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1.
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
2.
Stem Cell Reports ; 17(2): 307-320, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1712991

ABSTRACT

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling.


Subject(s)
Blood-Brain Barrier/virology , Central Nervous System/virology , SARS-CoV-2/physiology , Virus Internalization , Antibodies/pharmacology , Benzamidines/pharmacology , COVID-19/pathology , COVID-19/virology , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelial Cells/virology , Guanidines/pharmacology , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Models, Biological , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Virus Internalization/drug effects
3.
J Virol ; 96(4): e0196921, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702819

ABSTRACT

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited antiviral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , COVID-19/immunology , Central Nervous System Viral Diseases/immunology , Microglia/immunology , SARS-CoV-2/physiology , Virus Replication/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , Central Nervous System/immunology , Central Nervous System/virology , Central Nervous System Viral Diseases/genetics , Central Nervous System Viral Diseases/virology , Chemokines/genetics , Chemokines/immunology , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Microglia/virology , Neurons/immunology , Neurons/virology , Virus Replication/genetics
4.
J Stroke Cerebrovasc Dis ; 31(1): 106163, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1482759

ABSTRACT

The SARS-CoV-2 virus, which causes Coronavirus disease 2019 (COVID-19), has resulted in millions of worldwide deaths. When the SARS-CoV-2 virus emerged from Wuhan, China in December 2019, reports of patients with COVID-19 revealed that hospitalized patients had acute changes in mental status, cognition, and encephalopathy. Neurologic complications can be a consequence from overall severity of the systemic infection, direct viral invasion of the SARS-CoV-2 virus in the central nervous system, and possible immune mediated mechanisms. We will examine the landscape regarding this topic in this review in addition to current understandings of COVID-19 and hemostasis, treatment, and prevention, as well as vaccination.


Subject(s)
COVID-19 , Central Nervous System/virology , Nervous System Diseases , Thrombophilia/prevention & control , Anticoagulants , Hemostasis , Humans , Nervous System Diseases/diagnosis , Nervous System Diseases/etiology , SARS-CoV-2 , Thrombophilia/diagnosis
5.
Viruses ; 13(10)2021 10 17.
Article in English | MEDLINE | ID: covidwho-1471000

ABSTRACT

Coronavirus 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the lungs. COVID-19 symptoms include the presence of fevers, dry coughs, fatigue, sore throat, headaches, diarrhea, and a loss of taste or smell. However, it is understood that SARS-CoV-2 is neurotoxic and neuro-invasive and could enter the central nervous system (CNS) via the hematogenous route or via the peripheral nerve route and causes encephalitis, encephalopathy, and acute disseminated encephalomyelitis (ADEM) in COVID-19 patients. This review discusses the possibility of SARS-CoV-2-mediated Multiple Sclerosis (MS) development in the future, comparable to the surge in Parkinson's disease cases following the Spanish Flu in 1918. Moreover, the SARS-CoV-2 infection is associated with a cytokine storm. This review highlights the impact of these modulated cytokines on glial cell interactions within the CNS and their role in potentially prompting MS development as a secondary disease by SARS-CoV-2. SARS-CoV-2 is neurotropic and could interfere with various functions of neurons leading to MS development. The influence of neuroinflammation, microglia phagocytotic capabilities, as well as hypoxia-mediated mitochondrial dysfunction and neurodegeneration, are mechanisms that may ultimately trigger MS development.


