SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Cell, Journal Year: 2020, Volume and Issue: 181(5), P. 1016 - 1035.e19

Published: April 27, 2020

There is pressing urgency to understand the pathogenesis of severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme (ACE2), and in concert with host proteases, principally transmembrane serine protease (TMPRSS2), promotes cellular entry. The cell subsets targeted by tissues factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, mouse single-cell RNA-sequencing (scRNA-seq) datasets across health uncover putative targets among tissue-resident subsets. We identify TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, nasal goblet secretory cells. Strikingly, discovered a human interferon-stimulated gene (ISG) vitro using airway epithelial extend our findings vivo viral infections. Our data suggest could exploit species-specific interferon-driven upregulation ACE2, tissue-protective mediator during injury, enhance infection.

Language: Английский

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The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

Antiviral Research, Journal Year: 2020, Volume and Issue: 176, P. 104742 - 104742

Published: Feb. 10, 2020

Language: Английский

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Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 11, 2021

Abstract The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 exceptionally high level transmissibility extremely broad tissue tropism. However, the underlying molecular mechanism responsible sustaining this degree virulence remains largely unexplored. In article, we review current knowledge crucial information about how attaches on surface host cells through a variety receptors, such as ACE2, neuropilin-1, AXL, antibody–FcγR complexes. We further explain its spike (S) protein undergoes conformational transition from prefusion to postfusion with help proteases like furin, TMPRSS2, cathepsins. then ongoing experimental studies clinical trials antibodies, peptides, or small-molecule compounds anti-SARS-CoV-2 activity, discuss these antiviral therapies targeting host–pathogen interaction could potentially suppress viral attachment, reduce exposure fusion peptide curtail membrane block formation six-helix bundle (6-HB) core. Finally, specter rapidly emerging variants deserves serious broad-spectrum drugs vaccines long-term prevention control COVID-19 future.

Language: Английский

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A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

Journal of Biomolecular Structure and Dynamics, Journal Year: 2020, Volume and Issue: 39(8), P. 3025 - 3033

Published: April 10, 2020

The widespread antigenic changes lead to the emergence of a new type coronavirus (CoV) called as severe acute respiratory syndrome (SARS)-CoV-2 that is immunologically different from previous circulating species. Angiotensin-converting enzyme-2 (ACE-2) one most important receptors on cell membrane host cells (HCs) which its interaction with spike protein (SP) furin-cleavage site results in SARS-CoV-2 invasion. Hence, this review, we presented an overview ACE-2 and furin SP. As several kinds CoVs, various genera, have at their S1/S2 binding preserved site, further surveyed role cleavage (FCS) life cycle CoV. Furthermore, discussed small molecular inhibitors can limit SP be used potential therapeutic platforms combat spreading CoV epidemic. Finally, some ongoing challenges future prospects for development drugs promote targeting specific activities were reviewed. In conclusion, review may pave way providing useful information about compounds involved improving effectiveness vaccine or minimum toxicity against human health.Communicated by Ramaswamy H. Sarma.

Language: Английский

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The Role of Lipid Metabolism in COVID-19 Virus Infection and as a Drug Target

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(10), P. 3544 - 3544

Published: May 17, 2020

The current Coronavirus disease 2019 or COVID-19 pandemic has infected over two million people and resulted in the death of one hundred thousand at time writing this review. is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though multiple vaccines treatments are under development so far, only slowing down extreme social distancing measures that difficult to maintain. SARS-COV-2 an enveloped virus surrounded a lipid bilayer. Lipids fundamental cell components play various biological roles ranging from being structural building block signaling molecule as well central energy store. role lipids viral infection involves fusion membrane host cell, replication, endocytosis exocytosis. Since crucial function life cycle, we asked whether drugs targeting metabolism, such statins, can be utilized against SARS-CoV-2 other viruses. In review, discuss metabolism possibility interfere with cycle.

