Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (38)

NSP5 (3)

ComplexRdRp (3)

ProteinS1 (2)

ORF1ab (1)


SARS-CoV-2 Proteins
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    SARS-CoV-2 spike PROTEIN protein induces brain pericyte immunoreactivity in absence of productive viral infection

    Authors: Rayan Khaddaj-Mallat; Natija Aldib; Anne-Sophie Paquette; Aymeric Ferreira; Sarah Lecordier; Maxime Bernard; Armen Saghatelyan; Ayman ElAli

    doi:10.1101/2021.04.30.442194 Date: 2021-05-03 Source: bioRxiv

    COVID-19 MESHD is a respiratory disease MESHD caused by severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2). COVID-19 MESHD pathogenesis causes vascular-mediated neurological disorders MESHD via still elusive mechanisms. SARS-CoV-2 infects host MESHD cells by binding to angiotensin-converting enzyme 2 HGNC (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein PROTEIN. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury MESHD in COVID-19 MESHD. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 HGNC expression in human brain vascular pericytes is highly dynamic and is increased upon S protein PROTEIN stimulation. Pericytes exposed to S protein PROTEIN underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely -smooth muscle actin (- SMA HGNC), fibronectin HGNC, collagen I, and neurogenic locus notch homolog protein-3 HGNC ( NOTCH3 HGNC). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein PROTEIN induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B ( NF-{kappa}B HGNC) signalling pathway, which was potentiated by hypoxia MESHD, a condition associated to vascular comorbidities, which exacerbate COVID-19 MESHD pathogenesis. S protein PROTEIN exposure combined to hypoxia MESHD enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 HGNC ( IL-8 HGNC), IL-18 HGNC, macrophage migration inhibitory factor HGNC ( MIF HGNC), and stromal cell-derived factor-1 HGNC ( SDF-1 HGNC). Finally, we found that S protein PROTEIN could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19 MESHD. Our data demonstrate that the released S protein PROTEIN is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury MESHD in absence of a productive viral infection MESHD. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders MESHD in COVID-19 MESHD, paving the way to develop new therapeutic interventions.

    Genome-wide, bidirectional CRISPR screens identify mucins as critical host factors modulating SARS-CoV-2 infection MESHD

    Authors: Scott B Biering; Sylvia A Sarnik; Eleanor Wang; James R Zengel; Varun Sathyan; Xammy Nguyenla; Erik Van Dis; Carmelle Catamura; Livia H Yamashiro; Adam Begeman; Jessica C Stark; D. Judy Shon; Douglas M Fox; Andreas S Puschnik; Carolyn R Bertozzi; Jan E Carette; Sarah A Stanley; Eva Harris; Silvana Konermann; Patrick D Hsu

    doi:10.1101/2021.04.22.440848 Date: 2021-04-23 Source: bioRxiv

    SARS-CoV-2 can cause a range of symptoms in infected individuals, from mild respiratory illness MESHD to acute respiratory distress syndrome MESHD. A systematic understanding of the host factors mediating viral infection MESHD or restriction is critical to elucidate SARS-CoV-2 host-pathogen interactions and the progression of COVID-19 MESHD. To this end, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 HGNC and TMPRSS2 HGNC. These screens uncovered proviral and antiviral host factors across highly interconnected host pathways, including components implicated in clathrin transport, inflammatory signaling, cell cycle regulation, and transcriptional and epigenetic regulation. Mucins, a family of high-molecular weight glycoproteins and the main constituent of mucus, are central components of a prominent viral restriction pathway that we identified. We demonstrate that multiple membrane-anchored mucins are critical inhibitors of SARS-CoV-2 entry MESHD and are upregulated in response to viral infection MESHD. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and suggests interactions between SARS-CoV-2 and airway mucins of COVID-19 MESHD patients as a host defense mechanism.