Subject(s)
COVID-19/complications , COVID-19/pathology , Central Nervous System/pathology , Multiple Sclerosis/pathology , Neurodegenerative Diseases/virology , Central Nervous System/virology , Cytokine Release Syndrome/pathology , Cytokines/blood , Cytokines/metabolism , History, 20th Century , Humans , Influenza Pandemic, 1918-1919/statistics & numerical data , Multiple Sclerosis/virology , Neurodegenerative Diseases/pathology , SARS-CoV-2/immunology
6.
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
7.
Trop Biomed ; 38(3): 435-445, 2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1451066

ABSTRACT

Ever since the first reported case series on SARS-CoV-2-induced neurological manifestation in Wuhan, China in April 2020, various studies reporting similar as well as diverse symptoms of COVID-19 infection relating to the nervous system were published. Since then, scientists started to uncover the mechanism as well as pathophysiological impacts it has on the current understanding of the disease. SARS-CoV-2 binds to the ACE2 receptor which is present in certain parts of the body which are responsible for regulating blood pressure and inflammation in a healthy system. Presence of the receptor in the nasal and oral cavity, brain, and blood allows entry of the virus into the body and cause neurological complications. The peripheral and central nervous system could also be invaded directly in the neurogenic or hematogenous pathways, or indirectly through overstimulation of the immune system by cytokines which may lead to autoimmune diseases. Other neurological implications such as hypoxia, anosmia, dysgeusia, meningitis, encephalitis, and seizures are important symptoms presented clinically in COVID-19 patients with or without the common symptoms of the disease. Further, patients with higher severity of the SARS-CoV-2 infection are also at risk of retaining some neurological complications in the long-run. Treatment of such severe hyperinflammatory conditions will also be discussed, as well as the risks they may pose to the progression of the disease. For this review, articles pertaining information on the neurological manifestation of SARS-CoV-2 infection were gathered from PubMed and Google Scholar using the search keywords "SARS-CoV-2", "COVID-19", and "neurological dysfunction". The findings of the search were filtered, and relevant information were included.


Subject(s)
COVID-19/pathology , Central Nervous System/pathology , Nervous System Diseases/virology , Peripheral Nervous System/pathology , Angiotensin-Converting Enzyme 2/metabolism , Anosmia/virology , Central Nervous System/virology , Dysgeusia/virology , Encephalitis, Viral/virology , Humans , Meningitis, Viral/virology , Nervous System Diseases/pathology , Peripheral Nervous System/virology , SARS-CoV-2 , Seizures/virology
8.
Viruses ; 13(7)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1448933

ABSTRACT

Virus-induced infections of the central nervous system (CNS) are among the most serious problems in public health and can be associated with high rates of morbidity and mortality, mainly in low- and middle-income countries, where these manifestations have been neglected. Typically, herpes simplex virus 1 and 2, varicella-zoster, and enterovirus are responsible for a high number of cases in immunocompetent hosts, whereas other herpesviruses (for example, cytomegalovirus) are the most common in immunocompromised individuals. Arboviruses have also been associated with outbreaks with a high burden of neurological disorders, such as the Zika virus epidemic in Brazil. There is a current lack of understanding in Brazil about the most common viruses involved in CNS infections. In this review, we briefly summarize the most recent studies and findings associated with the CNS, in addition to epidemiological data that provide extensive information on the circulation and diversity of the most common neuro-invasive viruses in Brazil. We also highlight important aspects of the prion-associated diseases. This review provides readers with better knowledge of virus-associated CNS infections. A deeper understanding of these infections will support the improvement of the current surveillance strategies to allow the timely monitoring of the emergence/re-emergence of neurotropic viruses.


Subject(s)
Central Nervous System Diseases/virology , Central Nervous System Infections/epidemiology , Prion Diseases/epidemiology , Alphavirus/pathogenicity , Brazil/epidemiology , Central Nervous System/virology , Central Nervous System Diseases/metabolism , Central Nervous System Diseases/physiopathology , Central Nervous System Infections/virology , Central Nervous System Viral Diseases/physiopathology , Central Nervous System Viral Diseases/virology , Enterovirus/pathogenicity , Flavivirus/pathogenicity , Herpesviridae/pathogenicity , Humans , Nervous System Diseases/epidemiology , Nervous System Diseases/virology , Prion Diseases/physiopathology , Prions/metabolism , Prions/pathogenicity , Simplexvirus/pathogenicity , Virus Diseases/virology , Viruses/pathogenicity , Zika Virus/pathogenicity
11.
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
12.
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
14.
Stroke Vasc Neurol ; 5(2): 146-151, 2020 06.
Article in English | MEDLINE | ID: covidwho-1318197

