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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (99)

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NSP5 (2)

ComplexRdRp (1)


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SARS-CoV-2 Proteins
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    Membrane-Mediated Sars-cov-2 Host Cell Entry: Potential Inhibitory Roles of Terpenoids in Silico

    Authors: Gideon Ampoma Gyebi; Oludare Ogunyemi; Ibrahim M. Ibrahim; Olalekan B. Ogunro; Adegbenro P. Adegunloye; Saheed Afolabi

    doi:10.21203/rs.3.rs-259624/v1 Date: 2021-02-20 Source: ResearchSquare

    Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection MESHD. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC), human transmembrane protease serine 2 HGNC ( TMPRSS2 HGNC) and the S proteins PROTEIN of SARS-CoV-2, SARS-CoV MESHD and MERS-CoV. In silico ADMET and drug-likeness prediction, molecular dynamics simulation ( MDS MESHD), binding free energy calculations and clustering analysis of MDS trajectories were performed on the top docked compounds to respective targets. The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Pentacyclic terpenoids: 24-methylene cycloartenol and isoiguesterin interacted with the hACE2 HGNC binding hotspots for the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN protein. 11-hydroxy-2 - (3,4-dihydroxybenzoyloxy) abieta -5,7,9 (11),13-tetraene-12-one, 11-hydroxy-2 -(4-hydroxybenzoyloxy)-abieta- 5,7,9(11),13-tetraene-12-one and other abietane diterpenes interacted strongly with the S1-specificy pocket of TMPRSS2 HGNC. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike PROTEIN protein respectively. The predicted druggable and ADMET favourable terpenoids formed structurally stable complexes in the simulated dynamics environment. These terpenoids provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell mediated entry, subject to further in vitro and in vivo studies. 

    Impaired local intrinsic immunity to SARS-CoV-2 infection MESHD in severe COVID-19 MESHD

    Authors:

    doi:10.1101/2021.02.20.431155 Date: 2021-02-20 Source: bioRxiv

    Infection with SARS-CoV-2, the virus that causes COVID-19 MESHD, can lead to severe lower respiratory illness MESHD including pneumonia MESHD and acute respiratory distress syndrome MESHD, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection MESHD, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection MESHD, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19 MESHD, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19 MESHD. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 MESHD show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13 HGNC+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous MESHD cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL HGNC, TMPRSS2 HGNC) or response (e.g., MX1 HGNC, IFITM3 HGNC, EIF2AK2 HGNC) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19 MESHD.

    Multiple Sites on SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD Protein are Susceptible to Proteolysis by Cathepsins B, K, L, S, and V

    Authors: Keval Bollavaram; Tiffanie Leeman; Akhil Kulkarni; Sophia Upshaw; Maggie Lee; Jiabei Yang; Hannah Song; Manu O Platt

    doi:10.1101/2021.02.17.431617 Date: 2021-02-17 Source: bioRxiv

    SARS-CoV-2 is the coronavirus responsible for the COVID-19 pandemic MESHD. Proteases are central to the infection process of SARS-CoV-2 MESHD. Cleavage of the spike protein PROTEIN on the virus capsid causes the conformational change that leads to membrane fusion and viral entry into the target cell. Since inhibition of one protease, even the dominant protease like TMPRSS2 HGNC, may not be sufficient to block SARS-CoV-2 entry into cells, other proteases that may play an activating role and hydrolyze the spike protein PROTEIN must be identified. We identified amino acid sequences in all regions of spike protein PROTEIN, including the S1/S2 region critical for activation and viral entry, that are susceptible to cleavage by furin HGNC and cathepsins B, K, L, S, and V using PACMANS, a computational platform that identifies and ranks preferred sites of proteolytic cleavage on substrates, and verified with molecular docking analysis and immunoblotting to determine if binding of these proteases can occur on the spike protein PROTEIN that were identified as possible cleavage sites. Together, this study highlights cathepsins B, K, L, S, and V for consideration in SARS-CoV-2 infection MESHD and presents methodologies by which other proteases can be screened to determine a role in viral entry. This highlights additional proteases to be considered in COVID-19 MESHD studies, particularly regarding exacerbated damage in inflammatory preconditions where these proteases are generally upregulated.

