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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (5)

NSP5 (1)

NSP3 (1)


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SARS-CoV-2 Proteins
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    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.

    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.

    Genomics-guided identification of potential modulators of SARS-CoV-2 entry proteases, TMPRSS2 HGNC and Cathepsins B/L

    Authors: Kartikay Prasad; Vijay Kumar

    doi:10.21203/rs.3.rs-138273/v1 Date: 2020-12-30 Source: ResearchSquare

    The entry of SARS-CoV-2 into host cells requires the activation of its spike protein PROTEIN by host cell proteases. The serine protease HGNC, transmembrane serine protease 2 ( TMPRSS2 HGNC) and cysteine proteases, cathepsins B, L ( CTSB HGNC/L) activate spike protein PROTEIN and enabling SARS-CoV-2 entry to the host cell through two completely different and independent pathways. Given that the uncertainty of how SARS-CoV-2 infects MESHD and kills, the need for a deep understanding of SARS-CoV-2 biology is imperative. Herein, we performed genomic-guided meta-analysis to identify upstream regulatory elements altering the expression of TMPRSS2 HGNC and CTSB HGNC/L genes. Further, drugs and medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 HGNC and CTSB HGNC/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Further, we analysed drug-gene and gene-gene interaction network using 332 human targets of SARS-CoV-2 proteins. The network results indicate that out of 332 human proteins, estradiol interacts with 135 (41%) and retinoic acid interacts with 40 (12%) proteins. Interestingly, a combination of both estradiol and retinoic acid interacts with 153 (46%) of human proteins acting as SARS-CoV-2 targets and affect the functions of nearly all of the SARS-CoV-2 viral proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggest that both the drugs binds to TMPRSS2 HGNC and CTSL HGNC with the nanomolar to low micromolar affinity. This study, for the first time, reports the molecules like estradiol and retinoic acid as candidate drugs against both the host proteases, TMPRSS2 HGNC and CTSB HGNC/L. We here thus suggest that these antiviral drugs alone or in combination can simultaneously target both the entry pathways and thus can be considered as a potential treatment option for COVID-19 MESHD.

    Host Cell Proteases Drive Early or Late SARS-CoV-2 Penetration

    Authors: Jana Koch; Zina M Uckeley; Patricio Doldan; Megan L Stanifer; Steeve Boulant; Pierre-Yves Lozach

    doi:10.1101/2020.12.22.423906 Date: 2020-12-23 Source: bioRxiv

    SARS-CoV-2 is a newly emerged coronavirus (CoV) that spread through human populations worldwide in early 2020. CoVs rely on host cell proteases for activation and infection. The trypsin-like protease TMPRSS2 HGNC at the cell surface, cathepsin L HGNC in endolysosomes, and furin HGNC in the Golgi have all been implicated in the SARS-CoV-2 proteolytic processing. Whether SARS-CoV-2 depends on endocytosis internalization and vacuolar acidification for infectious entry remains unclear. Here, we examined the dynamics of SARS-CoV-2 activation during the cell entry process in tissue culture. Using four cell lines representative of lung, colon MESHD, and kidney epithelial tissues, we found that TMPRSS2 HGNC determines the SARS-CoV-2 entry pathways. In TMPRSS2 HGNC-positive cells, infection was sensitive to aprotinin, a TMPRSS2 HGNC inhibitor, but not to SB412515, a drug that impairs cathepsin L HGNC. Infectious penetration was marginally dependent on endosomal acidification, and the virus passed the protease-sensitive step within 10 min. In a marked contrast, in TMPRSS2 HGNC-negative cells cathepsin L HGNC and low pH were required for SARS-CoV-2 entry. The cathepsin L HGNC-activated penetration occurred within 40-60 min after internalization and required intact endolysosomal functions. Importantly, pre-activation of the virus allowed it to bypass the need for endosomal acidification for viral fusion and productive entry. Overall, our results indicate that SARS-CoV-2 shares with other CoVs a strategy of differential use of host cell proteases for activation and infectious penetration. This study also highlights the importance of TMPRSS2 HGNC in dictating the entry pathway used by SARS-CoV-2. SignificancePreventing SARS-CoV-2 spread requires approaches affecting early virus-host cell interactions before the virus enters and infects target cells. Host cell proteases are critical for coronavirus activation and infectious entry. Here, we reconcile apparent contradictory observations from recent reports on endosomal acidification and the role of furin HGNC, TMPRSS2 HGNC, and cathepsin L HGNC in the productive entry and fusion process of SARS-CoV-2. Investigating authentic virus in various cell types, we demonstrated that SARS-CoV-2 developed the ability to use different entry pathways, depending on the proteases expressed by the target cell. Our results have strong implications for future research on the apparent broad tropism of the virus in vivo. This study also provides a handle to develop novel antiviral strategies aiming to block virus entry, as illustrated with the several drugs that we identified to prevent SARS-CoV-2 infection MESHD, some with low IC50.

