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1.
Lancet Neurol ; 20(9): 753-761, 2021 09.
Article in English | MEDLINE | ID: covidwho-1599333

ABSTRACT

BACKGROUND: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. RECENT DEVELOPMENTS: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.


Subject(s)
COVID-19/complications , COVID-19/diagnostic imaging , Olfaction Disorders/diagnostic imaging , Olfaction Disorders/etiology , Olfactory Mucosa/diagnostic imaging , Brain/diagnostic imaging , Brain/physiopathology , Brain/virology , COVID-19/physiopathology , Humans , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/physiopathology , Olfaction Disorders/physiopathology , Olfaction Disorders/virology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Prospective Studies , Smell/physiology
2.
Int J Mol Sci ; 22(24)2021 Dec 19.
Article in English | MEDLINE | ID: covidwho-1580688

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the pandemic Coronavirus Disease 19 (COVID-19), causing millions of deaths. The elderly and those already living with comorbidity are likely to die after SARS-CoV-2 infection. People suffering from Alzheimer's disease (AD) have a higher risk of becoming infected, because they cannot easily follow health roles. Additionally, those suffering from dementia have a 40% higher risk of dying from COVID-19. Herein, we collected from Gene Expression Omnibus repository the brain samples of AD patients who died of COVID-19 (AD+COVID-19), AD without COVID-19 (AD), COVID-19 without AD (COVID-19) and control individuals. We inspected the transcriptomic and interactomic profiles by comparing the COVID-19 cohort against the control cohort and the AD cohort against the AD+COVID-19 cohort. SARS-CoV-2 in patients without AD mainly activated processes related to immune response and cell cycle. Conversely, 21 key nodes in the interactome are deregulated in AD. Interestingly, some of them are linked to beta-amyloid production and clearance. Thus, we inspected their role, along with their interactors, using the gene ontologies of the biological process that reveals their contribution in brain organization, immune response, oxidative stress and viral replication. We conclude that SARS-CoV-2 worsens the AD condition by increasing neurotoxicity, due to higher levels of beta-amyloid, inflammation and oxidative stress.


Subject(s)
Alzheimer Disease/genetics , COVID-19/complications , COVID-19/genetics , Alzheimer Disease/complications , Alzheimer Disease/virology , Amyloid beta-Peptides/metabolism , Brain/virology , COVID-19/physiopathology , Comorbidity/trends , Databases, Factual , Gene Expression/genetics , Gene Expression Profiling/methods , Humans , Inflammation/metabolism , Neurotoxicity Syndromes/metabolism , Oxidative Stress/physiology , Pandemics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Transcriptome/genetics
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 Gen Virol ; 102(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1490495

ABSTRACT

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Subject(s)
Brain/pathology , Complement System Proteins/immunology , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/immunology , Brain/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Humans , Inflammation , Mice , Mice, Transgenic , Microglia/immunology , Microglia/pathology
5.
Int J Mol Sci ; 22(21)2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1488609

ABSTRACT

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRß in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain/virology , COVID-19/physiopathology , Encephalitis, Viral/virology , Pericytes/virology , Angiotensin-Converting Enzyme 2/genetics , Animals , Blood-Brain Barrier , Brain/pathology , COVID-19/etiology , Case-Control Studies , Encephalitis, Viral/pathology , Fibrinogen/metabolism , Humans , Immunohistochemistry/methods , Mice , Pericytes/metabolism , Pericytes/pathology , Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid
6.
Int J Mol Sci ; 22(14)2021 Jul 06.
Article in English | MEDLINE | ID: covidwho-1485149

ABSTRACT

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer's disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.


Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/virology , Brain/pathology , Brain/virology , Endogenous Retroviruses/pathogenicity , Virus Diseases/pathology , Virus Diseases/virology , Animals , Cognition Disorders/pathology , Cognition Disorders/virology , Encephalitis/pathology , Encephalitis/virology , Humans
7.
Viruses ; 13(10)2021 10 08.
Article in English | MEDLINE | ID: covidwho-1463838

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people's lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood-brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/pathology , COVID-19/pathology , Endothelial Cells/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Brain/metabolism , Brain/virology , Endothelial Cells/virology , Humans , Mice , Mitochondria/metabolism , Protein Domains , SARS-CoV-2/metabolism , rab5 GTP-Binding Proteins/metabolism
8.
J Virol ; 95(20): e0059221, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1440799

