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1.
J Neurol Neurosurg Psychiatry ; 93(12): 1343-1348, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2038335

ABSTRACT

BACKGROUND: To assess whether SARS-CoV-2 infection may affect the central nervous system, specifically neurons and glia cells, even without clinical neurological involvement. METHODS: In this single centre prospective study, serum levels of neurofilament light chain (sNfL) and glial fibrillar acidic protein (sGFAp) were assessed using SimoaTM assay Neurology 2-Plex B Assay Kit, in 148 hospitalised patients with COVID-19 without clinical neurological manifestations and compared them to 53 patients with interstitial pulmonary fibrosis (IPF) and 108 healthy controls (HCs). RESULTS: Age and sex-corrected sNfL levels were higher in patients with COVID-19 (median log10-sNfL 1.41; IQR 1.04-1.83) than patients with IPF (median log10-sNfL 1.18; IQR 0.98-1.38; p<0.001) and HCs (median log10-sNfL 0.89; IQR 0.72-1.14; p<0.001). Likewise, age and sex-corrected sGFAP levels were higher in patients with COVID-19 (median log10-sGFAP 2.26; IQR 2.02-2.53) in comparison with patients with IPF (median log10-sGFAP 2.15; IQR 1.94-2.30; p<0.001) and HCs (median log10-sGFAP 1.87; IQR 0.64-2.09; p<0.001). No significant difference was found between patients with HCs and IPF (p=0.388 for sNfL and p=0.251 for sGFAp). In patients with COVID-19, a prognostic model with mortality as dependent variable (26/148 patients died during hospitalisation) and sNfl, sGFAp and age as independent variables, showed an area under curve of 0.72 (95% CI 0.59 to 0.84; negative predictive value (NPV) (%):80,positive predictive value (PPV)(%): 84; p=0.0008). CONCLUSION: The results of our study suggest that neuronal and glial degeneration can occur in patients with COVID-19 regardless of overt clinical neurological manifestations. With age, levels of sNfl and GFAp can predict in-hospital COVID-19-associated mortality and might be useful to assess COVID-19 patient prognostic profile.


Subject(s)
Brain , COVID-19 , Neuroglia , Neurons , Humans , Biomarkers/blood , Brain/pathology , Brain/virology , COVID-19/mortality , COVID-19/pathology , Neurofilament Proteins/blood , Neuroglia/pathology , Neuroglia/virology , Neurons/pathology , Neurons/virology , Prospective Studies , SARS-CoV-2 , Male , Female , Prognosis
2.
Proc Natl Acad Sci U S A ; 119(35): e2200960119, 2022 08 30.
Article in English | MEDLINE | ID: covidwho-1991765

ABSTRACT

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.


Subject(s)
Brain , COVID-19 , Central Nervous System Viral Diseases , SARS-CoV-2 , Astrocytes/pathology , Astrocytes/virology , Brain/pathology , Brain/virology , COVID-19/complications , COVID-19/pathology , Central Nervous System Viral Diseases/etiology , Central Nervous System Viral Diseases/pathology , Humans
3.
J Mol Biol ; 434(3): 167243, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1851574

ABSTRACT

Brain organoids are self-organized three-dimensional aggregates generated from pluripotent stem cells. They exhibit complex cell diversities and organized architectures that resemble human brain development ranging from neural tube formation, neuroepithelium differentiation, neurogenesis and gliogenesis, to neural circuit formation. Rapid advancements in brain organoid culture technologies have allowed researchers to generate more accurate models of human brain development and neurological diseases. These models also allow for direct investigation of pathological processes associated with infectious diseases affecting the nervous system. In this review, we first briefly summarize recent advancements in brain organoid methodologies and neurodevelopmental processes that can be effectively modeled by brain organoids. We then focus on applications of brain organoids to investigate the pathogenesis of neurotropic viral infection. Finally, we discuss limitations of the current brain organoid methodologies as well as applications of other organ specific organoids in the infectious disease research.


Subject(s)
Brain , Central Nervous System Viral Diseases , Organoids , Brain/growth & development , Brain/virology , Central Nervous System Viral Diseases/virology , Humans , Neurogenesis , Organoids/virology
4.
Nature ; 604(7907): 633-634, 2022 04.
Article in English | MEDLINE | ID: covidwho-1735207
5.
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
6.
Nature ; 604(7907): 697-707, 2022 04.
Article in English | MEDLINE | ID: covidwho-1730297

ABSTRACT

There is strong evidence of brain-related abnormalities in COVID-191-13. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.


Subject(s)
Brain , COVID-19 , Aged , Aged, 80 and over , Biological Specimen Banks , Brain/diagnostic imaging , Brain/virology , COVID-19/pathology , Humans , Magnetic Resonance Imaging , Middle Aged , SARS-CoV-2 , Smell , United Kingdom/epidemiology
8.
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
9.
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
10.
EMBO Rep ; 23(1): e54342, 2022 01 05.
Article in English | MEDLINE | ID: covidwho-1543022

ABSTRACT

Various viruses can affect the brain directly or indirectly. The specter of Long COVID has focused research on how respiratory viruses can cause infection and inflammation of brain cells.


Subject(s)
Brain/virology , COVID-19 , COVID-19/complications , Humans , SARS-CoV-2
11.
Signal Transduct Target Ther ; 6(1): 406, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1532031

ABSTRACT

Currently, SARS-CoV-2 has caused a global pandemic and threatened many lives. Although SARS-CoV-2 mainly causes respiratory diseases, growing data indicate that SARS-CoV-2 can also invade the central nervous system (CNS) and peripheral nervous system (PNS) causing multiple neurological diseases, such as encephalitis, encephalopathy, Guillain-Barré syndrome, meningitis, and skeletal muscular symptoms. Despite the increasing incidences of clinical neurological complications of SARS-CoV-2, the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established. In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.


Subject(s)
Brain , COVID-19 , Nervous System Diseases , SARS-CoV-2/metabolism , Brain/metabolism , Brain/pathology , Brain/virology , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , Humans , Nervous System Diseases/etiology , Nervous System Diseases/metabolism , Nervous System Diseases/pathology , Nervous System Diseases/virology
12.
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
13.
Viruses ; 13(11)2021 11 11.
Article in English | MEDLINE | ID: covidwho-1512701

ABSTRACT

Small animal models are of crucial importance for assessing COVID-19 countermeasures. Common laboratory mice would be well-suited for this purpose but are not susceptible to infection with wild-type SARS-CoV-2. However, the development of mouse-adapted virus strains has revealed key mutations in the SARS-CoV-2 spike protein that increase infectivity, and interestingly, many of these mutations are also present in naturally occurring SARS-CoV-2 variants of concern. This suggests that these variants might have the ability to infect common laboratory mice. Herein we show that the SARS-CoV-2 beta variant attains infectibility to BALB/c mice and causes pulmonary changes within 2-3 days post infection, consistent with results seen in other murine models of COVID-19, at a reasonable virus dose (2 × 105 PFU). The findings suggest that common laboratory mice can serve as the animal model of choice for testing the effectiveness of antiviral drugs and vaccines against SARS-CoV-2.


Subject(s)
COVID-19/virology , Disease Models, Animal , SARS-CoV-2 , Animals , Brain/virology , COVID-19/pathology , Female , Inflammation , Lung/pathology , Lung/virology , Male , Mice, Inbred BALB C , Nose/virology , Pulmonary Alveoli/pathology , SARS-CoV-2/isolation & purification
14.
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
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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