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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

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SARS-CoV-2 Proteins
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    Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 HGNC Expression and Attenuates SARS-CoV-2 Infection MESHD in vitro

    Authors: Dean Gilham; Audrey L Smith; Li Fu; Dalia Y Moore; Abenaya Muralidharan; St. Patrick M Reid; Stephanie C Stotz; Jan O Johansson; Michael Sweeney; Norman CW Wong; Ewelina Kulikowski; Dalia El-Gamal

    doi:10.1101/2021.03.10.432949 Date: 2021-03-11 Source: bioRxiv

    Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 MESHD and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal ( BET HGNC) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection MESHD. Herein, we demonstrate apabetalone, the most clinical advanced BET HGNC inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry MESHD, including angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) and dipeptidyl-peptidase 4 HGNC ( DPP4 HGNC or CD26 HGNC) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection MESHD in vitro to levels comparable to antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19 MESHD, either alone or in combination with emerging therapeutics.

    Tropism of SARS-CoV-2 MESHD for Developing Human Cortical Astrocytes

    Authors: Madeline G Andrews; Tanzila Mukhtar; Ugomma C Eze; Camille R Simoneau; Yonatan Perez; Mohammed A Mostajo-Radji; Shaohui Wang; Dmitry Velmeshev; Jahan Salma; G. Renuka Kumar; Alex A Pollen; Elizabeth E Crouch; Melanie Ott; Arnold R Kriegstein

    doi:10.1101/2021.01.17.427024 Date: 2021-01-18 Source: bioRxiv

    The severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) readily infects MESHD a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms MESHD, which range in severity, accompany a significant proportion of COVID-19 MESHD cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 HGNC expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 HGNC and CD147 HGNC. Inhibition of DPP4 HGNC reduced infection and decreased expression of the cell stress marker, ARCN1 HGNC. We find tropism of SARS-CoV-2 MESHD for human astrocytes mediated by DPP4 HGNC, resulting in reactive gliosis-type injury MESHD.

    Host genome analysis of structural variations by Optical Genome Mapping provides clinically valuable insights into genes implicated in critical immune, viral infection MESHD, and viral replication pathways in patients with severe COVID-19 MESHD.

    Authors: Nikhil Sahajpal; Chi-Yu Jill Lai; Alex Hastie; Ashis K Mondal; Siavash Raeisi Dehkordi; Cas van der Made; Olivier Fedrigo; Farooq Al-Ajli; Sawan Jalnapurkar; Rashmi Kanagal-Shamanna; Brynn Levy; Silviu-Alin Bacanu; Michael C Zody; Catherine A. Brownstein; Amyn M. Rojiani; Alan H. Beggs; Vineet Bafna; Alexander Hoischen; Erich D. Jarvis; Alka Chaubey; Ravindra Kolhe; - COVID-19 Host Genome Structural Variant Consortium

    doi:10.1101/2021.01.05.21249190 Date: 2021-01-08 Source: medRxiv

    BackgroundThe varied clinical manifestations and outcomes in patients with SARS-CoV-2 infections MESHD implicate a role of host-genetics in the predisposition to disease severity. This is supported by evidence that is now emerging, where initial reports identify common risk factors and rare genetic variants associated with high risk for severe/ life-threatening COVID-19 MESHD. Impressive global efforts have focused on either identifying common genetic factors utilizing short-read sequencing data in Genome-Wide Association Studies (GWAS) or whole-exome and genome studies to interrogate the human genome at the level of detecting single nucleotide variants (SNVs) and short indels. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs) including copy number variants (CNVs), which account for a substantial proportion of variation among individuals. Thus, we investigated the host genomes of individuals with severe/life-threatening COVID-19 MESHD at the level of large SVs (500bp-Mb level) to identify events that might provide insight into the inter-individual clinical variability in clinical course and outcomes of COVID-19 MESHD patients. MethodsOptical genome mapping using Bionanos Saphyr(R) system was performed on thirty-seven severely ill COVID-19 MESHD patients admitted to intensive care units (ICU). To extract candidate SVs, three distinct analyses were undertaken. First, an unbiased whole-genome analysis of SVs was performed to identify rare/unique genic SVs in these patients that did not appear in population datasets to determine candidate loci as decisive predisposing factors associated with severe COVID-19 MESHD. Second, common SVs with a population frequency filter was interrogated for possible association with severe COVID-19 MESHD based on literature surveys. Third, genome-wide SV enrichment in severely ill patients versus the general population was investigated by calculating odds ratios to identify top-ranked genes/loci. Candidate SVs were confirmed using qPCR and an independent bioinformatics tool (FaNDOM). ResultsOur patient-centric investigation identified 11 SVs involving 38 genes implicated in three key host-viral interaction pathways: (1) innate immunity and inflammatory response, (2) airway resistance to pathogens, and (3) viral replication, spread, and RNA editing. These included seven rare/unique SVs (not present in the control dataset), identified in 24.3% (9/37) of patients, impacting up to 31 genes, of which STK26 HGNC and DPP4 HGNC are the most promising candidates. A duplication partially overlapping STK26 HGNC was corroborated with data showing upregulation of this gene in severely ill patients. Further, using a population frequency filter of less than 20% in the Bionano control dataset, four SVs involving seven genes were identified in 56.7% (21/37) of patients. ConclusionThis study is the first to systematically assess and highlight SVs potential role in the pathogenesis of COVID-19 MESHD severity. The genes implicated here identify novel SVs, especially STK26 HGNC, and extend previous reports involving innate immunity and type I interferon response in the pathogenesis of COVID-19 MESHD. Our study also shows that optical genome mapping can be a powerful tool to identify large SVs impacting disease outcomes with split survival and add valuable genomic information to the existing sequencing-based technology databases to understand the inter-individual variability associated with SARS-CoV-2 infections MESHD and COVID-19 MESHD mortality.