Language: Английский

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Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: April 20, 2020

ABSTRACT The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) associated proteases, transmembrane protease serine (TMPRSS2) Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess cell type-specific RNA expression ACE2 , TMPRSS2 CTSL through integrated analysis 107 single-cell single-nucleus RNA-Seq studies, including 22 lung airways datasets (16 unpublished), 85 from other diverse organs. Joint accessory proteases identifies specific subsets respiratory epithelial cells putative targets infection in nasal passages, airways, alveoli. Cells co-express are also organs, some which have been with transmission or pathology, gut enterocytes, corneal cells, cardiomyocytes, heart pericytes, olfactory sustentacular renal cells. Performing first meta-analyses scRNA-seq analyzed 1,176,683 282 nasal, airway, parenchyma samples 164 donors spanning fetal, childhood, adult, elderly age groups, associate increased levels types increasing age, male gender, smoking, all epidemiologically linked to susceptibility outcomes. Notably, there was a particularly low few young pediatric analysis. Further reveals gene program shared + tissues, genes may subtend key immune functions, epithelial-macrophage cross-talk. Amongst these IL6, its receptor co-receptor, IL1R TNF response pathways, complement genes. type specificity smoking effects conserved mice. Our analyses suggest differences SARS-CoV-2 entry be responsible aspects epidemiology clinical course, point pathways involved disease pathogenesis.

Language: Английский

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Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects

Cell Reports, Journal Year: 2020, Volume and Issue: 33(2), P. 108254 - 108254

Published: Sept. 23, 2020

Development of specific antiviral agents is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infection. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike protein, critical its fusion after binding to angiotensin-converting enzyme (ACE2), as targets. We first validate cleavage at a putative furin substrate motif spikes by expressing it in VeroE6 cells and find prominent syncytium formation. Cleavage are abolished treatment with inhibitors decanoyl-RVKR-chloromethylketone (CMK) naphthofluorescein, but not transmembrane protease serine (TMPRSS2) inhibitor camostat. CMK naphthofluorescein show effects SARS-CoV-2-infected decreasing virus production cytopathic effects. Further analysis reveals that, similar camostat, blocks entry, further suppresses syncytium. Naphthofluorescein acts primarily suppressing viral RNA transcription. Therefore, may be promising prevention

Language: Английский

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Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(3), P. 401 - 410

Published: March 1, 2021

Language: Английский

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Furin Cleavage Site Is Key to SARS-CoV-2 Pathogenesis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: Aug. 26, 2020

Abstract SARS-CoV-2 has resulted in a global pandemic and shutdown economies around the world. Sequence analysis indicates that novel coronavirus (CoV) an insertion of furin cleavage site (PRRAR) its spike protein. Absent other group 2B CoVs, may be key factor replication virulence SARS-CoV-2. To explore this question, we generated mutant lacking (ΔPRRA) This virus replicated with faster kinetics improved fitness Vero E6 cells. The also had reduced protein processing as compared to wild-type In contrast, ΔPRRA Calu3 cells, human respiratory cell line, attenuated disease hamster pathogenesis model. Despite disease, offered robust protection from rechallenge. Importantly, plaque reduction neutralization tests (PRNT 50 ) COVID-19 patient sera monoclonal antibodies against receptor-binding domain found shift, resulting consistently PRNT titers. Together, these results demonstrate critical role for pathogenesis. addition, findings illustrate importance evaluating downstream assays. Importance As impacted world, understanding how replicates causes offers potential pathways disrupt disease. By removing site, cells indicate likelihood culture adaptations stocks can influence reagent generation interpretation wide range data including drug efficacy. Overall, our work highlights motif infection Article Summary A deletion amplifies but attenuates vivo. Loss reduces susceptibility vitro .

Language: Английский

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Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and Their Interactions with ACE2

Cells, Journal Year: 2020, Volume and Issue: 9(12), P. 2638 - 2638

Published: Dec. 8, 2020

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus 2019 (COVID-19). virus quickly spread around the world, causing sustained global outbreak. Although SARS-CoV-2, other coronaviruses, SARS-CoV Middle East CoV (MERS-CoV) are highly similar genetically at protein production level, there significant differences between them. Research shown that structural spike (S) plays an important role evolution transmission of SARS-CoV-2. So far, studies have various genes encoding primarily for elements S undergo frequent mutation. We performed in-depth review literature covering mutational aspects context compared them with those MERS-CoV. Our analytical approach consisted initial genome transcriptome analysis, followed by primary, secondary tertiary structure analysis. Additionally, we investigated potential effects these on binding interactions to angiotensin-converting enzyme 2 (ACE2), established, after extensive analysis previous research articles, SARS-CoV-2 use different ends/regions receptor-binding motif (RBM) types their chief ACE2. These may implications pathogenesis, entry ability infect intermediate hosts coronaviruses. This comprehensively addresses detail variations protein, its characteristics detailed interactions, process cleavage involved priming, as well

Language: Английский

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