    Viral neuroinvasion and neurotropism without neuronal damage MESHD in the hACE2 HGNC mouse model of COVID-19 MESHD

    Authors: Frauke Seehusen; Jordan J. Clark; Parul Sharma; Krishanthi Subramaniam; Sabina Wunderlin Giuliani; Grant Hughes; Edward I Patterson; Benedict D Michael; Andrew Owen; Julian Alexander Hiscox; James P Stewart; Anja Kipar

    doi:10.1101/2021.04.16.440173 Date: 2021-04-16 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is a primarily respiratory disease MESHD with variable clinical courses for which animal models are needed to gather insights into the pathogenesis of its causative virus, Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2), in human patients. SARS-CoV-2 not only affects the respiratory tract but also the central nervous system (CNS), leading to neurological symptoms such as loss of smell and taste, headache MESHD, fatigue MESHD or severe complications like cerebrovascular diseases MESHD. Transgenic mice expressing human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) under the cytokeratin 18 promoter (K18- hACE2 HGNC) represent a well-known model of SARS-CoV-2 infection MESHD. In the present study, it served to investigate the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with relatively low SARS-CoV-2 doses and after prior influenza A virus infection MESHD. In K18- hACE2 HGNC mice, SARS-CoV-2 was found to frequently spread to and within the CNS during the later phase (day 7) of infection. Infection was restricted to neurons and appeared to first affect the olfactory bulb and spread from there mainly in basally orientated regions in the brain and into the spinal cord, in a dose dependent manner and independent of ACE2 HGNC expression. Neuronal infection MESHD was not associated with cell death, axonal damage or demyelination MESHD. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed. This was accompanied by apoptotic death of endothelial, microglial and immune cells, without evidence of viral infection MESHD of glial cells, endothelial cells and leukocytes. Taken together, microgliosis and immune cell apoptosis indicate a potential important role of microglial cells for the pathogenesis and viral effect in COVID-19 MESHD and possible impairment of neurological functions MESHD, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.

    Human pulmonary artery endothelial cells upregulate ACE2 HGNC expression in response to iron-regulatory elements: potential implications for SARS-CoV-2 infection MESHD of vascular endothelial cells.

    Authors: Quezia K Toe; Theo Issitt; Abdul Mahomed; Ioannis Panselinas; Fatma Almaghlouth; Anne Burke-Gaffney; Stephen John Wort; Gregory J Quinlan

    doi:10.1101/2021.04.08.437687 Date: 2021-04-08 Source: bioRxiv

    Emerging studies from the ongoing covid-19 pandemic MESHD have implicated vascular dysfunction MESHD and endotheliitis MESHD in many patients presenting with severe disease. However, there is limited evidence for the expression of ACE2 HGNC (the principal co-receptor for Sars-Cov-2 cellular attachment) in vascular endothelial cells which has prompted the suggestion that the virus does not infect these cell types. However, the studies presented here demonstrate enhanced expression of ACE2 HGNC at the level of both mRNA and protein, in human pulmonary artery endothelial cells (PAECs) challenged with either IL-6 HGNC or hepcidin HGNC. Notably elevated levels both these iron-regulatory elements have been described in Covid-19 MESHD patients with severe disease and are further associated with morbidity and mortality. Additionally, levels of both IL-6 HGNC and hepcidin HGNC are often elevated in the elderly and in chronic disease MESHD settings, these populations being at greater risk of adverse outcomes from Sars-Cov-2 infection MESHD. A role for IL-6 HGNC and hepcidin HGNC as modulators of ACE2 HGNC expression seems plausible, additional, studies are required to determine if viral infection MESHD can be demonstrated in PAECs challenged with either of these iron-regulatory elements.

    Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways

    Authors: Ke Xu; Xingyi Shi; Chris Husted; Rui Hong; Yichen Wang; Boting Ning; Travis Sullivan; Kimberly M Rieger-Christ; Fenghai Duan; Helga Marques; Adam C Gower; Xiaohui Xiao; Hanqiao Liu; Gang Liu; Grant Duclos; Avrum Spira; Sarah A Mazzilli; Ehab Billatos; Marc E Lenburg; Joshua D Campbell; Jennifer Beane

    doi:10.1101/2021.03.30.21254564 Date: 2021-04-04 Source: medRxiv

    Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) is caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2 HGNC, TMPRSS2 HGNC, and CTSL HGNC. Proposed risk factors for viral infection MESHD, as well as the rate of disease progression, include age, sex, chronic obstructive pulmonary disease MESHD, cancer MESHD, and cigarette smoking. To investigate whether the proposed risk factors increase viral infection MESHD by modulation of the VE genes, we examined gene expression profiles of 796 nasal and 1,673 bronchial samples across four lung cancer MESHD screening cohorts containing individuals without COVID-19 MESHD. Smoking was the only clinical factor reproducibly associated with the expression of any VE gene across cohorts. ACE2 HGNC expression was significantly up-regulated with smoking in the bronchus but significantly down-regulated with smoking in the nose. Furthermore, expression of individual VE genes were not correlated between paired nasal and bronchial samples from the same patients. Single-cell RNA-seq of nasal brushings revealed that an ACE2 HGNC gene module was detected in a variety of nasal secretory cells with the highest expression in the C15orf48 HGNC+ secretory cells, while a TMPRSS2 HGNC gene module was most highly expressed in nasal keratinizing epithelial cells. In contrast, single-cell RNA-seq of bronchial brushings revealed that ACE2 HGNC and TMPRSS2 HGNC gene modules were most enriched in MUC5AC HGNC+ bronchial goblet cells. The CTSL HGNC gene module was highly expressed in immune populations of both nasal and bronchial brushings. Deconvolution of bulk RNA-seq showed that the proportion of MUC5AC HGNC+ goblet cells was increased in current smokers in both the nose and bronchus but proportions of nasal keratinizing epithelial cells, C15orf48 HGNC+ secretory cells, and immune cells were not associated with smoking status. The complex association between VE gene expression and smoking in the nasal and bronchial epithelium revealed by our results may partially explain conflicting reports on the association between smoking and SARS-CoV-2 infection MESHD.

    Antidepressant and antipsychotic drugs reduce viral infection MESHD by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro

    Authors: Merve Senem Fred; Suvi Kuivanen; Hasan Ugurlu; Plinio Cabrera Casarotto; Lev Levanov; Kalle Saksela; Olli Vapalahti; Eero Castren

    doi:10.1101/2021.03.22.436379 Date: 2021-03-23 Source: bioRxiv

    Background and Purpose: Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19 MESHD. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Experimental Approach: Several antidepressant drugs and antipsychotic drugs with different primary mechanisms of action were tested in ACE2 HGNC/ TMPRSS2 HGNC-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike PROTEIN protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7 and B.1.351. Key Results: Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the (B.1) lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudo viruses with N501Y, K417N, and E484K spike mutations, and the VoC-1 (B.1.1.7) and VoC-2 (B.1.351) variants of SARS-CoV-2. Conclusion and Implications: Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection MESHD including different variants of concern.

    Differential gene expression by RNA-Seq in Sigma-2 Receptor/ TMEM97 HGNC knockout cells reveals its role in complement activation and SARS-CoV-2 viral uptake


    doi:10.1101/2021.03.14.435180 Date: 2021-03-15 Source: bioRxiv

    Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (sigma- 2R/ TMEM97 HGNC) interacts with the low-density lipoprotein receptor HGNC ( LDLR HGNC) and facilitates the enhanced uptake of various ligands including lipoproteins and intrinsically disordered proteins. TMEM97 HGNC has been recently been shown to interact with severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) viral proteins, highlighting its potential involvement with viral entry into the cell. We hypothesized that sigma-2R/ TMEM97 HGNC may play a role in facilitating viral uptake, and with the regulation of inflammatory and thrombotic MESHD pathways that are involved with viral infection MESHD. In this study, we identified the top differentially expressed genes upon the knockout of sigma-2R/ TMEM97 HGNC, and analyzed the genes involved with the inflammatory and thrombotic MESHD cascades, effects that are observed in patients infected with SARS-CoV-2. We found that the ablation of sigma-2R/ TMEM97 HGNC resulted in an increase in Complement Component MESHD 4 Binding Protein ( C4BP HGNC) proteins, at both the translational and transcriptional levels. We also showed that sigma-2R/ TMEM97 HGNC interacts with the cellular receptor for SARS-CoV-2, the human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptor, forming a protein complex, and that disruption of this complex results in the inhibition of viral uptake. The results of this study suggest that sigma-2R/ TMEM97 HGNC may be a novel therapeutic target to inhibit SARS- CoV-2 viral uptake, as well as to decrease inflammatory and thrombotic MESHD effects through the modulation of the complement cascade.