    A One Health Approach to Studying the Differences in the Evolutionary Dynamics of MERS and SARS Coronaviruses

    Authors: Xu Zhang; Jamal S. M. Sabir; Xuejuan Shen; Zhiqing Pu; Nahid H. Hajrah; Mohamed M. M. Ahmed; Tingting Luo; Meshaal J. Sabir; Onaizan Godian Al-Zogabi; Junbin Pan; David M. Irwin; Yongyi Shen

    doi:10.21203/rs.3.rs-122443/v1 Date: 2020-12-05 Source: ResearchSquare

    BackgroundSARS-CoV and MERS-CoV are two coronaviruses that received great attention due to their high pathogenicity and mortality rates in human populations. While SARS was controlled, MERS continues to be a global public health concern. To examine differences in the epidemic patterns of these two viruses, we collected all available sequences to compare the different evolutionary characteristics of SARS-CoV MESHD and MERS-CoV. Notably, almost all of the human infection cases occurred in the Middle East, and cases that occurred outside of the Middle East involved travelers from this region, while African infections have so far not been reported. It is not clear that genetic differences between Africans and Arabs lead to differences in susceptibility.ResultsIn this study, we compared their evolutionary dynamics to provide a One Health perspective of their different results of disease control. The phylogenetic network of SARS-CoVs showed that human isolates gathered into a “super-spreader” cluster, and were distinct from civet isolates. In contrast, dromedary camel- and human-isolated MERS-CoVs were clustered together. Thus, most clades of MERS-CoV can infect humans, and MERS-CoVs seem easier to spill over from animal-to-human interface. Although MERS-CoVs are endemic to dromedary camels in both the Middle East and Africa, all human infections are linked to the Middle East. The nucleotide sequences of the MERS-CoV receptor gene--dipeptidyl peptidase 4 ( DPP4 HGNC) from 30 Egyptians, 36 Sudanese, and 34 Saudi Arabians showed little difference.ConclusionsOur study reveals the reason why MERS-CoV is not easily controlled. Analysis of genetic differences between Africans and Arabs suggest that human population differences in DPP4 HGNC might not be the reason for their different MERS prevalence, raising the possibility that other reasons, such as poorer disease surveillance in Africa, might explain these observations.

    Beta-cells from patients with COVID-19 MESHD and from isolated human islets exhibit ACE2 HGNC, DPP4 HGNC, and TMPRSS2 HGNC expression, viral infiltration and necroptotic cell death

