Enrichment of SARS-CoV-2 entry factors and interacting intracellular genes in peripheral immune cells

Devaprasad, Abhinandan; Pandit, Aridaman

doi:10.1101/2021.03.29.437515

Cited by 3 publications

(4 citation statements)

References 46 publications

(75 reference statements)

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“…[27][28][29][30]32,33 There is additional evidence that retinoid signaling activation can effectively suppress coronaviruses. 34 Our docking study reveals that COVID-19 spike protein binds directly to the integral membrane receptor (STRA 6). STRA 6 mediates cellular uptake of retinol (Vitamin A) by recognizing a molecule of RBP-retinol to trigger release and internalization of retino.…”

Section: Introductionmentioning

confidence: 92%

In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19

Elkazzaz,

Ahmed,

Abo Amer

et al. 2023

Ind. J. Pharm. Edu. Res

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A global pandemic of pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, at the end of 2019. Although, the ACE2 receptor has been demonstrated to be the main entry receptor of COVID-19, but our docking analysis, predicted and discovered a novel receptor termed STRA 6 that may play a critical role in the pathogenicity of COVID-19. STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid jm6 (STRA 6) was the first protein to be identified in a novel category of proteins, cytokine signaling transporters, due to its ability to function as both a cell surface receptor and a membrane protein that binds to retinol binding protein facilitating cellular uptake of retinol. The primary ligand of STRA6 (vitamin/retinol) was shown to be drastically reduced during COVID-19 infection, which agrees with our findings. We analyze the STRA6 and ACE2 receptor networks to predict the specific association among certain other proteins which might rely on similar functionality. Molecular docking showed a high affinity between the Spike protein with STRA6, the docking score of COVID-19 spike protein with STRA6 (-354.68) kcal/mol was higher than the docking score of spike protein with ACE2 (-341.21) kcal/mol. Results of MD simulations revealed significant stability of the spike protein with STRA6 up to 100 ns. SARS-CoV-2 spike protein binds strongly and directly to STRA6. Which are highly expressed in Lymphatic system and Immune cells. This study paves the way towards understanding the complex mechanism of existing of covid-19 infection complications such as immune suppression and ineffective RIG-I pathway. Restoring the balance between the STRA6 and ACE2 in the context of spike protein RBD may be promising target in SARS CoV-2 Pathogenesis and may reveal new drug targets for new variants of COVID-19.

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Section: Introductionmentioning

confidence: 92%

In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19

Elkazzaz,

Ahmed,

Abo Amer

et al. 2023

Ind. J. Pharm. Edu. Res

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“…Interestingly, lymphocytes in alveoli, pancreas, oesophagus, and spleen did not express ACE2 gene. but a small fraction of T-cells in kidney , colon , heart and lung expressed ACE2 gene (34). It was found that the fraction of ACE2 expressing immune cells is very small (34).…”

Section: -Reducing Plasma Retinol and Inducing Circulating Rbp4mentioning

confidence: 99%

“…but a small fraction of T-cells in kidney , colon , heart and lung expressed ACE2 gene (34). It was found that the fraction of ACE2 expressing immune cells is very small (34). Another study investigated the expression of TMPRSS2 and ACE2 across databases of multiple single-cell sequencing including 9 independent studies.…”

Section: -Reducing Plasma Retinol and Inducing Circulating Rbp4mentioning

confidence: 99%

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STRA6, as A Novel Binding Receptor of COVID-19, A Breakthrough That could Explain COVID-19 Symptoms with Unknown Aetiology.

