Nicotinic Cholinergic System and COVID-19: Identification of a Potentially Crucial Snake Toxin-Like Sequence in the SARS-CoV-2 Spike Glycoprotein

Smoking is a risk factor for respiratory infections and there is reasonable concern that it may affect COVID-19 susceptibility and severity. Recent studies have focused on the interaction between smoking (and nicotine) and ACE2 expression, suggesting that ACE2 up-regulation could contribute to enhanced viral cell entry. However, case series have shown that there is an unexpectedly low prevalence of smoking among hospitalized COVID-19 cases. Since early April, we were the first to hypothesize that dysfunction of the nicotinic cholinergic system (NCS) may be implicated in the pathophysiology of severe COVID-19. We recently reported that many of the clinical manifestations of severe COVID-19 could be explained by dysregulation of the NCS. In this study, we present an amino acid sequence in the receptor binding domain of the SARS-CoV-2 Spike glycoprotein which is homologous to a sequence of a snake venom toxin. We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein. These findings suggest that SARS-CoV-2 could potentially interact with acetylcholine receptors causing dysregulation of the NCS and the cholinergic anti-inflammatory pathway.

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Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications

International Journal of Molecular Sciences ◽

10.3390/ijms21165807 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5807 ◽

Cited By ~ 9

Author(s):

Konstantinos Farsalinos ◽

Elias Eliopoulos ◽

Demetres D. Leonidas ◽

Georgios E. Papadopoulos ◽

Socrates Tzartos ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Cholinergic System ◽

Acetylcholine Receptors ◽

Extracellular Domain ◽

Spike Glycoprotein ◽

Angiotensin Converting Enzyme 2 ◽

Toxin Binding ◽

Therapeutic Value ◽

The Many ◽

Low Prevalence

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine other potential interactions between the virus and other cell receptors. Based on the clinical observation of low prevalence of smoking among hospitalized COVID-19 patients, we examined and identified a “toxin-like” amino acid (aa) sequence in the Receptor Binding Domain of the Spike Glycoprotein of SARS-CoV-2 (aa 375–390), which is homologous to a sequence of the Neurotoxin homolog NL1, one of the many snake venom toxins that are known to interact with nicotinic acetylcholine receptors (nAChRs). We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein and the superposition of the modelled structure of the Neurotoxin homolog NL1 and the SARS-CoV-2 Spike Glycoprotein. We also performed computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 Spike Glycoprotein and the extracellular domain of the nAChR α9 subunit. We identified a main interaction between the aa 381–386 of the SARS-CoV-2 Spike Glycoprotein and the aa 189–192 of the extracellular domain of the nAChR α9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the α9 nAChR and α-bungarotoxin. A similar interaction was observed between the pentameric α7 AChR chimera and SARS-CoV-2 Spike Glycoprotein. The findings raise the possibility that SARS-CoV-2 may interact with nAChRs, supporting the hypothesis of dysregulation of the nicotinic cholinergic system being implicated in the pathophysiology of COVID-19. Nicotine and other nicotinic cholinergic agonists may protect nAChRs and thus have therapeutic value in COVID-19 patients.

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Molecular Modelling and Docking Experiments Examining the Interaction between SARS-CoV-2 Spike Glycoprotein and Neuronal Nicotinic Acetylcholine Receptors

10.20944/preprints202005.0365.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Konstantinos Farsalinos ◽

Elias Eliopoulos ◽

Demetres Leonidas ◽

Georgios Papadopoulos ◽

Socrates Tzartos ◽

...

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Molecular Modelling ◽

Acetylcholine Receptors ◽

Extracellular Domain ◽

Spike Glycoprotein ◽

Nicotinic Acetylcholine ◽

Venom Toxin ◽

Toxin Binding ◽

Snake Venom Toxin ◽

Alpha Bungarotoxin

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine for other potential interactions between the virus and other cell receptors. Based on the clinical observation of low smoking prevalence among hospitalized COVID-19 patients, we recently identified a “toxin-like” amino acid (aa) sequence on the receptor binding domain of the spike glycoprotein of SARS-CoV-2 (aa 375-390) with homology to a sequence of a snake venom toxin, which could interact with nicotinic acetylcholine receptors (nAChRs). We now present computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 spike glycoprotein and the extracellular domain of the nAChR alpha9 subunit. We identified an interaction between the aa381-386 of the SARS-CoV-2 spike glycoprotein and the aa189-192 of the extracellular domain of the nAChR alpha9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the alpha9 nAChR and alpha-bungarotoxin. A similar interaction was observed between the pentameric alpha7 AChR and the SARS-CoV-2 spike glycoprotein. Our findings support the hypothesis that severe COVID-19 may be associated with disruption of the nicotinic cholinergic system which could be caused by an interaction between SARS-CoV-2 and nAChRs.