    Genetic variability in COVID-19 MESHD-related genes in the Brazilian population

    Authors: Rodrigo Secolin; Tania K de Araujo; Marina C. Gonsales; Cristiane S. Rocha; Michel Satya Naslavsky; Luiz De Marco; Maria Bicalho; Vinicius L Vazquez; Mayana Zatz; Wilson A Silva Jr.; Iscia Lopes-Cendes; Sebla B Kutluay; Mei-Ling Li; Gary Brewer; Blanton S Tolbert; Amanda E Hargrove; Alexandra W. Dretler; Ria Gripaldo; Andrea N. Lane; Hao Wu; Saeyun Lee; Mindy Hernandez; Vanessa Engineer; John Varghese; Sang Le; Iñaki Sanz; John L. Daiss; Frances Eun-Hyung Lee

    doi:10.1101/2020.12.04.411736 Date: 2020-12-06 Source: bioRxiv

    SARS-CoV-2 employs the angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) receptor and the transmembrane serine protease ( TMPRSS2 HGNC) to infect human lung cells. Previous studies have suggested that different host genetic backgrounds in ACE2 HGNC and TMPRSS2 HGNC could contribute to differences in the rate of infection or severity of COVID-19 MESHD. Recent studies also showed that variants in 15 genes related to type I interferon immunity to influenza virus could predispose to life-threatening COVID-19 MESHD pneumonia MESHD. Additional genes ( SLC6A20 HGNC, LZTFL1 HGNC, CCR9 HGNC, FYCO1 HGNC, CXCR6 HGNC, XCR1 HGNC, IL6 HGNC, CTSL HGNC, ABO, and FURIN HGNC) and HLA alleles have also been implicated in response to infection with SARS-CoV-2. Currently, Brazil has recorded the third-highest number of COVID-19 MESHD patients worldwide. We aim to investigate the genetic variation present in COVID-19 MESHD-related genes in the Brazilian population. We analysed 27 candidate genes and HLA alleles in 954 admixed Brazilian exomes. We used the information available in two public databases (http://www.bipmed.org and http://abraom.ib.usp.br/), and additional exomes from individuals born in southeast Brazil, the region with the highest number of COVID-19 MESHD patients in the country. Variant allele frequencies were compared with the 1000 Genomes Project phase 3 (1KGP) and the gnomAD databases. We found 395 non-synonymous variants; of these, 325 were also found in the 1000 Genome Project phase 3 (1KGP) and/or gnomAD. Six of these variants were previously reported as putatively influencing the rate of infection or clinical prognosis for COVID-19 MESHD. The remaining 70 variants were identified exclusively in the Brazilian sample, with a mean allele frequency of 0.0025. In silico prediction of the impact in protein function revealed that three of these rare variants were pathogenic. Furthermore, we identified HLA alleles that were previously associated with COVID-19 MESHD response at loci DQB1 HGNC and DRB1 HGNC. Our results showed genetic variability common to other populations, but also rare and ultra-rare variants exclusively found in the Brazilian population. These findings could potentially lead to differences in the rate of infection or response to infection by SARS-CoV-2 and should be further investigated in patients with the disease.

    Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19 MESHD

    Authors: Kas Steuten; Heeyoung Kim; John C. Widen; Brett M. Babin; Ouma Onguka; Scott Lovell; Oguz Bolgi; Berati Cerikan; Mirko Cortese; Ryan K. Muir; John M. Bennett; Ruth Geiss-Friedlander; Christoph Peters; Ralf Bartenschlager; Matthew Bogyo; Nuria Izquierdo-Useros; Roger Paredes; Lourdes Mateu; Anna Chamorro; Marta Massanella; Jorge Carrillo; Bonaventura Clotet; Julià Blanco; Benjamin Pinsky; Manisha Desai; Julie Parsonnet; Upinder Singh

    doi:10.1101/2020.11.21.392753 Date: 2020-11-23 Source: bioRxiv

    Two proteases produced by the SARS-CoV-2 virus, Mpro PROTEIN and PLpro PROTEIN, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19 MESHD. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro PROTEIN and PLpro PROTEIN proteases. These efforts identified a small number of hits for the Mpro PROTEIN protease and no viable hits for the PLpro PROTEIN protease. Of the Mpro PROTEIN hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2 HGNC, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mpro PROTEIN inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro PROTEIN inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L HGNC and B and showed similar loss in activity in cells expressing TMPRSS2 HGNC. Our results highlight the challenges of targeting Mpro PROTEIN and PLpro PROTEIN proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.