ABSTRACT

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to dramatic economic and health burdens. Although the worldwide SARS-CoV-2 vaccination campaign has begun, exploration of other vaccine candidates is needed due to uncertainties with the current approved vaccines, such as durability of protection, cross-protection against variant strains, and costs of long-term production and storage. In this study, we developed a methyltransferase-defective recombinant vesicular stomatitis virus (mtdVSV)-based SARS-CoV-2 vaccine candidate. We generated mtdVSVs expressing SARS-CoV-2 full-length spike (S) protein, S1, or its receptor-binding domain (RBD). All of these recombinant viruses grew to high titers in mammalian cells despite high attenuation in cell culture. The SARS-CoV-2 S protein and its truncations were highly expressed by the mtdVSV vector. These mtdVSV-based vaccine candidates were completely attenuated in both immunocompetent and immunocompromised mice. Among these constructs, mtdVSV-S induced high levels of SARS-CoV-2-specific neutralizing antibodies (NAbs) and Th1-biased T-cell immune responses in mice. In Syrian golden hamsters, the serum levels of SARS-CoV-2-specific NAbs triggered by mtdVSV-S were higher than the levels of NAbs in convalescent plasma from recovered COVID-19 patients. In addition, hamsters immunized with mtdVSV-S were completely protected against SARS-CoV-2 replication in lung and nasal turbinate tissues, cytokine storm, and lung pathology. Collectively, our data demonstrate that mtdVSV expressing SARS-CoV-2 S protein is a safe and highly efficacious vaccine candidate against SARS-CoV-2 infection. IMPORTANCE Viral mRNA cap methyltransferase (MTase) is essential for mRNA stability, protein translation, and innate immune evasion. Thus, viral mRNA cap MTase activity is an excellent target for development of live attenuated or live vectored vaccine candidates. Here, we developed a panel of MTase-defective recombinant vesicular stomatitis virus (mtdVSV)-based SARS-CoV-2 vaccine candidates expressing full-length S, S1, or several versions of the RBD. These mtdVSV-based vaccine candidates grew to high titers in cell culture and were completely attenuated in both immunocompetent and immunocompromised mice. Among these vaccine candidates, mtdVSV-S induces high levels of SARS-CoV-2-specific neutralizing antibodies (Nabs) and Th1-biased immune responses in mice. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2-specific NAbs at higher levels than those in convalescent plasma from recovered COVID-19 patients. Furthermore, hamsters immunized with mtdVSV-S were completely protected against SARS-CoV-2 challenge. Thus, mtdVSV is a safe and highly effective vector to deliver SARS-CoV-2 vaccine.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Vesicular stomatitis Indiana virus/genetics , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Brain/virology , COVID-19/immunology , Cell Line , Cytokine Release Syndrome/prevention & control , DNA-Directed RNA Polymerases/genetics , DNA-Directed RNA Polymerases/metabolism , Humans , Immunogenicity, Vaccine , Lung/immunology , Lung/pathology , Lung/virology , Mesocricetus , Methyltransferases/genetics , Methyltransferases/metabolism , Mice , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Vaccines, Synthetic/immunology , Vesicular stomatitis Indiana virus/enzymology , Vesicular stomatitis Indiana virus/physiology , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Replication
9.
Front Immunol ; 12: 729776, 2021.
Article in English | MEDLINE | ID: covidwho-1403478