Elkazzaz

Haydara

Abo-Amer³

et al. 2021

Preprint

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Background The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. Although, ACE2 has been identified as the principal host cell receptor of 2019-nCoV, and it is thought to play a critical role in the virus's entrance into the cell and subsequent infection, many cells can be infected by COVID-19 while also expressing little or no ACE2. Furthermore, COVID-19 may case a variety of pre and post symptoms with unknown etiology . It was documented that COVID-19 infection leads to a loss of smell (anosmia) but The COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. Moreover It was demonstrated that COVID-19 infects and kills lymphocyte thorough its ACE2 receptor. But numerous studies found that lymphocytes did not express ACE2 receptors or express it with a little, insufficient amount. It is clear from the information and findings presented and addressed below that COVID-19 not only binds to ACE2, but also to additional receptors, leading to existence of pre- and post-covid-19 symptoms which remain unexplained. As a result, discovering and identifying these receptors could lead to the development of new treatments that could suppress COVID-19 and reduce its severity and pathogenicityMethods The STRA6 receptor protein were submitted to the server for functional interaction associated network between partners for the STRING (Research Online of Interacting Genes/Proteins Data Basis version 10.0)13 .Docking study of each Spike -ACE 2 and STRA6 receptor protein were carried out using HDOCK server (http://hdock.phys.hust.edu.cn/). The binding mode of Spike -ACE 2 and STRA6 receptor protein is retrieved form the PDB https://www.rcsb.org/ with accession number (7DMU , 5sy1)ResultsOur results showed that COVID-19 Spike protein exhibited a high binding affinity for human STRA6 and a low binding energy with it. The docking score of COVID-19 spike protein with STRA6( -354.68) kcal/mol was higher than the docking score of spike protein with ACE2((-341.21 ) kcal/mol. Spike protein Receptor Binding Domain(RDB) of COVID-19 strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA6 receptor. The docking of STRA6 target protein with spike viral protein revealed the involvement of the spike protein into the extracellular and membrane part of the STRA6 receptor and amino acids residues of STRA6 along with spike protein which make interactions and play an important role in formation of complexes. The corresponding distances about the residue contacts between proteins STRA6- Spike protein complex are documented here where the STRA6- Spike protein complexes binding site are the RDB of the CHOLESTEROL in STRA6 receptor which bind with interface residue( ARG 511A , VAL 512A THR 515A ALA 516A ASN 519A with interface residue degree (2.965 , 3.595 , 3.286 , 4.592 , and 4.235) representatively, also the ability of the spike to bind to RDB of the STRA 6 protein in the ILE 131C , MET 145C , HIS 86A with interface residue( 4.961 , 4.953 and 3.271) representatively. STRA6- Spike protein complex with PDB ID (5SY1 , 6LZG) representatively ,the chain A ,B with Align – length ( 582 ,194 ) then the quarry coverage of proteins 0.793 and 1.000 with sequence identity 96.2 % and 100,0 % representatively. The surface view of complex reveals that the binding pocket of STRA6- Spike protein and Spike ACE 2 complexes with RMSD (189.44 Å , 1.00 Å ) representatively and docking score (-341.21 ,-354.68) kcal/mol, the quality of the receptor and the ligand are LGscore and MaxSub ( 2.416 , 0.147 ) where the structure are correct representatively for the STRA6 receptor protein, and LGscore and MaxSub ,(5.056 ,0.217) .ConclusionSTRA6 is a critical regulator of many biological processes thorough initiating cellular retinol uptake, in different organs and tissues as in immune cells for improving the immune system homeostasis in various populations. Our docking study reveals that COVID-19 spike protein binds directly to The integral membrane receptor (STRA6) in addition to its binding sites of the cholesterol. STRA6 mediates cellular uptake of retinol (vitamin A) by recognizing a molecule of RBP-retinol to trigger release and internalization of retinol . Therefore COVID-19 may leads to downregulation of STRA6 receptor leading to inhibition the regulatory function of retinoic acid and cholesterol helps in existing of pre and post-covid-91 symptoms and complications including lymhopenia, Nuerogical disorders, Ineffective RIG-I pathway, Interferon inhibition, Cytokine storm, Diabetes, Hormonal imbalance, Thrombosis, and Smell loss. Therefore, we believe that this novel discovery that STRA6 receptor acts as a novel binding receptor for COVID-19 could explain many previously unexplained pre and post-covid-91 infection symptoms . Moreover, retinoic acid metabolism was found to be defective in COVID-19 (cytokine storm), sepsis, ARDS and SIRS .As a result reconstitution of the retinoid signaling may prove to be a valid strategy for COVID-19 management. We suggest that Vitamin A metabolites ,especially, retinoic acid will be promising and effective treatments for COVID-91 infection and its unknown aetiology symptoms. It worth mentioning that aerosolized all- trans retinoic acid and 13 cis retinoic acid is currently under clinical investigation (ClinicalTrials.gov Identifier: NCT05002530, NCT04353180)

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TMPRSS2 Impacts Cytokine Expression in Murine Dendritic Cells

et al. 2023

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Background: The transmembrane protease serine 2 (TMPRSS2) proteolytically activates the envelope proteins of several viruses for viral entry via membrane fusion and is therefore an interesting and promising target for the development of broad-spectrum antivirals. However, the use of a host protein as a target may lead to potential side effects, especially on the immune system. We examined the effect of a genetic deletion of TMPRSS2 on dendritic cells. Methods: Bone marrow cells from wild-type (WT) and TMPRSS2-deficient mice (TMPRSS2−/−) were differentiated to plasmacytoid dendritic cells (pDCs) and classical DCs (cDCs) and activated with various toll-like receptor (TLR) agonists. We analyzed the released cytokines and the mRNA expression of chemokine receptors, TLR7, TLR9, IRF7 and TCF4 stimulation. Results: In cDCs, the lack of TMPRSS2 led to an increase in IL12 and IFNγ in TLR7/8 agonist resiquimod or TLR 9 agonist ODN 1668-activated cells. Only IL-10 was reduced in TMPRSS2−/− cells in comparison to WT cells activated with ODN 1668. In resiquimod-activated pDCs, the lack of TMPRSS2 led to a decrease in IL-6, IL-10 and INFγ. ODN 1668 activation led to a reduction in IFNα. The effect on receptor expression in pDCs and cDCs was low. Conclusion: The effect of TMPRSS2 on pDCS and cDCs depends on the activated TLR, and TMPRSS2 seems to affect cytokine release differently in pDCs and cDCs. In cDCs, TMPRSS2 seems to suppress cytokine release, whereas in pDCS TMPRSS2 possibly mediates cytokine release.

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Enrichment of SARS-CoV-2 entry factors and interacting intracellular genes in peripheral immune cells

Cited by 3 publications

References 46 publications

In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19

In silico Discovering STRA 6 Vitamin A Receptor, as a Novel Binding Receptor of COVID-19

STRA6, as A Novel Binding Receptor of COVID-19, A Breakthrough That could Explain COVID-19 Symptoms with Unknown Aetiology.

TMPRSS2 Impacts Cytokine Expression in Murine Dendritic Cells

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