    Single cell profiling of COVID-19 MESHD patients: an international data resource from multiple tissues

    Authors: Esteban Ballestar; Donna L Farber; Sarah Glover; Bruce Horwitz; Kerstin Meyer; Marko Nikolic; Jose Ordovas-Montanes; Peter A Sims; Alex K Shalek; Niels Vandamme; Linos Vandekerckhove; Roser Vento-Tormo; Alexandra Chloe Villani; - Chan Zuckerberg Initiative Single-Cell COVID-19 Consortia

    doi:10.1101/2020.11.20.20227355 Date: 2020-11-23 Source: medRxiv

    In late 2019 and through 2020, the COVID-19 MESHD COVID-19 MESHD pandemic swept the world, presenting both scientific and medical challenges associated with understanding and treating a previously unknown disease. To help address the need for great understanding of COVID-19 MESHD, the scientific community mobilized and banded together rapidly to characterize SARS-CoV-2 infection MESHD, pathogenesis and its distinct disease trajectories. The urgency of COVID-19 MESHD provided a pressing use-case for leveraging relatively new tools, technologies, and nascent collaborative networks. Single-cell biology is one such example that has emerged over the last decade as a powerful approach that provides unprecedented resolution to the cellular and molecular underpinnings of biological processes. Early foundational work within the single-cell community, including the Human Cell Atlas, utilized published and unpublished data to characterize the putative target cells of SARS-CoV-2 sampled from diverse organs based on expression of the viral receptor ACE2 HGNC and associated entry factors TMPRSS2 HGNC and CTSL HGNC (Muus et al., 2020; Sungnak et al., 2020; Ziegler et al., 2020). This initial characterization of reference data provided an important foundation for framing infection and pathology in the airway as well as other organs. However, initial community analysis was limited to samples derived from uninfected donors and other previously-sampled disease indications. This report provides an overview of a single-cell data resource derived from samples from COVID-19 MESHD patients along with initial observations and guidance on data reuse and exploration.

    Polyunsaturated ω-3 fatty acids inhibit ACE2 HGNC-controlled SARS-CoV-2 binding and cellular entry

    Authors: Anna Goc; Aleksandra Niedzwiecki; Matthias Rath

    doi:10.21203/rs.3.rs-99688/v1 Date: 2020-10-28 Source: ResearchSquare

    The strain SARS-CoV-2, newly emerged in late 2019, has been identified as the cause of COVID-19 MESHD and the pandemic declared by WHO in early 2020. Although lipids have been shown to possess antiviral efficacy, little is currently known about lipid compounds with anti-SARS-CoV-2 binding and entry properties. To address this issue, we screened, overall, 17 polyunsaturated fatty acids, monounsaturated fatty acids and saturated fatty acids, as wells as lipid-soluble vitamins. In performing target-based ligand screening utilizing the RBD-SARS-CoV-2 sequence, we observed that polyunsaturated fatty acids most effectively interfere with binding to hACE2 HGNC, the receptor for SARS-CoV-2. Using a spike protein PROTEIN pseudo-virus, we also found that linolenic acid and eicosapentaenoic acid significantly block the entry of SARS-CoV-2. In addition, eicosapentaenoic acid showed higher efficacy than linolenic acid in reducing activity of TMPRSS2 HGNC and cathepsin L HGNC proteases, but neither of the fatty acids affected their expression at the protein level. Also, neither reduction of hACE2 HGNC activity nor binding to the hACE2 HGNC receptor upon treatment with these two fatty acids was observed. Although further in vivo experiments are warranted to validate the current findings, our study provides a new insight into the role of lipids as antiviral compounds against the SARS-CoV-2 strain.   