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus that has spread rapidly around the world, leading to high mortality because of multiple organ dysfunction; however, its underlying molecular mechanism is unknown. To determine the molecular mechanism of multiple organ dysfunction, a bioinformatics analysis method based on a time-order gene co-expression network (TO-GCN) was performed. First, gene expression profiles were downloaded from the gene expression omnibus database (GSE161200), and a TO-GCN was constructed using the breadth-first search (BFS) algorithm to infer the pattern of changes in the different organs over time. Second, Gene Ontology enrichment analysis was used to analyze the main biological processes related to COVID-19. The initial gene modules for the immune response of different organs were defined as the research object. The STRING database was used to construct a protein-protein interaction network of immune genes in different organs. The PageRank algorithm was used to identify five hub genes in each organ. Finally, the Comparative Toxicogenomics Database played an important role in exploring the potential compounds that target the hub genes. The results showed that there were two types of biological processes: the body's stress response and cell-mediated immune response involving the lung, trachea, and olfactory bulb (olf) after being infected by COVID-19. However, a unique biological process related to the stress response is the regulation of neuronal signals in the brain. The stress response was heterogeneous among different organs. In the lung, the regulation of DNA morphology, angiogenesis, and mitochondrial-related energy metabolism are specific biological processes related to the stress response. In particular, an effect on tracheal stress response was made by the regulation of protein metabolism and rRNA metabolism-related biological processes, as biological processes. In the olf, the distinctive stress responses consist of neural signal transmission and brain behavior. In addition, myeloid leukocyte activation and myeloid leukocyte-mediated immunity in response to COVID-19 can lead to a cytokine storm. Immune genes such as SRC, RHOA, CD40LG, CSF1, TNFRSF1A, FCER1G, ICAM1, LAT, LCN2, PLAU, CXCL10, ICAM1, CD40, IRF7, and B2M were predicted to be the hub genes in the cytokine storm. Furthermore, we inferred that resveratrol, acetaminophen, dexamethasone, estradiol, statins, curcumin, and other compounds are potential target drugs in the treatment of COVID-19.


Subject(s)
COVID-19/complications , Multiple Organ Failure/genetics , Antiviral Agents/therapeutic use , Brain/metabolism , Brain/virology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Gene Expression Profiling , Gene Ontology , Humans , Lung/metabolism , Lung/virology , Multiple Organ Failure/drug therapy , Multiple Organ Failure/etiology , Multiple Organ Failure/metabolism , Olfactory Bulb/metabolism , Olfactory Bulb/virology , Protein Interaction Maps , SARS-CoV-2/physiology , Trachea/metabolism , Trachea/virology , Transcriptome
10.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390541

ABSTRACT

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.


Subject(s)
COVID-19/pathology , Cerebral Cortex/pathology , Aged , Aged, 80 and over , Autopsy , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , CD8-Positive T-Lymphocytes/pathology , Cerebral Cortex/virology , Female , Humans , Inflammation , Macrophages/pathology , Male , Microvessels/pathology , Microvessels/virology , Middle Aged , Nervous System Diseases/pathology , Nervous System Diseases/virology , SARS-CoV-2/pathogenicity
11.
Cells ; 10(7)2021 07 20.
Article in English | MEDLINE | ID: covidwho-1389305

ABSTRACT

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Subject(s)
Aging , Brain/physiopathology , Inflammation/physiopathology , Microglia/virology , Virus Diseases/physiopathology , Animals , Brain/immunology , Brain/virology , COVID-19/immunology , COVID-19/physiopathology , COVID-19/virology , Humans , Inflammation/immunology , Inflammation/virology , Microglia/immunology , Microglia/pathology , SARS-CoV-2/physiology , Virus Diseases/immunology , Virus Diseases/virology
14.
Cell Rep ; 36(10): 109664, 2021 09 07.
Article in English | MEDLINE | ID: covidwho-1375910

ABSTRACT

SARS-CoV-2 infection causes respiratory insufficiency and neurological manifestations, including loss of smell and psychiatric disorders, and can be fatal. Most vaccines are based on the spike antigen alone, and although they have shown efficacy at preventing severe disease and death, they do not always confer sterilizing immunity. Here, we interrogate whether SARS-CoV-2 vaccines could be improved by incorporating nucleocapsid as an antigen. We show that, after 72 h of challenge, a spike-based vaccine confers acute protection in the lung, but not in the brain. However, combining a spike-based vaccine with a nucleocapsid-based vaccine confers acute protection in both the lung and brain. These findings suggest that nucleocapsid-specific immunity can improve the distal control of SARS-CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.


Subject(s)
COVID-19 Vaccines/immunology , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Brain/drug effects , Brain/virology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Humans , Immunogenicity, Vaccine , Lung/drug effects , Lung/virology , Mice , Phosphoproteins/immunology , Viral Load/drug effects
15.
Viruses ; 13(8)2021 08 20.
Article in English | MEDLINE | ID: covidwho-1367923