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Fucosidosis—Clinical Manifestation, Long-Term Outcomes, and Genetic Profile—Review and Case Series

Genes ◽

10.3390/genes11111383 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1383 ◽

Cited By ~ 1

Author(s):

Karolina M. Stepien ◽

Elżbieta Ciara ◽

Aleksandra Jezela-Stanek

Keyword(s):

Neurodegenerative Disorder ◽

Respiratory Infections ◽

Clinical Manifestations ◽

Case Series ◽

Genetic Profile ◽

Nonsense Mutations ◽

Pathogenic Variants ◽

One Stop ◽

Stop Loss

Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the FUCA1 gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described—one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype–phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases.

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Structure and selectivity engineering of the M1 muscarinic receptor toxin complex

Science ◽

10.1126/science.aax2517 ◽

2020 ◽

Vol 369 (6500) ◽

pp. 161-167 ◽

Cited By ~ 2

Author(s):

Shoji Maeda ◽

Jun Xu ◽

Francois Marie N. Kadji ◽

Mary J. Clark ◽

Jiawei Zhao ◽

...

Keyword(s):

Acetylcholine Receptors ◽

Muscarinic Acetylcholine Receptors ◽

Tertiary Structures ◽

Venom Toxin ◽

Natural Toxins ◽

Subtype Specificity ◽

Snake Venom Toxin ◽

M1 Muscarinic ◽

Subtype Selective

Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein–coupled receptor modulators.

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Aluminum Suppresses Effect of Nicotine on Gamma Oscillations (20-40 Hz) in Mouse Hippocampal Slices

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180619155644 ◽

2018 ◽

Vol 17 (6) ◽

pp. 404-411 ◽

Cited By ~ 4

Author(s):

Syeda Mehpara Farhat ◽

Touqeer Ahmed

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Cholinergic System ◽

Acetylcholine Receptors ◽

Peak Power ◽

Hippocampal Slices ◽

Field Potential ◽

Gamma Oscillations ◽

Gamma Oscillation ◽

Facilitatory Effect

Background: Aluminum (Al) causes neurodegeneration and its toxic effects on cholinergic system in the brain is well documented. However, it is unknown whether and how Al changes oscillation patterns, driven by the cholinergic system, in the hippocampus. Objective: We studied acute effects of Al on nicotinic acetylcholine receptors (nAChRs)-mediated modulation of persistent gamma oscillations in the hippocampus. Method: The field potential recording was done in CA3 area of acute hippocampal slices. Results: Carbachol-induced gamma oscillation peak power increased (1.32±0.09mV2/Hz, P<0.01) in control conditions (without Al) by application of 10µM nicotine as compared to baseline value normalized to 1. This nicotine-induced facilitation of gamma oscillation peak power was found to depend on non-α7 nAChRs. In slices with Al pre-incubation for three to four hours, gamma oscillation peak power was reduced (5.4±1.8mV2/Hz, P<0.05) and facilitatory effect of nicotine on gamma oscillation peak power was blocked as compared to the control (18.06±2.1mV2/Hz) or one hour Al pre-incubated slices (11.3±2.5mV2/Hz). Intriguingly wash-out, after three to four hours of Al incubation, failed to restore baseline oscillation power and its facilitation by nicotine as no difference was observed in gamma oscillation peak power between Al wash-out slices (3.4±1.1mV2/Hz) and slices without washout (3.6±0.9mV2/Hz). Conclusion: This study shows that at cellular level, exposure of hippocampal tissue to Al compromised nAChR-mediated facilitation of cholinergic hippocampal gamma oscillations. Longer in vitro Al exposure caused permanent changes in hippocampal oscillogenic circuitry and changed its sensitivity to nAChR-modulation. This study will help to understand the possible mechanism of cognitive decline induced by Al.