    Endothelial cells elicit a pro-inflammatory response to SARS-COV-2 without productive viral infection MESHD

    Authors: Lilian Schimmel; Keng Yih Chew; Claudia Stocks; Teodor Yordanov; Tish Essebier; Arutha Kulasinghe; James Monkman; Anna Flavia Ribeiro dos Santos Miggiolaro; Lucia De Noronha; Anne K Lagendijk; Kate Schroder; Larisa Labzin; Emma J Gordon; Kirsty R Short

    doi:10.1101/2021.02.14.431177 Date: 2021-02-16 Source: bioRxiv

    Thrombotic and microvascular complications are frequently seen in deceased COVID-19 MESHD patients, suggesting that vascular pathology is a major driver of severe disease. However, whether this is caused by direct viral infection of the endothelium or inflammation MESHD-induced endothelial activation remains highly contentious. What role the endothelium plays in viral amplification and inflammation MESHD thus remains a key unresolved question in the pathogenesis of SARS-CoV-2. Here, we use patient autopsy samples, primary human endothelial cells and an in vitro model of the pulmonary epithelial-endothelial cell barrier to show that primary human endothelial cells express the SARS-CoV-2 receptor ACE2 HGNC and the protease TMPRSS2 HGNC, albeit at low levels. Accordingly, when present in a sufficiently high concentration, SARS-CoV-2 can enter primary human endothelial cells from either the apical or basolateral surface. Whilst inducing an inflammatory response, this is not a productive infection. We further demonstrate that in a co-culture model of the pulmonary epithelial-endothelial barrier, endothelial cells are not infected with SARS-CoV-2. They do however, sense and respond to an infection in the adjacent epithelial cells, resulting in the induction of a pro-inflammatory response. Taken together, these data suggest that in vivo, endothelial cells are unlikely to be infected with SARSCoV-2 and that infection is only likely to occur if the adjacent pulmonary epithelium is denuded (basolateral infection) or a high viral load is present in the blood (apical infection). In such a scenario, whilst SARS-CoV-2 infection MESHD of the endothelium can occur, it does not contribute to viral amplification. However, endothelial cells are still likely to play a key role in SARS-CoV-2 pathogenesis by sensing and mounting a pro-inflammatory response to SARS-CoV-2.

    COVIDENZA - A Prospective, Multicenter, Randomized PHASE II Clinical Trial of Enzalutamide Treatment to Decrease the Morbidity in Patients with Corona Virus Disease MESHD 2019 ( COVID-19 MESHD)

    Authors: Karin Welen; Anna Överby Wernstedt; Clas Ahlm; Eva Freyhult; David Robinsson; Anna Jonsson Henningsson; Johan Stranne; Daniel Bremell; Martin Angelin; Elisabeth Lindquist; Robert Buckland; Camilla Thellenberg Karlsson; Karlis Pauksens; Anna Bill Axelsson; Olof Akre; Cecilia Ryden; Magnus Wagenius; Anders Bjartell; Anna Nilsson; Johan Styrke; Johanna Repo; Åse Östholm Balkhed; Katarina Niward; Magnus Gisslen; Andreas Josefsson