    Authors: Charlotte Steenblock; Stefanie Richter; Ilona Berger; Marko Barovic; Janine Schmid; Undine Schubert; Natalia Jarzebska; Anne von Mässenhausen; Andreas Linkermann; Annette Schürmann; Jessica Pablik; Katja Evert; Roman Rodionov; Natalia Semenova; Vsevolod Zinslering; Raul Gainetdinov; Gustavo Baretton; Dirk Lindemann; Michaele Solimena; Barbara Ludwig; Stefan Bornstein

    doi:10.21203/rs.3.rs-88524/v1 Date: 2020-10-06 Source: ResearchSquare

    Here we report a possible mechanistic link between coronavirus disease 2019 MESHD ( COVID-19 MESHD) and diabetes MESHD. In addition to its known role on the respiratory system, the human coronavirus SARS-CoV-2 has been shown to affect the endocrine system including the pancreas MESHD 1-4. It has been suggested that the virus can induce type 1 diabetes MESHD 5-8. Therefore, we isolated human pancreatic islets and examined the expression of angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) and the protease TMPRSS2 HGNC, known to be important for SARS-CoV-2 entry 9. Furthermore, we investigated the expression of an alternative entry receptor, dipeptidyl peptidase-4 HGNC ( DPP4 HGNC also known as CD26 HGNC) 10. We found all three proteins expressed in pancreatic beta-cells and confirmed that beta-cells are permissive to infection with SARS-CoV-2 pseudoviruses. Additionally, we performed a comprehensive analysis of ACE2 HGNC, TMPRSS2 HGNC and DPP4 HGNC expression in pancreata of 10 patients who died of COVID-19 MESHD. We report significant variation between the samples and detected the highest levels of ACE2 HGNC and DPP4 HGNC expression in patients exhibiting SARS-CoV-2 infiltration shown by confocal microscopy, RNAscope and electron microscopy. Furthermore, necroptotic cell death was observed in beta-cells of the COVID-19 MESHD patients. Taken together, these data suggest that SARS-CoV-2 viral infection of pancreatic MESHD beta-cells may trigger necroptosis and islet impairment MESHD.

    New insights into n COVID-19 MESHD binding domain and its cellular receptors

    Authors: Ankush Garg; Gaurav Kumar; Sharmistha Sinha; Kiersten P Tucker; Karen Lin; Mario Cortese; Sean Tucker; Maribel Huaringa Nunez; Nancy Rojas Serrano; Omar Caceres Rey

    doi:10.1101/2020.09.06.285023 Date: 2020-09-06 Source: bioRxiv

    n COVID-19 MESHD virus makes cellular entry using its spike protein PROTEIN protruding out on its surface. Angiotensin converting enzyme 2 receptor has been identified as a receptor that mediates the viral entry by binding with the receptor binding motif of spike protein PROTEIN. In the present study, we elucidate the significance of N-terminal domain of spike protein PROTEIN in spike-receptor interactions. Recent clinical reports indicate a link between n COVID-19 MESHD infections with patient comorbidities. The underlying reason behind this relationship is not clear. Using molecular docking, we study the affinity of the n COVID-19 MESHD spike protein PROTEIN with cell receptors overexpressed under disease conditions. Our results suggest that certain cell receptors such as DC/L-SIGN, DPP4 HGNC, IL22R HGNC and ephrin receptors could act as potential receptors for the spike protein PROTEIN. The receptor binding domain of n COVID-19 MESHD is more flexible than that of SARS-COV MESHD and has a high propensity to undergo phase separation. Higher flexibility of n COVID-19 MESHD receptor binding domain might enable it to bind multiple receptor partners. Further experimental work on the association of these receptors with spike protein PROTEIN may help us to explain the severity of n COVID-19 MESHD infection in patients with comorbidities.

    ACE2 HGNC interaction networks in COVID-19 MESHD: a physiological framework for prediction of outcome in patients with cardiovascular risk factors

    Authors: Zofia Wicik; Ceren Eyileten; Daniel Jakubik; Rodrigo Pavao; Jolanta M Siller-Matula; Marek Postula