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Facial cleft? The first case of manitoba‐oculo‐tricho‐anal syndrome with novel mutations in China: a case report

BMC Pediatrics ◽

10.1186/s12887-021-02506-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Shuchen Gu ◽

Yimin Khoong ◽

Xin Huang ◽

Tao Zan

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Manifestations ◽

Sporadic Case ◽

Facial Cleft ◽

Ocular Manifestations ◽

First Case ◽

Whole Exome ◽

Chinese Girl ◽

Low Prevalence

Abstract Background Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare syndrome with only 27 cases reported worldwide so far, but none was reported in the population of Eastern Asia. Such extremely low prevalence might be contributed by misdiagnosis due to its similarities in ocular manifestations with facial cleft. In our study, we discovered the first case of MOTA syndrome in the population of China, with 2 novel FRAS1 related extracellular matrix 1 (FREM1) gene stop-gain mutations confirmed by whole exome sequencing. Case presentation A 12-year-old Chinese girl presented with facial cleft-like deformities including aberrant hairline, blepharon-coloboma and broad bifid nose since birth. Whole exome sequencing resulted in the identification of 2 novel stop-gain mutations in the FREM1 gene. Diagnosis of MOTA syndrome was then established. Conclusions We discovered the first sporadic case of MOTA syndrome according to clinical manifestations and genetic etiology in the Chinese population. We have identified 2 novel stop-gain mutations in FREM1 gene which further expands the spectrum of mutational seen in the MOTA syndrome. Further research should be conducted for better understanding of its mechanism, establishment of an accurate diagnosis, and eventually the exploitation of a more effective and comprehensive therapeutic intervention for MOTA syndrome.

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Vitamin C in the Treatment of COVID-19

Nutrients ◽

10.3390/nu13041172 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1172

Author(s):

Gregorio Paolo Milani ◽

Marina Macchi ◽

Anat Guz-Mark

Keyword(s):

Clinical Trials ◽

Vitamin C ◽

Respiratory Infections ◽

Medical Condition ◽

Case Reports ◽

Case Series ◽

Theoretical Background ◽

Current Evidence ◽

Vitamin C Supplementation ◽

Essential Nutrient

Vitamin C is an essential nutrient that serves as antioxidant and plays a major role as co-factor and modulator of various pathways of the immune system. Its therapeutic effect during infections has been a matter of debate, with conflicting results in studies of respiratory infections and in critically ill patients. This comprehensive review aimed to summarize the current evidence regarding the use of vitamin C in the prevention or treatment of patients with SARS-CoV2 infection, based on available publications between January 2020 and February 2021. Overall, 21 publications were included in this review, consisting of case-reports and case-series, observational studies, and some clinical trials. In many of the publications, data were incomplete, and in most clinical trials the results are still pending. No studies regarding prevention of COVID-19 with vitamin C supplementation were found. Although some clinical observations reported improved medical condition of patients with COVID-19 treated with vitamin C, available data from controlled studies are scarce and inconclusive. Based on the theoretical background presented in this article, and some preliminary encouraging studies, the role of vitamin C in the treatment of patients with SARS-CoV-2 infection should be further investigated.

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766. Everything Old is New Again-A Case Series of New World Leishmaniasis in African Children in Portland, Maine

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.956 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S428-S428

Author(s):

Jennifer Jubulis ◽

Amanda Goddard ◽

Elizabeth Seiverling ◽

Marc Kimball ◽

Carol A McCarthy

Keyword(s):