    The human brain vasculature shows a distinct expression pattern of SARS-CoV-2 entry factors

    Authors: Moheb Ghobrial; Jason Charish; Shigeki Takada; Taufik Valiante; Philippe Monnier; Ivan Radovanovic; Gary Bader; Thomas Waelchli; John E. Bradley; Shihong Qiu; Guang Yang; Fen Zhou; Esther Zumaquero; Thomas S. Simpler; Betty Mousseau; John T. Killian Jr.; Brittany Dean; Qiao Shang; Jennifer L. Tipper; Christopher Risley; Kevin S. Harrod; Ray Feng; Young Lee; Bethlehem Shiberu; Vyjayanthi Krishnan; Isabelle Peguillet; Jianfeng Zhang; Todd Green; Troy D. Randall; Bertrand Georges; Frances E Lund; Scot Roberts; Akshay Pai; Mads Nielsen; Martin Sillesen

    doi:10.1101/2020.10.10.334664 Date: 2020-10-11 Source: bioRxiv

    A large number of hospitalized COVID-19 MESHD patients show neurological symptoms such as ischemic- and hemorrhagic stroke MESHD as well as encephalitis MESHD, and SARS-CoV-2 can directly infect endothelial cells leading to endotheliitis across multiple vascular beds. These findings suggest an involvement of the brain- and peripheral vasculature in COVID-19 MESHD, but the underlying molecular mechanisms remain obscure. To understand the potential mechanisms underlying SARS-CoV-2 tropism MESHD for brain vasculature, we constructed a molecular atlas of the expression patterns of SARS-CoV-2 viral entry-associated genes (receptors and proteases) and SARS-CoV-2 interaction partners in human (and mouse) adult and fetal brain as well as in multiple non-CNS tissues in single-cell RNA-sequencing data across various datasets. We observed a distinct expression pattern of the cathepsins B ( CTSB HGNC) and -L ( CTSL HGNC) - which are able to substitute for the ACE2 HGNC co-receptor TMPRSS2 HGNC - in the human vasculature with CTSB HGNC being mainly expressed in the brain vasculature and CTSL HGNC predominantly in the peripheral vasculature, and these observations were confirmed at the protein level in the Human Protein Atlas and using immunofluorescence stainings. This expression pattern of SARS-CoV-2 viralentry associated proteases and SARS-CoV-2 interaction partners was also present in endothelial cells and microglia in the fetal brain, suggesting a developmentally establishedSARS-CoV-2 entry machinery in the human vasculature. At both the adult and fetal stages, we detected a distinct pattern of SARS-CoV-2 entry associated genes' transcripts in brain vascular endothelial cells and microglia, providing a potential explanation for an inflammatory response in the brain endothelium upon SARS-CoV-2 infection MESHD. Moreover, CTSB HGNC was co-expressed in adult and fetal brain endothelial cells with genes and pathways involved in innate immunity and inflammation MESHD, angiogenesis, blood-brain-barrier permeability, vascular metabolism, and coagulation, providing a potential explanation for the role of brain endothelial cells in clinically observed (neuro)vascular symptoms in COVID-19 MESHD patients. Our study serves as a publicly available single-cell atlas of SARS-CoV-2 related entry factors and interaction partners in human and mouse brain endothelial- and perivascular cells, which can be employed for future studies in clinical samples of COVID-19 MESHD patients.

    Single-cell RNA Expression of SARS-CoV-2 Cell Entry Factors in Human Endometrium during Preconception

    Authors: Felipe Vilella Mitjana; Wanxin Wang; Inmaculada Moreno Gimeno; Stephen Quake; Carlos Simon; Jeff Green; Julia Schaletzky; Ahmet Yildiz; Louise Rowntree; Thi Nguyen; Katherine Kedzierska; Denise Doolan; Carola Vinuesa; Matthew Cook; Nicholas Coatsworth; Paul Myles; Florian Kurth; Leif Sander; Russell Gruen; Graham Mann; Amee George; Elizabeth Gardiner; Ian Cockburn; Bala Pesala; Debojyoti Chakraborty; Souvik Maiti

    doi:10.1101/2020.09.14.296806 Date: 2020-09-14 Source: bioRxiv

    We investigated potential SARS-CoV-2 tropism MESHD in human endometrium by single-cell RNA-sequencing of viral entry-associated genes in healthy women. Percentages of endometrial cells expressing ACE2 HGNC, TMPRSS2 HGNC, CTSB HGNC, or CTSL HGNC were <2%, 12%, 80%, and 80%, respectively, with 0.7% of cells expressing all four genes. Our findings imply low efficiency of SARS-CoV-2 infection MESHD in the endometrium before embryo implantation, providing information to assess preconception risk in asymptomatic carriers.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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