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1.
Acta Neurol Scand ; 146(3): 225-236, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1886639

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than merely a respiratory disease, as it also presents with various neurological symptoms. SARS-CoV-2 may infect the central nervous system (CNS) and thus is neurotropic. However, the pathophysiological mechanism of coronavirus disease 2019 (COVID-19)-associated neuropathy remains unclear. Many studies have reported that SARS-CoV-2 enters the CNS through the hematogenous and neuronal routes, as well as through the main host neurological immune responses and cells involved in these responses. The neurological immune responses to COVID-19 and potential mechanisms of the extensive neuroinflammation induced by SARS-CoV-2 have been investigated. Although CNS infection with SARS-CoV-2 was shown to lead to neuronal impairment, certain aspects of this mechanism remain controversial and require further analysis. In this review, we discussed the pathway and mechanisms of SARS-CoV-2 invasion in the CNS, and associated clinical manifestations, such as anosmia, headache, and hyposmia. Moreover, the mechanism of neurological damage caused by SARS-CoV-2 may provide potential treatment methods for patients presenting with SARS-CoV-2-associated neuropathy.


Subject(s)
COVID-19 , Nervous System Diseases , COVID-19/complications , Central Nervous System/metabolism , Humans , Nervous System Diseases/etiology , Peripheral Nervous System , SARS-CoV-2
2.
Cell Mol Biol Lett ; 27(1): 10, 2022 Feb 02.
Article in English | MEDLINE | ID: covidwho-1753103

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.


Subject(s)
COVID-19/drug therapy , Central Nervous System/drug effects , Inflammasomes/drug effects , Neurodegenerative Diseases/drug therapy , Receptors, Virus/genetics , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , Basigin/genetics , Basigin/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Central Nervous System/metabolism , Central Nervous System/virology , Ephrins/genetics , Ephrins/metabolism , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunologic Factors/therapeutic use , Inflammasomes/genetics , Inflammasomes/metabolism , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/metabolism , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/virology , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Purinergic P2X7/genetics , Receptors, Purinergic P2X7/metabolism , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction
3.
Geroscience ; 44(2): 547-565, 2022 04.
Article in English | MEDLINE | ID: covidwho-1681580

ABSTRACT

SARS-CoV-2 is a recently identified coronavirus that causes the current pandemic disease known as COVID-19. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, suggesting that the initial steps of SARS-CoV-2 infection may have an impact on the renin-angiotensin system (RAS). Several processes are influenced by RAS in the brain. The neurological symptoms observed in COVID-19 patients, including reduced olfaction, meningitis, ischemic stroke, cerebral thrombosis, and delirium, could be associated with RAS imbalance. In this review, we focus on the potential role of disturbances in the RAS as a cause for central nervous system sequelae of SARS-CoV-2 infection in elderly patients.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Central Nervous System/metabolism , Humans , Peptidyl-Dipeptidase A , Renin-Angiotensin System/physiology
4.
Int J Neuropsychopharmacol ; 25(1): 1-12, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1467332

ABSTRACT

From the earliest days of the coronavirus disease 2019 (COVID-19) pandemic, there have been reports of significant neurological and psychological symptoms following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This narrative review is designed to examine the potential psychoneuroendocrine pathogenic mechanisms by which SARS-CoV-2 elicits psychiatric sequelae as well as to posit potential pharmacologic strategies to address and reverse these pathologies. Following a brief overview of neurological and psychological sequelae from previous viral pandemics, we address mechanisms by which SARS-CoV-2 could enter or otherwise elicit changes in the CNS. We then examine the hypothesis that COVID-19-induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19-induced psychoneuroendocrine disorders.


Subject(s)
COVID-19/virology , Central Nervous System Viral Diseases/virology , Central Nervous System/virology , Neurosecretory Systems/virology , SARS-CoV-2/pathogenicity , Anti-Inflammatory Agents/therapeutic use , Antidepressive Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/psychology , Central Nervous System/drug effects , Central Nervous System/metabolism , Central Nervous System/physiopathology , Central Nervous System Viral Diseases/drug therapy , Central Nervous System Viral Diseases/physiopathology , Central Nervous System Viral Diseases/psychology , Host-Pathogen Interactions , Humans , Neuroimmunomodulation , Neurosecretory Systems/drug effects , Neurosecretory Systems/metabolism , Neurosecretory Systems/physiopathology , Prognosis , Risk Factors , Virus Internalization
5.
Cell Signal ; 87: 110121, 2021 11.
Article in English | MEDLINE | ID: covidwho-1370457

ABSTRACT

The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.