    Molecular strategies for antibody binding and escape of SARS-CoV-2 and its mutations

    Authors: Mohamed Hendy; Samuel Kaufman; Mauricio Ponga

    doi:10.1101/2021.03.04.433970 Date: 2021-03-05 Source: bioRxiv

    The COVID19 MESHD pandemic, caused by SARS-CoV-2, has infected more than 100 million people worldwide. Due to the rapid spreading of SARS-CoV-2 and its impact, it is paramount to find effective treatments against it. Human neutralizing antibodies are an effective method to fight viral infection MESHD. However, the recent discovery of new strains that substantially change the S-protein HGNC S-protein PROTEIN sequence has raised concern about vaccines and antibodies' effectiveness. Here, we investigated the binding mechanisms between the S-protein HGNC S-protein PROTEIN and several antibodies. Multiple mutations were included to understand the strategies for antibody escape in new variants. We found that the combination of mutations K417N and E484K produced higher binding energy to ACE2 HGNC than the wild type, suggesting higher efficiency to enter host cells. The mutations' effect depends on the antibody class. While Class I enhances the binding avidity in the presence of N501Y mutation, class II antibodies showed a sharp decline in the binding affinity. Our simulations suggest that Class I antibodies will remain effective against the new strains. In contrast, Class II antibodies will have less affinity to the S-protein HGNC S-protein PROTEIN, potentially affecting these antibodies' efficiency.

    Discovery of a AhR HGNC flavonoid agonist that counter-regulates ACE2 HGNC expression in rodent models of inflammation MESHD and attenuates ACE2 HGNC-SARS-CoV2 interaction in vitro


    doi:10.1101/2021.02.24.432203 Date: 2021-02-24 Source: bioRxiv

    The severe acute respiratory syndrome MESHD (SARS)-CoV-2, a newly emerged coronavirus first identified in 2019, is the pathogenetic agent od Corona Virus Induced Disease MESHD (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE) 2 HGNC receptor in target tissues. ACE2 HGNC expression is induced in response to inflammation MESHD. The colon expression of ACE2 HGNC is upregulated in patients with inflammatory bowel disease MESHD ( IBD MESHD), highlighting a potential risk of intestinal inflammation MESHD in promoting viral entry in the human body. Because mechanisms that regulate ACE2 HGNC expression in the intestine are poorly understood and there is a need of anti-SARS-CoV2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of ACE2 HGNC in intestinal models of inflammation MESHD. The results of these studies demonstrated that pelargonidin, a natural flavonoid bind and activates the Aryl hydrocarbon Receptor HGNC ( AhR HGNC) in vitro and reverses intestinal inflammation MESHD caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent DSS in a AhR HGNC-dependent manner. In these two models, development of colon inflammation MESHD associated with upregulation of ACE2 HGNC mRNA expression. Colon levels of ACE2 HGNC mRNA were directly correlated with TNF HGNC mRNA levels. In contrast to ACE2 HGNC the angiotensin 1-7 receptor MAS was downregulated in the inflamed tissues. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV2 Spike protein PROTEIN. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV2 Spike protein PROTEIN to ACE2 HGNC and reduces the SARS-CoV2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation MESHD and ACE2 HGNC induction in the inflamed colon in a AhR HGNC-dependent manner.

    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.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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