    doi:10.21203/rs.3.rs-229140/v1 Date: 2021-02-10 Source: ResearchSquare

    ObjectivesThe main goal of the COVIDENZA trial is to evaluate if inhibition of testosterone signalling by enzalutamide can improve the outcome of patients hospitalized for COVID-19 MESHD. The hypothesis is based on the observation that the majority of patients in need of intensive care are male, and the connection between androgen receptor HGNC signalling and expression of TMPRSS2 HGNC, an enzyme important for SARS-CoV-2 host cell internalization.Trial designHospitalized COVID-19 MESHD patients will be randomised (2:1) to enzalutamide plus standard of care vs. standard of care designed to identify superiority.ParticipantsIncluded participants, men or women above 50 years of age, must be hospitalized for PCR confirmed COVID-19 MESHD symptoms and not in need of immediate mechanical ventilation. Major exclusion criteria are breast-feeding or pregnant women, hormonal treatment for prostate or breast cancer MESHD, treatment with immunosuppressive drugs, current symptomatic unstable cardiovascular disease MESHD (see additional file 1 for further details). The trial is registered at Umeå University Hospital, Region Västerbotten, Sweden and 8 hospitals are approved for inclusion in Sweden.Intervention and comparatorPatients randomised to the treatment arm will be treated orally with 160 mg (4x40 mg) enzalutamide (Xtandi®) daily, for five consecutive days. The study is not placebo controlled. The comparator is standard of care treatment for patients hospitalised with COVID-19 MESHD.Main outcomesThe primary endpoints of the study are (time to) need of mechanical ventilation or discharge from hospital as assessed by a clinical 7-point ordinal scale (up to 30 days after inclusion).RandomisationRandomisation was stratified by center and sex. Each strata was randomized separately with block size six with a 2:1 allocation ratio (enzalutamide + “standard of care”: “standard of care”). The randomisation list, with consecutive subject numbers, was generated by an independent statistician using the PROC PLAN procedure of SAS version 9.4 software (SAS Institute, Inc, Cary, North Carolina)Blinding (masking)This is an open-label trial.Numbers to be randomised (sample size)The trial is designed to have three phases. The first, an exploration phase of 45 participants (30 treatment and 15 control) will focus on safety and includes a more extensive laboratory assessment as well as more frequent safety evaluation. The second prolongation phase, includes the first 100 participants followed by an interim analysis to define the power of the study. The third phase is the continuation of the study up to maximum 600 participants included in total.Trial StatusThe current protocol version is COVIDENZA v2.0 as of September 10, 2020. Recruitment started July 29, 2020 and is presently in safety pause after the first exploration phase. Recruitment is anticipated to be complete by 31 December 2021.Trial registrationEudract number 2020-002027-10ClinicalTrials.gov Identifier: NCT04475601, registered June 8, 2020

    A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 HGNC KO.IL-2Rγc KO. NOD) for COVID-19 MESHD

    Authors: Teodor-Doru Brumeanu; Pooja Vir; Ahmad Faisal Karim; Swagata Kar; Dalia Benetiene; Megan Lok; Jack Greenhouse; Tammy Putmon-Taylor; Christopher Kitajewski; Kevin K. Chung; Kathleen P. Pratt; Sofia A. Casares

    doi:10.21203/rs.3.rs-225156/v1 Date: 2021-02-09 Source: ResearchSquare

    We report the first Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2RgcKO.NOD) for COVID-19 MESHD research. This mouse is reconstituted with human cord blood-derived, HLA-matched hematopoietic stem cells. It engrafts human epi/endothelial cells expressing the human ACE2 receptor for SARS-CoV-2 and TMPRSS2 HGNC serine protease co-localized on lung epithelia. HIS-DRAGA mice sustained SARS-CoV-2 infection MESHD, showing deteriorated clinical condition, replicating virus in the lungs, and human-like lung immunopathology including T-cell infiltrates, microthrombi and pulmonary sequelae MESHD. Among T-cell infiltrates, lung-resident (CD103+) CD8+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B HGNC and perforin, indicating cytotoxic potential. Infected mice also developed antibodies against the SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathology and for testing the safety and efficacy of candidate vaccines and therapeutics.