Latin America ◽

Cutaneous Leishmaniasis ◽

New World ◽

Pediatric Patients ◽

Data Extraction ◽

Clinical Manifestations ◽

Case Series ◽

Surgical Excision ◽

Skin Lesions ◽

Travel History

Abstract Background Leishmaniasis has many clinical manifestations and treatment regimens, dependent on species and host. Old world leishmaniasis is found primarily in Africa and Asia, and is associated with visceral disease, while new world disease, seen primarily in Latin America, is more commonly mucocutaneous. We present a case series of pediatric African patients with New World cutaneous leishmaniasis (NWCL). Methods Data extraction was performed via chart review, analyzing travel history, clinical presentation, diagnosis, and management in children with cutaneous leishmaniasis presenting to the pediatric infectious diseases clinic in Portland, ME. Biopsy specimens were sent to the federal CDC for identification by PCR and culture. Results Five cases of NWCL were diagnosed in pediatric patients in Maine from November 2018 through February 2020. Median age of patients was 10 years (range 1.5-15 years). Four cases (80%) occurred in children from Angola or Democratic Republic of Congo, arriving in Maine via Central/South America, with one case in a child from Rwanda who arrived in Maine via Texas. Three patients had multiple skin lesions and two had isolated facial lesions. Leishmaniasis was not initially suspected resulting in median time to diagnosis of 5 months (range 1-7 months). Four patients were initially treated with antibacterials for cellulitis and one was treated with griseofulvin. After no improvement, patients underwent biopsy with 2 patients diagnosed with L panamensis, 1 with L braziliensis, 1 with mixed infection (L panamensis and L mexicana), and 1 with Leishmania species only. One patient was managed with surgical excision, 3 with ketoconazole, and 1 was observed off therapy. Four patients were referred to otolaryngology. All continue to be followed in infectious disease clinic. Conclusion We present five cases of new world cutaneous leishmaniasis in African pediatric patients arriving to Maine through Latin America or Texas. Patients were diagnosed with cellulitis, tinea corporis or atopic dermatitis initially, underscoring importance of high index of suspicion in migrant patients. Detailed travel history and epidemiologic knowledge is essential to diagnosis, as patients may present with illness not congruent with country of origin. Optimal therapy remains unclear. Disclosures All Authors: No reported disclosures

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Clinical Features and Maternal-fetal Results of Pregnant Women in COVID-19 Times

Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics ◽

10.1055/s-0041-1729145 ◽

2021 ◽

Vol 43 (05) ◽

pp. 384-394

Author(s):

Ana Paula Nogueira Godoi ◽

Gilcelia Correia Santos Bernardes ◽

Leilismara Sousa Nogueira ◽

Patrícia Nessralla Alpoim ◽

Melina de Barros Pinheiro

Keyword(s):

Pregnant Women ◽

Vertical Transmission ◽

Postpartum Period ◽

Scientific Literature ◽

Respiratory Infections ◽

Clinical Manifestations ◽

Fetal Distress ◽

Medical Subject Headings ◽

Substantial Evidence ◽

The Subject

Abstract Objective Coronavirus disease 2019 (COVID-19) is a disease caused by a newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which usually leads to non-specific respiratory symptoms. Although pregnant women are considered at risk for respiratory infections by other viruses, such as SARS and Middle East respiratory syndrome (MERS), little is known about their vulnerability to SARS-CoV-2. Therefore, this study aims to identify and present the main studies on the topic, including the postpartum period. Methods In this narrative review, articles were searched in various databases, organizations, and health entities using keywords compatible with medical subject headings (MeSH), such as: COVID-19, pregnancy, vertical transmission, coronavirus 2019, and SARS-CoV-2. Results The review of the scientific literature on the subject revealed that pregnant women with COVID-19 did not present clinical manifestations significantly different from those of non-pregnant women; however, there are contraindicated therapies. Regarding fetuses, studies were identified that reported that infection by SARS-CoV-2 in pregnant women can cause fetal distress, breathing difficulties and premature birth, but there is no substantial evidence of vertical transmission. Conclusion Due to the lack of adequate information and the limitations of the analyzed studies, it is necessary to provide detailed clinical data on pregnant women infected with SARS-CoV-2 and on the maternal-fetal repercussions caused by this infection. Thus, this review may contribute to expand the knowledge of professionals working in the area as well as to guide more advanced studies on the risk related to pregnant women and their newborns. Meanwhile, monitoring of confirmed or suspected pregnant women with COVID-19 is essential, including in the postpartum period.

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The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽

10.3390/diagnostics10121102 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1102

Author(s):

Fatima Domenica Elisa De Palma ◽

Valeria Raia ◽

Guido Kroemer ◽

Maria Chiara Maiuri

Keyword(s):

Cystic Fibrosis ◽

Respiratory Infections ◽

Current Knowledge ◽

Pancreatic Insufficiency ◽

Clinical Manifestations ◽

Predictive Biomarkers ◽

Loss Of Function ◽

Gene Encoding ◽

Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

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