ABSTRACT

Coronavirus disease 2019 (COVID-19) has become a pandemic disease globally. Although COVID-19 directly invades lungs, it also involves the nervous system. Therefore, patients with nervous system involvement as the presenting symptoms in the early stage of infection may easily be misdiagnosed and their treatment delayed. They become silent contagious sources or 'virus spreaders'. In order to help neurologists to better understand the occurrence, development and prognosis, we have developed this consensus of prevention and management of COVID-19. It can also assist other healthcare providers to be familiar with and recognise COVID-19 in their evaluation of patients in the clinic and hospital environment.


Subject(s)
Betacoronavirus/pathogenicity , Central Nervous System Infections/therapy , Central Nervous System/virology , Clinical Laboratory Techniques/standards , Coronavirus Infections/therapy , Neurologists/standards , Pneumonia, Viral/therapy , COVID-19 , COVID-19 Testing , Central Nervous System/physiopathology , Central Nervous System Infections/diagnosis , Central Nervous System Infections/physiopathology , Central Nervous System Infections/virology , Consensus , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Early Diagnosis , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , Predictive Value of Tests , Prognosis , SARS-CoV-2
15.
PLoS One ; 16(7): e0254872, 2021.
Article in English | MEDLINE | ID: covidwho-1317145

ABSTRACT

BACKGROUND: COVID-19 is only partly understood, and the level of evidence available in terms of pathophysiology, epidemiology, therapy, and long-term outcome remains limited. During the early phase of the pandemic, it was necessary to effectively investigate all aspects of this new disease. Autopsy can be a valuable procedure to investigate the internal organs with special techniques to obtain information on the disease, especially the distribution and type of organ involvement. METHODS: During the first wave of COVID-19 in Germany, autopsies of 19 deceased patients were performed. Besides gross examination, the organs were analyzed with standard histology and polymerase-chain-reaction for SARS-CoV-2. Polymerase chain reaction positive localizations were further analyzed with immunohistochemistry and RNA-in situ hybridization for SARS-CoV-2. RESULTS: Eighteen of 19 patients were found to have died due to COVID-19. Clinically relevant histological changes were only observed in the lungs. Diffuse alveolar damage in considerably different degrees was noted in 18 cases. Other organs, including the central nervous system, did not show specific micromorphological alterations. In terms of SARS-CoV-2 detection, the focus remains on the upper airways and lungs. This is true for both the number of positive samples and the viral load. A highly significant inverse correlation between the stage of diffuse alveolar damage and viral load was found on a case and a sample basis. Mediastinal lymph nodes and fat were also affected by the virus at high frequencies. By contrast, other organs rarely exhibited a viral infection. Moderate to strong correlations between the methods for detecting SARS-CoV-2 were observed for the lungs and for other organs. CONCLUSIONS: The lung is the most affected organ in gross examination, histology and polymerase chain reaction. SARS-CoV-2 detection in other organs did not reveal relevant or specific histological changes. Moreover, we did not find CNS involvement.


Subject(s)
COVID-19/virology , Central Nervous System/virology , Lung/virology , Lymph Nodes/virology , Viral Load , Aged , Aged, 80 and over , Autopsy/statistics & numerical data , COVID-19/epidemiology , COVID-19/pathology , Central Nervous System/pathology , Female , Humans , Lung/pathology , Lymph Nodes/pathology , Male , Middle Aged
17.
Neurotox Res ; 39(5): 1613-1629, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1281337

