ABSTRACT
COVID-19 patients have presented with a wide range of neurological disorders, among which stroke is the most devastating. We have reviewed current studies, case series, and case reports with a focus on COVID-19 patients complicated with stroke, and presented the current understanding of stroke in this patient population. As evidenced by increased D-dimer, fibrinogen, factor VIII and von Willebrand factor, SARS-CoV-2 infection induces coagulopathy, disrupts endothelial function, and promotes hypercoagulative state. Collectively, it predisposes patients to cerebrovascular events. Additionally, due to the unprecedented strain on the healthcare system, stroke care has been inevitably compromised. The underlying mechanism between COVID-19 and stroke warrants further study, so does the development of an effective therapeutic or preventive intervention.
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the globe, causing innumerable deaths and a massive economic catastrophe. Exposure to household members with confirmed COVID-19 is the most common source of infection among children. Children are just as likely as adults to get infected with SARS-CoV-2. Most children are asymptomatic and when symptoms occur, they are usually mild. Infants <12 months old are at a higher risk for severe or critical disease. COVID-19 is diagnosed the same way in pediatric population as adults by testing specimen obtained from upper respiratory tract for nucleic acid amplification test (NAAT) using reverse transcriptase viral polymerase chain reaction (RT-PCR). The common laboratory findings in hospitalized patient include leukopenia, lymphopenia, and increased levels of inflammatory markers. Chest X-ray findings are variable and computed tomography scans of the chest may show ground glass opacities similar to adults or non-specific findings. Prevention is the primary intervention strategy. Recently the U.S. Food and Drug Administration (FDA) has provided emergency authorization of the Pfizer-BioNTech COVID-19 vaccine and many other vaccine candidates are in the investigational stage. There is limited data in children on the use of antivirals, hydroxychloroquine, azithromycin, monoclonal antibody, and convalescent plasma. Oxygen therapy is required in hypoxic children (saturation <92%). Similar to adults, other measures to maintain oxygenation such as high flow nasal cannula, CPAP, or ventilatory support may be needed. Ventilatory management strategies should include use of low tidal volumes (5-6 cc/kg), high positive expiratory pressure, adequate sedation, paralysis, and prone positioning. Recently, a new entity associated with COVID-19 called multisystem inflammatory syndrome in children (MIS-C) has emerged. Clinical, laboratory, and epidemiological criteria are the basis for this diagnosis. Management options include ICU admission, steroids, intravenous gamma globulin, aspirin, anakinra, and anticoagulants. Vasoactive-inotropic score (VIS) is used to guide vasopressor support.
ABSTRACT
Blood pressure is controlled through a complex network of interacting peptide systems, principally involving the angiotensin, natriuretic peptide, endothelin and apelin families. The most complex and thoroughly investigated is the renin-angiotensin system (RAS) in which selective and potent inhibitors of the key biosynthetic proteolytic enzymes, renin and angiotensin-converting enzyme (ACE), have proved to be valuable drugs for the effective treatment of hypertension and heart failure, as well as other cardiovascular and renal disorders. Some of the other proteases in these pathways, e.g.neprilysin and ACE2, are also being explored as potential drug targets. © 2023 Elsevier Inc. All rights reserved.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the outbreak of pneumonia which originated in Wuhan, China, at the end of 2019 has turned into a global pandemic—now termed coronavirus diseases 2019 (COVID-19). Like previously reported SARS-CoV strains, the newly discovered SARS-CoV-2 was also found to initiate the pathogenesis by binding with the angiotensin-converting enzyme 2 (ACE2), a receptor produced by various organs in the human body. Hence, COVID-19 is a viral multisystem disease which particularly infects the vascular system expressing ACE2 and reduced the ACE2 function;this further complexed by organ-specific pathogenesis related to the damage of cells expressing ACE2, such as alveolus, glomerulus, endothelium, and cardiac microvasculature. Under these conditions, it was advocated that the upregulation of ACE2 expression in predisposing individuals with aberrant renin–angiotensin system (RAS) level to advanced viral load on infection and relatively a greater number of cell death. Recently, a significant role of decreased ACE2 production and inequality between the RAS and ACE2/angiotensin-(1–7)/ MAS (mitochondrial Ang system) after the onset of SARS-CoV-2 infection was established as a key factor for multiple organ injury in SARS-CoV-2-infected individuals. Furthermore, restoration of this imbalance has been suggested as a therapeutic approach to attenuate organ injuries in SARS-CoV-2 infection. Based on available data, this chapter presents the updated mechanism of the multi-organ diseases causes by COVID-19 via ACE2 which can be further helpful in the development of specific therapeutics. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.