Subject(s)
COVID-19/pathology , Signal Transduction/physiology , Vitamin A/metabolism , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Central Nervous System/metabolism , DEAD Box Protein 58/metabolism , Humans , Immune Tolerance , Interferon Type I/metabolism , Receptors, Immunologic/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Viral Tropism/physiology , Vitamin A/blood
6.
Br J Anaesth ; 127(4): 648-659, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1329691

ABSTRACT

Mechanical ventilation induces a number of systemic responses for which the brain plays an essential role. During the last decade, substantial evidence has emerged showing that the brain modifies pulmonary responses to physical and biological stimuli by various mechanisms, including the modulation of neuroinflammatory reflexes and the onset of abnormal breathing patterns. Afferent signals and circulating factors from injured peripheral tissues, including the lung, can induce neuronal reprogramming, potentially contributing to neurocognitive dysfunction and psychological alterations seen in critically ill patients. These impairments are ubiquitous in the presence of positive pressure ventilation. This narrative review summarises current evidence of lung-brain crosstalk in patients receiving mechanical ventilation and describes the clinical implications of this crosstalk. Further, it proposes directions for future research ranging from identifying mechanisms of multiorgan failure to mitigating long-term sequelae after critical illness.


Subject(s)
Brain/metabolism , Lung Injury/physiopathology , Respiration, Artificial/methods , Animals , Central Nervous System/metabolism , Critical Illness , Humans , Multiple Organ Failure/physiopathology , Positive-Pressure Respiration/methods
7.
Inflammopharmacology ; 29(4): 1049-1059, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1303332

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the central nervous system and cause several neurological manifestations. Data from cerebrospinal fluid analyses and postmortem samples have been shown that SARS-CoV-2 has neuroinvasive properties. Therefore, ongoing studies have focused on mechanisms involved in neurotropism and neural injuries of SARS-CoV-2. The inflammasome is a part of the innate immune system that is responsible for the secretion and activation of several pro-inflammatory cytokines, such as interleukin-1ß, interleukin-6, and interleukin-18. Since cytokine storm has been known as a major mechanism followed by SARS-CoV-2, inflammasome may trigger an inflammatory form of lytic programmed cell death (pyroptosis) following SARS-CoV-2 infection and contribute to associated neurological complications. We reviewed and discussed the possible role of inflammasome and its consequence pyroptosis following coronavirus infections as potential mechanisms of neurotropism by SARS-CoV-2. Further studies, particularly postmortem analysis of brain samples obtained from COVID-19 patients, can shed light on the possible role of the inflammasome in neurotropism of SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Central Nervous System/metabolism , Inflammasomes/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Brain/immunology , Brain/metabolism , COVID-19/immunology , Central Nervous System/immunology , Humans , Inflammasomes/immunology , SARS-CoV-2/immunology
8.
Immunity ; 54(7): 1594-1610.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1281436

ABSTRACT

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Microglia/immunology , Blood-Brain Barrier/immunology , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain/metabolism , Brain/pathology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/pathology , Cell Communication , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Humans , Immune Checkpoint Proteins/metabolism , Inflammation , Lymphocyte Activation , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Olfactory Bulb/immunology , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
9.
Brain Behav Immun ; 91: 740-755, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064860

ABSTRACT

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes and microglia are the principal cells that mediate innate immunity in the CNS. Pattern recognition receptors (PRRs), expressed by astrocytes and microglia, sense pathogen-derived or endogenous ligands released by damaged cells and initiate the innate immune response. Toll-like receptors (TLRs) are a well-characterized family of PRRs. The contribution of microglial TLR signaling to CNS pathology has been extensively investigated. Even though astrocytes assume a wide variety of key functions, information about the role of astroglial TLRs in CNS disease and injuries is limited. Because astrocytes display heterogeneity and exhibit phenotypic plasticity depending on the effectors present in the local milieu, they can exert both detrimental and beneficial effects. TLRs are modulators of these paradoxical astroglial properties. The goal of the current review is to highlight the essential roles played by astroglial TLRs in CNS infections, injuries and diseases. We discuss the contribution of astroglial TLRs to host defense as well as the dissemination of viral and bacterial infections in the CNS. We examine the link between astroglial TLRs and the pathogenesis of neurodegenerative diseases and present evidence showing the pivotal influence of astroglial TLR signaling on sterile inflammation in CNS injury. Finally, we define the research questions and areas that warrant further investigations in the context of astrocytes, TLRs, and CNS dysfunction.