ABSTRACT

Strategies to combat COVID-19 require multiple ways to protect vulnerable people from infection. SARS-CoV-2 is an airborne pathogen and the nasal cavity is a primary target of infection. The K18-hACE2 mouse model was used to investigate the anti-SARS-CoV-2 efficacy of astodrimer sodium formulated in a mucoadhesive nasal spray. Animals received astodrimer sodium 1% nasal spray or PBS intranasally, or intranasally and intratracheally, for 7 days, and they were infected intranasally with SARS-CoV-2 after the first product administration on Day 0. Another group was infected intranasally with SARS-CoV-2 that had been pre-incubated with astodrimer sodium 1% nasal spray or PBS for 60 min before the neutralisation of test product activity. Astodrimer sodium 1% significantly reduced the viral genome copies (>99.9%) and the infectious virus (~95%) in the lung and trachea vs. PBS. The pre-incubation of SARS-CoV-2 with astodrimer sodium 1% resulted in a significant reduction in the viral genome copies (>99.9%) and the infectious virus (>99%) in the lung and trachea, and the infectious virus was not detected in the brain or liver. Astodrimer sodium 1% resulted in a significant reduction of viral genome copies in nasal secretions vs. PBS on Day 7 post-infection. A reduction in the viral shedding from the nasal cavity may result in lower virus transmission rates. Viraemia was low or undetectable in animals treated with astodrimer sodium 1% or infected with treated virus, correlating with the lack of detectable viral replication in the liver. Similarly, low virus replication in the nasal cavity after treatment with astodrimer sodium 1% potentially protected the brain from infection. Astodrimer sodium 1% significantly reduced the pro-inflammatory cytokines IL-6, IL-1α, IL-1ß, TNFα and TGFß and the chemokine MCP-1 in the serum, lung and trachea vs. PBS. Astodrimer sodium 1% nasal spray blocked or reduced SARS-CoV-2 replication and its sequelae in K18-hACE2 mice. These data indicate a potential role for the product in preventing SARS-CoV-2 infection or for reducing the severity of COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Dendrimers/administration & dosage , Nasal Cavity/virology , Nasal Sprays , Polylysine/administration & dosage , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/therapeutic use , Brain/virology , COVID-19/prevention & control , COVID-19/virology , Dendrimers/therapeutic use , Disease Models, Animal , Female , Liver/virology , Male , Mice , Mice, Transgenic , Polylysine/therapeutic use , Respiratory System/virology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Viral Load/drug effects , Viremia , Virus Replication/drug effects
16.
Immunity ; 54(9): 2143-2158.e15, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1364125

ABSTRACT

Neutralizing antibodies (NAbs) are effective in treating COVID-19, but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment during prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. Real-time imaging revealed that the virus spread sequentially from the nasal cavity to the lungs in mice and thereafter systemically to various organs including the brain, culminating in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days. In addition to direct neutralization, depletion studies indicated that Fc effector interactions of NAbs with monocytes, neutrophils, and natural killer cells were required to effectively dampen inflammatory responses and limit immunopathology. Our study highlights that both Fab and Fc effector functions of NAbs are essential for optimal in vivo efficacy against SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Brain/pathology , COVID-19/immunology , Lung/pathology , SARS-CoV-2/physiology , Testis/pathology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Neutralizing/genetics , Antibodies, Viral/genetics , Brain/virology , COVID-19/therapy , Cells, Cultured , Disease Models, Animal , Humans , Immunoglobulin Fc Fragments/genetics , Luciferases/genetics , Luminescent Measurements , Lung/virology , Male , Mice , Mice, Transgenic , Testis/virology
17.
Front Immunol ; 12: 697329, 2021.
Article in English | MEDLINE | ID: covidwho-1357529

ABSTRACT

Various neurological symptoms have been associated to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection including headache, fever, anosmia, ageusia, but also, encephalitis, Guillain-Barre syndrome and ischemic stroke. Responsible for the current coronavirus disease (COVID-19) pandemic, SARS-CoV-2 may access and affect the central nervous system (CNS) by several pathways such as axonal retrograde transport or through interaction with the blood-brain barrier (BBB) or blood-cerebrospinal fluid (CSF) barrier. Here, we explored the molecular and cellular effects of direct SARS-CoV-2 infection of human BBB cells. We observed low replication of SARS-CoV-2 that was accompanied by very moderate inflammatory response. Using a human in vitro BBB model, we also described low replication levels without strong inflammatory response or modulation of endothelium integrity. Finally, using serum samples from COVID-19 patients, we highlighted strong concentrations of pro-inflammatory factors that did not perturb BBB integrity after short term exposure. Altogether, our results show that the main mechanism of brain access following SARS-CoV-2 infection does not seem to be directed by brain infection through endothelial cells.