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Typical manifestations of coronavirus disease-2019 (COVID-19) include mild-to-moderate "flu-like” symptoms, although more severe manifestations have been reported. The pathophysiology of COVID-19 is complex, and its clinical spectrum might not be limited to local pneumonia, but rather may represent a multisystem illness with potential for severe acute respiratory distress syndrome (ARDS) and multiorgan impairment. In this context, the aim of the present handbook is to provide an overview of possible multisystemic manifestations and therapeutic strategies, in order to guide the clinician to deal with COVID-19 critical illness and to prevent potential systemic consequences. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.
ABSTRACT
Background: COVID-19 (coronavirus disease 2019) is still a major challenge worldwide. The disease is caused by binding the coronavirus to ACE2 receptors on lung cells, infecting the cells and triggering the onset of symptoms. The prevention of such a binding in which the virus is eventually unable to enter the cell could be a promising therapeutic approach.Methods: In this in silico study, 306 compounds of Lamiaceae family native in Iran (native Mints) were retrieved from several databases as 3D structures, and after that molecular docking and virtual screening, the compounds with inhibitory potential were selected in terms of free energy binding against the spike protein of the virus. The pharmacokinetic profile of selected compounds was evaluated, and by molecular dynamic simulation and MM/PBSA, four compounds were further assessed for binding affinities against the receptor-binding domain of the spike.Results: The results showed the Catechin gallate and Perovskone B from Stachys and Salvia genus generated a stronger binding affinity, and therefore could act as potential inhibitory compounds of RBD of the SARS-CoV-2 spike protein.Conclusion: This study revealed that some members of the Lamiaceae family could be employed to inhibit SARS-CoV-2 activity through interaction with spike protein and therefore could be used for further investigation in vitro and in vivo.
ABSTRACT
SARS-CoV-2, a member of the family Coronaviridae, is a positive-stranded RNA virus with the spike glycoproteins present on its envelope. ACE2 serves as the entry mediator of SARS-CoV-2 as it attacks mainly the organs of the respiratory, cardiovascular, digestive, and urinary system showing high expression of ACE2 or TMPRSS2. ACE2 is found to have significant differential expression in all the reproductive tissues, thus posing the reproductive system vulnerable to the adverse effects of SARS-CoV-2 infection. Previous coronavirus attacks (SARSCoV and MERS) have also been known to impose adverse effects on the reproductive system. Therefore, there is a dire need to safeguard the reproductive system against COVID-19 as it not only bothers the present generation but may also affect the well-being of future progeny. Since the inception of pandemic, several scientific studies have been carried out to assess its impact;yet there are research lacunas to claim reproductive system as a potential target of this deadly virus. To avoid the detrimental effects of the current pandemic on reproductive sustainability, well-planned large-scale and multicentric cohort follow-up studies are mandatory for accurate evaluation of the enduring effects of SARS-CoV-2 infection on human fertility and pregnancy outcomes. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.