    Nasopharyngeal Expression of Angiotensin-Converting Enzyme 2 HGNC ( ACE2 HGNC) and Transmembrane Serine Protease 2 ( TMPRSS2 HGNC) in Children Compared to Adults Within Family Clusters Exposed to COVID-19 MESHD

    Authors: Mohammad Hasan; Muneera Ahmad; Soha Dargham; Hatem Ibrahim; Alaa Al Hashemi; Nonhlanhla Ngwabi; Andres Lopez; Simon Dobson; Laith Abu-Raddad; Patrick Tang

    doi:10.21203/rs.3.rs-208994/v1 Date: 2021-02-04 Source: ResearchSquare

    There is accumulating evidence that the lower levels of angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) and transmembrane serine protease 2 ( TMPRSS2 HGNC) in the nasal epithelium of children may be related to a lower incidence of COVID-19 MESHD compared to adults. However, no direct evidence is available to support this hypothesis. In this study, we compared the transcript levels of ACE2 HGNC and TMPRSS2 HGNC in nasopharyngeal swabs (n=207) from children and adult members within COVID-19 MESHD-exposed families and assessed their association with SARS-CoV-2 infection MESHD status. The expression of both genes was higher in adults compared to the children (n=115 adults and 92 children, p<0.05), but was not significantly different between COVID-19 MESHD positive and negative patients of all ages or within the same age groups. Using paired data, expression of both genes was significantly higher in COVID-19 MESHD positive adults compared to COVID-19 MESHD negative children (n=47 pairs; p<0.001) within the same families. ACE2 HGNC and TMPRSS2 HGNC expression is positively associated [OR:1.16(1.06-1.3) and 1.14(1.04-1.26) for ACE2 HGNC and TMPRSS2 HGNC, respectively, p<0.001)] with SARS-CoV-2 infection MESHD status in the sub-group of families with COVID-19 MESHD positive adults and COVID-19 MESHD negative children, suggesting that children with lower levels of nasal ACE2 HGNC and TMPRSS2 HGNC are more likely to remain COVID-19 MESHD negative despite being exposed to a COVID-19 MESHD-positive adult family member.

    The nasal symbiont Staphylococcus epidermidis shapes the cellular environment to decrease expression of SARS-CoV-2 entry factors in nasal epithelium

    Authors: Jeong Yeon Ji; Ara Jo; Jina Won; Chan Hee Gil; Haeun Shin; Sujin Kim; Yung Jin Jeon; Hyun Jik Kim

    doi:10.21203/rs.3.rs-208802/v1 Date: 2021-02-04 Source: ResearchSquare

    Background Emerging evidence indicates that severe acute respiratory syndrome MESHD-related coronavirus-2 (SARS-CoV-2) targets the human nasal epithelium via the principal entry factors angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) and transmembrane serine protease 2 ( TMPRSS2 HGNC), which are highly expressed in the nasal epithelium. However, little is known about suppressive biologics against SARS-CoV-2 entry factors. Here, we report that the nasal commensal Staphylococcus epidermidis altered the host transcriptional response against SARS-CoV-2 in the nasal epithelium by reducing ACE2 HGNC and TMPRSS2 HGNC gene expression in concert with an increase in serine-peptidase inhibitors.Results Our data reveal that ACE2 HGNC was more abundantly expressed in nasal epithelial (NHNE) cells than bronchial epithelial cells, and inoculation with S. epidermidis reduced ACE2 HGNC transcription in NHNE cells. Our data also show that TMPRSS2 HGNC mRNA was significantly decreased in NHNE cells and that S. epidermidis colony number MESHD in human nasal mucus was inversely correlated with ACE2 HGNC and TMPRSS2 HGNC gene expression in the nasal mucosa. In addition, levels of the serine-peptidase inhibitors SERPINE1 and SERPINE2 were significantly increased by S. epidermidis, and this accompanied reduction of TMPRSS2 HGNC transcription in nasal epithelial cells.Conclusion These results characterize the S. epidermidis-regulated host transcriptional response restricting SARS-CoV-2 entry to the nasal epithelium via downregulation of receptors and host protease for SARS-CoV-2 cellular invasion coupled with SERPINE1 and SERPINE2 induction.