ABSTRACT

Aside from the respiratory distress as the predominant clinical presentation of SARS-CoV-2 infection, various neurological complications have been reported with the infection during the ongoing pandemic, some of which cause serious morbidity and mortality. Herein, we gather the latest anatomical evidence of the virus's presence within the central nervous system. We then delve into the possible SARS-CoV-2 entry routes into the neurological tissues, with the hematogenous and the neuronal routes as the two utmost passage routes into the nervous system. We then give a comprehensive review of the neurological manifestations of the SARS-CoV-2 invasion in both the central and peripheral nervous system and its underlying pathophysiology via investigating large studies in the field and case reports in cases of study scarcity.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Nervous System Diseases/etiology , Nervous System Diseases/physiopathology , COVID-19/virology , Central Nervous System/virology , Humans , Nervous System Diseases/virology , Peripheral Nervous System/virology
18.
Mol Neurobiol ; 58(9): 4694-4715, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1281328

ABSTRACT

The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic.


Subject(s)
COVID-19/complications , Nervous System Diseases/etiology , Pandemics , SARS-CoV-2/pathogenicity , Adult , Age Factors , Aged , Aged, 80 and over , Autoimmune Diseases of the Nervous System/epidemiology , Autoimmune Diseases of the Nervous System/etiology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Central Nervous System/virology , Child , Comorbidity , Female , Humans , Immune System/virology , Inflammation , Male , Middle Aged , Models, Biological , Muscular Diseases/etiology , Nervous System Diseases/drug therapy , Nervous System Diseases/epidemiology , Nervous System Diseases/physiopathology , Neurodegenerative Diseases/complications , Neurons/virology , Organ Specificity , Sex Factors , Viremia/chemically induced , Viremia/immunology , Virus Internalization
19.
Mol Neurobiol ; 58(9): 4575-4587, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1263176

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 or COVID-19 has been declared as a pandemic disease by the World Health Organization (WHO). Globally, this disease affected 159 million of the population and reported ~ 3.3 million deaths to the current date (May 2021). There is no definitive treatment strategy that has been identified, although this disease has prevailed in its current form for the past 18 months. The main challenges in the (SARS-CoV)-2 infections are in identifying the heterogeneity in viral strains and the plausible mechanisms of viral infection to human tissues. In parallel to the investigations into the patho-mechanism of SARS-CoV-2 infection, understanding the fundamental processes underlying the clinical manifestations of COVID-19 is very crucial for designing effective therapies. Since neurological symptoms are very apparent in COVID-19 infected patients, here, we tried to emphasize the involvement of redox imbalance and subsequent mitochondrial dysfunction in the progression of the COVID-19 infection. It has been articulated that mitochondrial dysfunction is very apparent and also interlinked to neurological symptoms in COVID-19 infection. Overall, this article provides an in-depth overview of redox imbalance and mitochondrial dysfunction involvement in aggravating COVID-19 infection and its probable contribution to the neurological manifestation of the disease.


Subject(s)
COVID-19/complications , Mitochondria/physiology , SARS-CoV-2/pathogenicity , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/metabolism , Central Nervous System/virology , Drug Repositioning , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Humans , Mice , Mitochondria/drug effects , Mitochondria/pathology , Models, Biological , Olfactory Nerve/virology , Organ Specificity , Oxidation-Reduction , Oxidative Stress/drug effects , Pandemics , SARS-CoV-2/physiology , Viral Proteins/physiology , Viral Tropism , Viremia/complications , Virulence , Virus Internalization
20.
Viruses ; 13(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1227070

ABSTRACT

Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD, some hypotheses have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients, in general, and for the PD cases reported, in particular. Given the importance of this potential connection, we present here a molecular-level mechanistic hypothesis that explains well these findings and will serve to explore the potential CNS damage in COVID-19 patients. The model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Our hypothesis is supported by finding 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. The molecular-level mechanistic hypothesis presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.


Subject(s)
COVID-19/complications , Parkinson Disease, Secondary/etiology , COVID-19/metabolism , Central Nervous System/virology , Exosomes/metabolism , Humans , Lung/metabolism , Models, Theoretical , Parkinson Disease/etiology , Parkinson Disease/metabolism , Parkinson Disease/virology , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/virology , Protein Interaction Maps , SARS-CoV-2/pathogenicity , Viral Proteins/metabolism
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