A71 infection, a type III intermediate neurofilament involved in neurodegenerative conditions. In mice infected with EV-A71 PRPH co-localizes with viral particles in the muscles at NMJs, and in the spinal cord. In motor neuron-like and neuroblastoma cell lines, surface-expressed PRPH facilitates viral entry, while intracellular PRPH influences viral genome replication through interactions with structural and non-structural viral components. Importantly, PRPH does not play a role during infection with coxsackievirus A16, another causative agent of HFMD rarely associated with neurological complications; suggesting that EV-A71 ability to exploit PRPH represents a unique attribute for successful CNS invasion. Finally, we show that EV-A71 also exploits some of the many PRPH interacting partners. Of these, small GTP binding protein Rac1 represents a potential druggable host target to limit neuroinvasion of EV-A71. -

| S-SCDT-EMBOR-2020-51777-T | biostudies-other

<i>Chlamydia muridarum</i> Can Invade the Central Nervous System <i>via</i> the Olfactory and Trigeminal Nerves and Infect Peripheral Nerve Glial Cells.

Project description:Chlamydia pneumoniae can infect the brain and has been linked to late-onset dementia. Chlamydia muridarum, which infects mice, is often used to model human chlamydial infections. While it has been suggested to be also important for modelling brain infection, nervous system infection by C. muridarum has not been reported in the literature. C. pneumoniae has been shown to infect the olfactory bulb in mice after intranasal inoculation, and has therefore been suggested to invade the brain via the olfactory nerve; however, nerve infection has not been shown to date. Another path by which certain bacteria can reach the brain is via the trigeminal nerve, but it remains unknown whether Chlamydia species can infect this nerve. Other bacteria that can invade the brain via the olfactory and/or trigeminal nerve can do so rapidly, however, whether Chlamydia spp. can reach the brain earlier than one-week post inoculation remains unknown. In the current study, we showed that C. muridarum can within 48 h invade the brain via the olfactory nerve, in addition to infecting the trigeminal nerve. We also cultured the glial cells of the olfactory and trigeminal nerves and showed that C. muridarum readily infected the cells, constituting a possible cellular mechanism explaining how the bacteria can invade the nerves without being eliminated by glial immune functions. Further, we demonstrated that olfactory and trigeminal glia differed in their responses to C. muridarum, with olfactory glia showing less infection and stronger immune response than trigeminal glia.

| S-EPMC7819965 | biostudies-literature

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