    doi:10.1101/2020.05.13.094714 Date: 2020-05-14 Source: bioRxiv

    BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection MESHD ( coronavirus disease 2019 MESHD; COVID-19 MESHD) is associated with adverse outcome in patients with cardiovascular disease MESHD ( CVD MESHD). AimTo characterize the interaction between SARS-CoV-2 and Angiotensin Converting Enzyme 2 HGNC ( ACE2 HGNC) functional networks with focus on CVD. MethodsUsing bioinformatic tools, network medicine approaches and publicly available datasets, we investigated ACE2 HGNC tissue expression and described ACE2 HGNC interaction network which could be affected by SARS-CoV-2 infection MESHD. We identified top ACE2 HGNC interactors, including miRNAs which are shared regulators between the ACE2 HGNC, virus-infection related proteins and heart interaction networks, using lung and nervous system networks as a reference. We also identified main SARS-CoV-2 risk groups and performed drug predictions for them. ResultsWe found the same range of ACE2 HGNC expression confidence in respiratory and cardiovascular systems (averaging 4.48 and 4.64, respectively). Analysing the complete ACE2 HGNC interaction network, we identified 11 genes ( ACE2 HGNC, DPP4 HGNC, ANPEP HGNC, CCL2 HGNC, TFRC HGNC, MEP1A HGNC, ADAM17 HGNC, FABP2 HGNC, NPC1 HGNC, CLEC4M HGNC, TMPRSS2 HGNC) associated with virus-infection related processes. Previously described genes associated with cardiovascular risk factors DPP4 HGNC, CCL2 HGNC and ANPEP HGNC were extensively connected with top regulators of ACE2 HGNC network, including ACE HGNC, INS and KNG1 HGNC. Enrichment analysis revealed several disease phenotypes associated with interaction networks of ACE2 HGNC, heart tissue, and virus-infection related protein, with the strongest associations with the following diseases (in decreasing rank order): obesity, hypertensive disease, non-insulin dependent diabetes mellitus, congestive heart failure, and coronary artery disease. We described for the first time microRNAs- miR HGNC (miR-302c-5p, miR-1305 HGNC, miR-587 HGNC, miR-26b HGNC-5p, and mir-27a-3p), which were common regulators of the three networks: ACE2 HGNC, heart tissue and virus-infection related proteins. ConclusionOur study provides novel information regarding the complexity of signaling pathways affected by SARS-CoV-2 and proposes predictive tools as miR HGNC towards personalized diagnosis and therapy in COVID-19 MESHD. Additionally, our study provides a list of miRNAs with biomarker potential in prediction of adverse outcome in patients with COVID-19 MESHD and CVD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/094714v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@11e52b0org.highwire.dtl.DTLVardef@1c6d9ceorg.highwire.dtl.DTLVardef@57be3org.highwire.dtl.DTLVardef@8889c_HPS_FORMAT_FIGEXP M_FIG C_FIG

    Network proteins of angiotensin-converting enzyme 2 but not angiotensin-converting enzyme 2 itself are host cell receptors for SARS-Coronavirus-2 attachment

    Authors: Arun Kumar

    doi:10.21203/rs.3.rs-27149/v1 Date: 2020-05-05 Source: ResearchSquare

    Background: Coronaviruses causing severe acute respiratory syndrome MESHD ( SARS-CoV MESHD) are known to enter the host cells by attaching to the membrane bound angiotensin-converting enzyme 2 ( ACE2 HGNC). Using molecular docking the efficiency of interaction between SARS-CoV-2 surface proteins and ACE2 HGNC network proteins was assessed. Materials and Methods: The ACE2 HGNC protein network was identified using the STRING database. The reported SARS-CoV-2 target proteins were searched in the protein data bank and uniport database. The protein-protein interactions were assessed by molecular docking using the Chimera software. The PubChem database was searched for known inhibitors of host cell receptors interacting with SARS-CoV-2 surface proteins. Molecular docking was performed to evaluate the binding efficacy of these compounds against the SARS-CoV-2 targets using AutoDock Vina and the docked protein-ligand complex were visualised using the Chimera and PyMOL software. Results: A low binding affinity was observed between SARS-CoV-2 spike PROTEIN proteins ( protein S PROTEIN, M and 6YLA) and ACE2 HGNC. Coronaviruses are also reported to bind to dipeptidyl peptidase 4 HGNC ( DPP4 HGNC), which is a network protein of ACE2 HGNC. Network analysis showed five membrane proteins associated with ACE2 HGNC. The ACE2 HGNC network proteins were assessed for their binding affinity with all known SARS-CoV-2 surface proteins. The SARS-CoV-2 surface proteins showed preferential binding to network proteins such as DPP4 HGNC and Meprin A alpha but not ACE2 HGNC. The binding efficacy (affinity (-5.86 to -7.10 Kcal/mol), Ki (6.32 – 22.04 mM) and IC50 (12.63 – 113.71 mM) values) of DPP4 HGNC inhibitors (saxagliptin and sitagliptin) against SARS-CoV-2 surface proteins, was observed to be at a therapeutically feasible concentration to prevent SARS-CoV-2 attachment MESHD and entry into host cells. Conclusion: SARS-CoV-2 surface proteins has better interactions with DPP4 HGNC and Meprin A alpha host cells receptors rather than ACE2 HGNC. DPP4 HGNC inhibitors (saxagliptin and sitagliptin) by binding with SARS-CoV-2 surface proteins may be helpful in preventing the virus entry into the host cells.                  

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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