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The last discovered organ of the human body is microbiome which is present at different sites in it. Gut microbiome consists of about 1000–1500 bacterial species and as regulated by genetic makeup, lifestyle, and environmental conditions, the gut microbiota of a healthy individual can comprise approximately 160 species of bacteria. Majority of gut microbiome consists of Firmicutes, Actinobacteria, Bacteroidetes, and to a lesser extent Proteobacteria, Euryarchaeota, Fusobacteria, and Verrucomicrobia. The gut-lung axis is involved in the migration of immune cells from gut to respiratory tract through circulation and encourages the host's ability to fight infections. The gut regulates the responses in lungs via host-acquired inflammatory mediators in the circulation. Dendritic cells located in the Peyer's patches of the intestine, macrophages, and Langerhans cells are the major antigen-presenting cells that play a vital role in the modulation and development of innate immune response. Gut microbiota interacts via the regulation and development of adaptive immune response. B and T lymphocytes are the key players of adaptive immunity. CD4 + T cells after activation differentiate into four major kinds of cell classes: (1) regulatory T cells (Treg), (2) Th2, (3) Th1, and (4) Th17 cells. Gut microbial interactions can induce the production of various types of immune cells as demonstrated by various studies. For instance, Clostridia induces the formation of Treg cells. Likewise, Bacteroides fragilis inhabiting the gut can incite the production of Th1 cells and production of T17 cells is stimulated by segmental filamentous bacteria. Gut microbiota also plays a vital role in the physiology and metabolism leading to the synthesis of various immunoregulatory metabolites such as SCFAs, antimicrobial peptides (AMPs), amino acids, and polyamines. SARS-CoV-2 virus entry to the cell is via ACE2 receptor present in respiratory epithelium and gut epithelium. This receptor is highly expressed (100 times more than in the lung) in the epithelial cells of the stomach, duodenum, ileum, and rectum as well as cholangiocytes and hepatocytes. High level of ACE2 receptor expressing in the gastrointestinal epithelial cells along with high-level co-expression of TMPRSS2 (cellular serine peptidase) causes coronavirus to infect gastrointestinal tract along with lungs leading to altered intestinal permeability and enterocyte malabsorption with symptoms of diarrhea in patients of COVID-19. Hence, COVID-19 patients with gastrointestinal symptoms have significantly longer duration of illness and viral clearance time than patients without any gastrointestinal symptoms. Obese patients with gut dysbiosis have decreased population of Bacteroides species. COVID-19 patients with type 2 diabetics have increased population of Fusobacterium, Ruminococcus, and Blautia with decreased population of Bacteroides, Bifidobacterium, Faecalibacterium, Akkermansia, and Roseburia. Diet with low fiber, high fat, and high carbohydrate causes gut dysbiosis. Intake of high-fiber diet consisting of whole grains, vegetables, and fruits induces growth of Bifidobacterium, Bacteroides, and Lactobacilli. Probiotics are nonpathogenic live organisms which are safe to be taken as dietary supplements. The major genera of probiotics are Lactobacillus, Bifidobacterium, and Saccharomyces. These probiotics increase the activity of T cells, NK cell, and polymorphonuclear cells. Prebiotics in the form of maize fiber, inulin, and polydextrose improves digestion and immunity. Hence, healthy gut microbiome with its strong immune intervention may bring recovery in COVID-19 patients. However, so far no published studies have reported that probiotics can be used as an adjunctive therapy in our fight against the SARS-CoV-2 infection. A far-reaching approach should consist of randomized, multicenter, controlled trials to explore the potential benefits of gut microbiome and how changes in dietary habits can be used as an add-on strategy against the COVID-19 pandemic. © The Author(s), under exc us ve licence to Springer Nature Singapore Pte Ltd. 2021.
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Context: The coronavirus disease 2019 (COVID-19) pandemic is still a cause of worldwide health concern. Diabetes and its associated comorbidities are risk factors for mortality and morbidity in COVID-19. Selecting the right antidiabetic drug to achieve optimal glycemic control might mitigate some of the negative impacts of diabetes. Metformin continues to be the most widely administered antidiabetic agent. There is evidence of its beneficial outcome in COVID-19 independent of its glucose-lowering effect. Evidence Acquisition: A thorough literature search was conducted in PubMed, Google Scholar, Scopus, and Web of Science to identify studies investigating metformin in COVID-19. Result(s): Several overlapping mechanisms have been proposed to explain its antiviral properties. It could bring about conformational changes in the angiotensin-converting enzyme-2 receptor and decrease viral entry. The effects on the mammalian target of the rapamycin pathway and cellular pH have been proposed to reduce viral protein synthesis and replication. The immunomodulatory effects of metformin might counter the detrimental effects of hyperinflammation associated with COVID-19. Conclusion(s): These findings call for broader metformin usage to manage hyperglycemia in COVID-19.Copyright © 2023, International Journal of Endocrinology and Metabolism.