    Immune response to SARS-CoV-2 in the nasal mucosa in children and adults

    Authors: Clarissa M Koch; Andrew D Prigge; Kishore R Anekalla; Avani Shukla; Hanh Chi Do-Umehara; Leah Setar; Jairo Chavez; Hiam Abdala-Valencia; Yuliya Politanska; Nikolay S Markov; Grant R Hahn; Taylor Heald-Sargent; L Nelson Sanchez-Pinto; William J Muller; Alexander V Misharin; Karen M Ridge; Bria M Coates

    doi:10.1101/2021.01.26.21250269 Date: 2021-01-28 Source: medRxiv

    Rationale: Despite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms. Objectives: To investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults. Methods: Clinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection MESHD, 24 children with RSV infection MESHD, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection MESHD, and 7 healthy pediatric and 13 healthy adult controls. Results: In both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV MESHD and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection MESHD. Expression of ACE2 HGNC and TMPRSS2 HGNC - key entry factors for SARS-CoV-2 - did not correlate with age or presence or absence of viral infection MESHD. Conclusions: Our findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site. Keywords: COVID-19 MESHD, pneumonia MESHD, viral infections MESHD, interferons

    Renin HGNC-Angiotensin System Blockade Influences ACE2 HGNC in Human Type II Pneumocytes

    Authors: Mauro G Silva; Nora L Falcoff; Gerardo C Corradi; José Alfie; Rolando F. Seguel; Gabriela Tabaj; Laura Iglesias; Myriam Nuñez; Gabriela R. Guman; Mariela M. Gironacci

    doi:10.21203/rs.3.rs-159733/v2 Date: 2021-01-27 Source: ResearchSquare

    Rationale— Angiotensin converting enzyme (ACE) 2 HGNC and the transmembrane protease serine 2 HGNC ( TMPRSS2 HGNC) are key for cellular entry of the type 2 coronavirus that causes severe acute respiratory syndrome MESHD (SARS-CoV2), the etiological agent of coronavirus-19 disease MESHD ( COVID-19 MESHD). There has been a growing concern that renin HGNC-angiotensin system (RAS) blockade with ACE HGNC inhibitors (ACEIs) or type 1 angiotensin (Ang II) receptor blockers (ARBs) increases ACE2 HGNC expression and then elevate patient susceptibility to SARS-CoV-2.  However, evidence about RAS blockade and ACE2 HGNC in human lung are lacking.Objective– To investigate RAS blockade on ACE2 HGNC and TMPRSS2 HGNC in type II pneumocytes of human lung parenchymal of untreated and ACEI/ARB-treated hypertensive MESHD subjects.Methods and Results– ACE2 HGNC and TMPRSS2 HGNC protein expression were measured by immunohistochemistry. We found that smoking and RAS blockade influence on the percentage of human ACE2 HGNC-expressing type II pneumocytes (p= 0.026). Smokers subjects under RAS blockade treatment exhibited higher percentage of ACE2 HGNC-expressing type II pneumocytes than normotensive ones. Within the ACEI/ARB-treated group, the percentage of ACE2 HGNC-expressing type II pneumocytes was higher in smokers than never smokers. A significant association between ACE2 HGNC immunostaining intensity and smoking on subjects over 60 years old was found (p= 0.05): older smokers exhibited higher ACE2 HGNC protein levels compared to youngers. The percentage of TMPRSS2 HGNC-expressing type II pneumocytes was greater in men than women (p= 0.026) and in subjects under 60 years old (p= 0.040) and trend to be higher in ACEI/ARB-treated subjects than normotensives (p= 0.060). A significant association between TMPRSS2 HGNC immunostaining intensity with smoking and age or with RAS blockade MESHD and age or with RAS blockade MESHD and smoking was observed. Older or smokers subjects under ACEI/ARB treatment exhibited higher TMPRSS2 HGNC protein levels than youngers or never smokers.Conclusions— ACE2 HGNC and TMPRSS2 HGNC are influenced by smoking and ACEI/ARB treatment. These findings help explain the increased susceptibility to COVID-19 MESHD in subjects with treated cardiovascular-related pathologies. 

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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