Subject(s)
Astrocytes/metabolism , Neurodegenerative Diseases/physiopathology , Toll-Like Receptors/physiology , Animals , Astrocytes/physiology , Brain/metabolism , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System Diseases/immunology , Central Nervous System Infections/pathology , Encephalitis/immunology , Humans , Immunity, Innate/physiology , Microglia/metabolism , Neurodegenerative Diseases/metabolism , Neurons/metabolism , Receptors, Pattern Recognition/immunology , Signal Transduction , Spinal Cord/pathology , Spinal Cord Injuries/pathology , Toll-Like Receptors/metabolism
11.
J Neurosci Res ; 99(3): 750-777, 2021 03.
Article in English | MEDLINE | ID: covidwho-938490

ABSTRACT

Without protective and/or therapeutic agents the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection known as coronavirus disease 2019 is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body cross talk between organs. The majority of SARS-CoV-2-infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.


Subject(s)
COVID-19/complications , COVID-19/metabolism , Central Nervous System/metabolism , Nervous System Diseases/etiology , Nervous System Diseases/metabolism , Peripheral Nervous System/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/virology , COVID-19/transmission , Central Nervous System/virology , Humans , Nervous System Diseases/virology , Olfactory Nerve/metabolism , Olfactory Nerve/virology , Peripheral Nervous System/virology
12.
Mol Med Rep ; 22(5): 4221-4226, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-808490

ABSTRACT

Infection by the severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV­2) is the cause of the new viral infectious disease (coronavirus disease 2019; COVID­19). Emerging evidence indicates that COVID­19 may be associated with a wide spectrum of neurological symptoms and complications with central nervous system (CNS) involvement. It is now well­established that entry of SARS­CoV­2 into host cells is facilitated by its spike proteins mainly through binding to the angiotensin­converting enzyme 2 (ACE­2). Preclinical studies have suggested that neuropilin­1 (NRP1), which is a transmembrane receptor that lacks a cytosolic protein kinase domain and exhibits high expression in the respiratory and olfactory epithelium, may also be implicated in COVID­19 by enhancing the entry of SARS­CoV­2 into the brain through the olfactory epithelium. In the present study, we expand on these findings and demonstrate that the NRP1 is also expressed in the CNS, including olfactory­related regions such as the olfactory tubercles and paraolfactory gyri. This furthers supports the potential role of NRP1 as an additional SARS­CoV­2 infection mediator implicated in the neurologic manifestations of COVID­19. Accordingly, the neurotropism of SARS­CoV­2 via NRP1­expressing cells in the CNS merits further investigation.


Subject(s)
Central Nervous System/metabolism , Coronavirus Infections/metabolism , Neuropilin-1/metabolism , Pneumonia, Viral/metabolism , Receptors, Virus/metabolism , Betacoronavirus/physiology , Brain/metabolism , Brain/virology , COVID-19 , Central Nervous System/virology , Databases, Genetic , Humans , Pandemics , Receptors, Coronavirus , SARS-CoV-2
13.
Int J Mol Sci ; 21(15)2020 Jul 31.
Article in English | MEDLINE | ID: covidwho-693402

ABSTRACT

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called "cytokine storm"), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.


Subject(s)
Betacoronavirus/physiology , Central Nervous System/virology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/isolation & purification , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/virology , Brain Diseases/complications , Brain Diseases/pathology , COVID-19 , Central Nervous System/metabolism , Coronavirus Infections/virology , Encephalitis/complications , Encephalitis/pathology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , SARS-CoV-2
14.
EBioMedicine ; 56: 102799, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-437271

ABSTRACT

A new strain of human coronaviruses (hCoVs), Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has been identified to be responsible for the current outbreak of the coronavirus disease 2019 (COVID-19). Though major symptoms are primarily generated from the respiratory system, neurological symptoms are being reported in some of the confirmed cases, raising concerns of its potential for intracranial invasion and neurological manifestations, both in the acute phase and in the long-term. At present, it remains unclear the extent to which SARS-CoV-2 is present in the brain, and if so, its pathogenic role in the central nervous system (CNS). Evidence for neuroinvasion and neurovirulence of hCoVs has been recognised in animal and human studies. Given that SARS-CoV-2 belongs to the same family and shares characteristics in terms of receptor binding properties, it is worthwhile exploring its potential CNS manifestations. This review summarises previous findings from hCoVs in relation to the CNS, and compares these with the new strain, aiming to provide a better understanding of the effects of SARS-CoV-2 on the CNS.


Subject(s)
Betacoronavirus/physiology , Brain/virology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/isolation & purification , COVID-19 , Central Nervous System/metabolism , Central Nervous System/virology , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Humans , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Viral Proteins/chemistry , Viral Proteins/metabolism
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