Subject(s)
Blood-Brain Barrier/virology , Brain/virology , Endothelial Cells/virology , SARS-CoV-2/growth & development , Virus Replication/physiology , Animals , COVID-19/pathology , Cell Line, Tumor , Chlorocebus aethiops , Humans , Vero Cells
18.
Brain Pathol ; 31(6): e13013, 2021 11.
Article in English | MEDLINE | ID: covidwho-1354468

ABSTRACT

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the new coronavirus responsible for the pandemic disease in the last year, is able to affect the central nervous system (CNS). Compared with its well-known pulmonary tropism and respiratory complications, little has been studied about SARS-CoV-2 neurotropism and pathogenesis of its neurological manifestations, but also about postmortem histopathological findings in the CNS of patients who died from COVID-19 (coronavirus disease 2019). We present a systematic review, carried out according to the Preferred Reporting Items for Systematic Review standards, of the neuropathological features of COVID-19. We found 21 scientific papers, the majority of which refer to postmortem examinations; the total amount of cases is 197. Hypoxic changes are the most frequently reported alteration of brain tissue, followed by ischemic and hemorrhagic lesions and reactive astrogliosis and microgliosis. These findings do not seem to be specific to SARS-CoV-2 infection, they are more likely because of systemic inflammation and coagulopathy caused by COVID-19. More studies are needed to confirm this hypothesis and to detect other possible alterations of neural tissue. Brain examination of patients dead from COVID-19 should be included in a protocol of standardized criteria to perform autopsies on these subjects.


Subject(s)
Brain/physiology , Brain/virology , COVID-19/pathology , Nervous System Diseases/virology , SARS-CoV-2/metabolism , Brain/physiopathology , COVID-19/metabolism , COVID-19/virology , Central Nervous System/physiology , Central Nervous System/virology , Humans , Inflammation/pathology , Inflammation/virology , Nervous System Diseases/etiology , Nervous System Diseases/pathology , Pandemics
19.
J Chem Neuroanat ; 117: 102006, 2021 11.
Article in English | MEDLINE | ID: covidwho-1330944

ABSTRACT

Nowadays, Covid-19 is considered a serious health problem worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). It is well known that the Corona Virus attacks mainly the respiratory system. Meanwhile, it has been established that coronavirus infection can extend beyond the respiratory system and unfortunately, can also affect our nervous system. Multiple neurological symptoms and signs had been documented during and post covid conditions. This virus gets access to the central nervous system (CNS) via the bloodstream leading to infect the endothelial lining cells. Also, it was reported that the virus can enter the peripheral nervous system via retrograde neuronal routes. The virus could be internalized in nerve synapses through endocytosis, transported retrogradely, and spread trans-synoptically to other brain regions. This minireview highlights the possible routes by which SARS-CoV-2 can invade the central nervous system (CNS) and its pathophysiology and manifestation.


Subject(s)
Brain/physiopathology , COVID-19/physiopathology , Central Nervous System Viral Diseases/physiopathology , SARS-CoV-2/physiology , Animals , Brain/virology , COVID-19/complications , COVID-19/epidemiology , Central Nervous System/physiopathology , Central Nervous System/virology , Central Nervous System Viral Diseases/etiology , Humans , SARS-CoV-2/isolation & purification
20.
Science ; 373(6551): 231-236, 2021 07 09.
Article in English | MEDLINE | ID: covidwho-1304152

ABSTRACT

In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells.


Subject(s)
DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , RNA Interference , RNA Viruses/physiology , RNA, Viral/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Stem Cells/enzymology , Stem Cells/virology , Alternative Splicing , Animals , Brain/enzymology , Brain/virology , Cell Line , DEAD-box RNA Helicases/chemistry , Humans , Immunity, Innate , Isoenzymes/chemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Mice , Organoids/enzymology , Organoids/virology , RNA Virus Infections/enzymology , RNA Virus Infections/immunology , RNA Virus Infections/virology , RNA Viruses/genetics , RNA Viruses/immunology , RNA, Double-Stranded/metabolism , RNA, Small Interfering/metabolism , Ribonuclease III/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Virus Replication , Zika Virus/genetics , Zika Virus/immunology , Zika Virus/physiology , Zika Virus Infection/enzymology , Zika Virus Infection/immunology , Zika Virus Infection/virology
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