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The 6XS6 is the structure of the SARS-CoV-2 spike protein. The physiological role of the spike protein is relative to the respiratory syndrome coronavirus and has a stronger infect on the human body than the ancestor virus. The purification of the 6XS6 is in the homo sapiens cell by the affinity chromatography, PBS supplemented and Size Exclusion chromatography. At last, using the Cryo-Electron Microscopy to see the structure. This paper is using the D614G mutation to illustrate the structure of the 6XS6. The N-terminal domain and C-terminal domain of the 6XS6 protein are ALA27 and VAL1137. Furthermore, the mutation doesn't have the hydrogen bond because the Asp614 is substituted by the Gly614, and the molecule that interacts with the Ala 647 may occur. While the 6XS6 structure has lots of non-covalent and disulfide bonds. Comparing the structure of the 6XS6 and 6VXX, both are glycoproteins, have three monomers, have two subunits, and have the same category of expression and classification. The different conformations of the two structures can affect the binding ability with the ACE2. This paper can help the researchers to further understand the structure and function of the 6XS6 which can be used in future experiments. © 2023 SPIE.
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SARS-CoV-2 has caused millions of infections and deaths worldwide and case numbers continue to rise. Besides the effect of the virus on key organs - leading to respiratory illness, anosmia, diarrhea, and fever and other complications - delayed inflammatory reactions to hyaluronic acid dermal fillers, mainly in the face, have also been reported to occur after confirmed SARS-CoV-2 infections and in vaccinated individuals. While delayed inflammatory reactions tend to be self-limiting, they should be diagnosed and treated with corticosteroids, hyaluronidase, and/or antibiotics when necessary. The inflammation is generally not severe, yet these complications are classified as serious adverse events by the US Food and Drug Administration. They appear to be delayed type IV hypersensitivity reactions triggered by the immune system in the presence of SARS-CoV-2 or other viruses, such as those causing influenza, although the underlying mechanisms have not been fully elucidated. Because the longevity of dermal fillers is increasing, while the pandemic continues to evolve and new vaccines are under development, the long-term effects on hyaluronic acid fillers and other bioimplant materials should be studied. Physicians must also be encouraged to report these reactions, however mild, to ensure accurate records.
Subject(s)
COVID-19 , Dermal Fillers , Anti-Bacterial Agents , COVID-19/prevention & control , Dermal Fillers/adverse effects , Humans , Hyaluronic Acid/adverse effects , Hyaluronoglucosaminidase/therapeutic use , SARS-CoV-2ABSTRACT
Broadly neutralizing ability is critical for developing the next-generation SARS-CoV-2 vaccine. We collected sera samples between December 2021-January 2022 from 113 Taiwan naïve participants after their second dose of homologous vaccine (AZD1222, mRNA-1273, BNT162-b2, and MVC-COV1901) and compared the differences in serological responses of various SARS-CoV-2 vaccines. Compared to AZD1222, the two mRNA vaccines could elicit a higher level of anti-S1-RBD binding antibodies with higher broadly neutralizing ability evaluated using pseudoviruses of various SARS-CoV-2 lineages. The antigenic maps produced from the neutralization data implied that Omicron represents very different antigenic characteristics from the ancestral lineage. These results suggested that constantly administering the vaccine with ancestral Wuhan spike is insufficient for the Omicron outbreak. In addition, we found that anti-ACE2 autoantibodies were significantly increased in all four vaccinated groups compared to the unvaccinated pre-pandemic group, which needed to be investigated in the future.
Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2 , ChAdOx1 nCoV-19 , Taiwan/epidemiology , COVID-19/prevention & controlABSTRACT
The World Health Organization announced on March 11, 2020 that COVID-19 could become a pandemic. COVID-19 is a contagious disease caused by the coronavirus that causes severe acute respiratory syndrome (SARS-CoV-2). Viruses usually enter the body through the mouth or nose. The virus then enters the alveoli, which are small air sacs inside the lungs. Cough, fatigue, fever, shortness of breath or breathing difficulties, and loss of smell and taste are all symptoms of COVID-19. Anosmia, also known as smell blindness, is a condition in which the ability to detect one or more smells is lost. Olfaction uses chemoreceptors to create signals that are processed in the brain and form the sense of smell in anosmia. Anosmia is recognised as a COVID-19 symptom in many countries, and some have developed "smell tests" as potential screening tools. The first level of screening, which is currently used in India, is primarily based on temperature and can result in false positives and negatives (fever as a symptom has not yet been developed although infection). One of the methods for detecting COVID-19 is an intermediate level of screening based on assessing an olfactory function, depending on the usage. This paper provides an overview of COVID-19 and its effects on the human body, as well as an overview of anosmia and how it contributes to one of the symptoms of COVID-19.
ABSTRACT
BACKGROUND: Angiotensin-converting enzyme (ACE) and ACE2 are two major enzymes of the renin-angiotensin-aldosterone system (RAAS), which control the formation/degradation of angiotensin (Ang) II and Ang1-7, regulating their opposite effects. We aimed at evaluating the catalytic activity of ACE and ACE2 in the intestinal content and corresponding intestinal tissue along the gut of Wistar Han rats. METHODS: Portions of the ileum, cecum, proximal colon, and distal colon, and the corresponding intestinal content were collected from Wistar Han rats. Enzyme activity was evaluated by fluorometric assays using different substrates: Hippuryl-His-Leu for ACE-C-domain, Z-Phe-His-Leu for ACE-N-domain, and Mca-APK(Dnp) for ACE2. ACE and ACE2 concentration was assessed by ELISA. Ratios concerning concentrations and activities were calculated to evaluate the balance of the RAAS. Statistical analysis was performed using Friedman test followed by Dunn's multiple comparisons test or Wilcoxon matched-pairs test whenever needed. KEY RESULTS: ACE and ACE2 are catalytically active in the intestinal content along the rat gut. The ACE N-domain shows higher activity than the C-domain both in the intestinal content and in the intestinal tissue. ACE and ACE2 are globally more active in the intestinal content than in the corresponding intestinal tissue. There was a distal-to-proximal prevalence of ACE2 over ACE in the intestinal tissue. CONCLUSIONS & INFERENCES: This work is the first to report the presence of catalytically active ACE and ACE2 in the rat intestinal content, supporting future research on the regulatory role of the intestinal RAAS on gut function and a putative link to the microbiome.
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Host proteases trypsin and trypsin-like proteases have been reported to facilitate the entry of coronavirus SARS-CoV-2 in its host cells. These protease enzymes cleave the viral surface glycoprotein, spike, leading to successful cell surface receptor attachment, fusion and entry of the virus in its host cell. The spike protein has protease cleavage sites between the two domains S1 and S2. Since the cleavage site is recognized by the host proteases, it can be a potential antiviral therapeutic target. Trypsin-like proteases play an important role in virus infectivity and the property of spike protein cleavage by trypsin and trypsin-like proteases can be used to design assays for screening of antiviral candidates against spike protein cleavage. Here, we have documented the development of a proof-of-concept assay system for screening drugs against trypsin/trypsin-like proteases that cleave spike protein between its S1 and S2 domains. The assay system developed uses a fusion substrate protein containing a NanoLuc luciferase reporter protein, the protease cleavage site between S1 and S2 domains of SARS-CoV-2 spike protein and a cellulose binding domain. The substrate protein can be immobilized on cellulose via the cellulose binding domain of the substrate. When trypsin and trypsin-like proteases cleave the substrate, the cellulose binding domain remain bound to the cellulose and the reporter protein is dislodged. Reporter assay using the released reporter protein is the read out of the protease activity. We have demonstrated the proof-of-concept using multiple proteases like trypsin, TMPRSS2, furin, cathepsin B, human airway trypsin and cathepsin L. A significant increment in fold change was observed with increasing enzyme concentration and incubation time. Introduction of increasing amounts of enzyme inhibitors in the reaction reduced the luminescent signal, thus validating the assay. Furthermore, we used SDS-PAGE and immunoblot analyses to study the cleavage band pattern and re-confirm the cleavage for enzymes tested in the assay. Taken together, we have tested an in-vitro assay system using the proposed substrate for screening drugs against trypsin like protease-based cleavage of SARS-CoV-2 spike glycoprotein. The assay system can also be potentially used for antiviral drug screening against any other enzyme that might cleave the used cleavage site.
Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Spike Glycoprotein, Coronavirus/metabolism , Trypsin , Virus Internalization , SARS-CoV-2/metabolism , Peptide HydrolasesABSTRACT
Several cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection transmitted from human owners to their dogs have recently been reported. The first ever case of SARS-CoV-2 transmission from a human owner to a domestic cat was confirmed on March 27, 2020. A tiger from a zoo in New York, USA, was also reportedly infected with SARS-CoV-2. It is believed that SARS-CoV-2 was transmitted to tigers from their caretakers, who were previously infected with this virus. On May 25, 2020, the Dutch Minister of Agriculture, Nature and Food Quality reported that two employees were infected with SARS-CoV-2 transmitted from minks. These reports have influenced us to perform a comparative analysis among angiotensin-converting enzyme 2 (ACE2) homologous proteins for verifying the conservation of specific protein regions. One of the most conserved peptides is represented by the peptide "353-KGDFR-357 (H. sapiens ACE2 residue numbering), which is located on the surface of the ACE2 molecule and participates in the binding of SARS-CoV-2 spike receptor binding domain (RBD). Multiple sequence alignments of the ACE2 proteins by ClustalW, whereas the three-dimensional structure of its binding region for the spike glycoprotein of SARS-CoV-2 was assessed by means of Spanner, a structural homology modeling pipeline method. In addition, evolutionary phylogenetic tree analysis by ETE3 was used. ACE2 works as a receptor for the SARS-CoV-2 spike glycoprotein between humans, dogs, cats, tigers, minks, and other animals, except for snakes. The three-dimensional structure of the KGDFR hosting protein region involved in direct interactions with SARS-CoV-2 spike RBD of the mink ACE2 appears to form a loop structurally related to the human ACE2 corresponding protein loop, despite of the reduced available protein length (401 residues of the mink ACE2 available sequence vs 805 residues of the human ACE2). The multiple sequence alignments of the ACE2 proteins shows high homology and complete conservation of the five amino acid residues: 353-KGDFR-357 with humans, dogs, cats, tigers, minks, and other animals, except for snakes. Where the information revealed from our examinations can support precision vaccine design and the discovery of antiviral therapeutics, which will accelerate the development of medical countermeasures, the World Health Organization recently reported on the possible risks of reciprocal infections regarding SARS-CoV-2 transmission from animals to humans.
Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/transmission , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/transmission , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/genetics , COVID-19 , Cats , Coronavirus Infections/prevention & control , Dogs , Humans , Mink , Pandemics/prevention & control , Peptidyl-Dipeptidase A/chemistry , Phylogeny , Pneumonia, Viral/prevention & control , Receptors, Virus/chemistry , Receptors, Virus/genetics , SARS-CoV-2 , Sequence Alignment , Spike Glycoprotein, Coronavirus/chemistry , TigersABSTRACT
CoViD-19 is the current pandemic caused by the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Infection by SARS-CoV-2 occurs via the binding of its S protein to the angiotensin-converting enzyme-2 receptor (ACE2-R). S binding to ACE2-R leads to a drop in ACE2, a homolog of angiotensin converting enzyme (ACE). In the central nervous system (CNS), ACE mediates neuroinflammation, neurodegeneration and neurotoxicity responsible for several CNS disorders. ACE2 counteracts the damaging effects of ACE on CNS neurons. SARS-CoV-2 can directly access the CNS via the circulation or via cranial nerve I and the olfactory bulb. Inactivation of ACE2 following binding of SARS-CoV-2 S protein to ACE2-R in situ might blunt ACE2-moderating effects upon ACE CNS neurotoxicity and neurodegeneration. Here, we propose a neurobiological mechanism directly involving SARS-CoV-2 binding to ACE2-R in the etiology of putative Neuro-CoViD-19.