A Single-Cell RNA Expression Map of Human Coronavirus Entry Factors

Cell Reports, Journal Year: 2020, Volume and Issue: 32(12), P. 108175 - 108175

Published: Sept. 1, 2020

To predict the tropism of human coronaviruses, we profile 28 SARS-CoV-2 and coronavirus-associated receptors factors (SCARFs) using single-cell transcriptomics across various healthy tissues. SCARFs include cellular both facilitating restricting viral entry. Intestinal goblet cells, enterocytes, kidney proximal tubule cells appear highly permissive to SARS-CoV-2, consistent with clinical data. Our analysis also predicts non-canonical entry paths for lung brain infections. Spermatogonial prostate endocrine be infection, suggesting male-specific vulnerabilities. Both pro- anti-viral are expressed within nasal epithelium, potential age-dependent variation, predicting an important battleground coronavirus infection. suggests that early embryonic placental development at moderate risk Lastly, SCARF expression appears broadly conserved a subset primate organs examined. study establishes resource investigations biology pathology.

Language: Английский

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SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 21, 2021

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated might lead to excessive inflammatory autoimmune responses as observed in severe long COVID-19 patients. Here we show that SARS-CoV-2 modulates reduces Accordingly, compound-driven induction of autophagy limits propagation. In detail, SARS-CoV-2-infected cells accumulation key metabolites, activation inhibitors (AKT1, SKP2) reduction proteins responsible for initiation (AMPK, TSC2, ULK1), membrane nucleation, phagophore formation (BECN1, VPS34, ATG14), well autophagosome-lysosome fusion ATG14 oligomers). Consequently, phagophore-incorporated markers LC3B-II P62 accumulate, which confirm a hamster model lung samples Single-nucleus single-cell sequencing patient-derived mucosal differential transcriptional regulation immune genes depending on cell type, disease duration, replication levels. Targeting autophagic pathways by exogenous administration the polyamines spermidine spermine, selective AKT1 inhibitor MK-2206, BECN1-stabilizing anthelmintic drug niclosamide inhibit propagation vitro with IC

Language: Английский

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SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Jan. 12, 2022

SARS-CoV-2 is a novel virus that has rapidly spread, causing global pandemic. In the majority of infected patients, leads to mild disease; however, in significant proportion infections, individuals develop severe symptoms can lead long-lasting lung damage or death. These cases are often associated with high levels pro-inflammatory cytokines and low antiviral responses, which cause systemic complications. Here, we have evaluated transcriptional cytokine secretion profiles detected distinct upregulation inflammatory cell cultures samples taken from patients. Building on these observations, found specific activation NF-κB block IRF3 nuclear translocation cells. This response was mediated by cGAS-STING could be attenuated through several STING-targeting drugs. Our results show directs mediated, NF-κB-driven immune human epithelial cells likely contributes responses seen patients therapeutically targeted suppress disease symptoms.

Language: Английский

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Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors

Cell Host & Microbe, Journal Year: 2020, Volume and Issue: 29(2), P. 267 - 280.e5

Published: Dec. 17, 2020

Language: Английский

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Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(13), P. 2851 - 2867.e7

Published: May 24, 2021

Highlights•A third of the RBPome remodels upon SARS-CoV-2 infection•Viral RNPs include 139 cellular and 6 viral RBPs•Inhibition these RBPs hampers infection•The tRNA ligase complex is a key regulator SARS-CoV-2SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes disease 2019 (COVID-19). relies on RNA-binding proteins (RBPs) to replicate spread, although which control its life cycle remains largely unknown. Here, we employ multi-omic approach identify systematically comprehensively that are involved in infection. We reveal infection profoundly RNA-bound proteome, includes wide-ranging effects RNA metabolic pathways, non-canonical RBPs, antiviral factors. Moreover, apply new method directly interact with RNA, uncovering dozens six proteins. Among them several components complex, show regulate Furthermore, discover available drugs targeting host inhibit Collectively, our results uncover universe host-virus interactions potential for therapies against COVID-19.Graphical abstract

Language: Английский

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Role of Heat Shock Proteins (HSP70 and HSP90) in Viral Infection

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(17), P. 9366 - 9366

Published: Aug. 29, 2021

Heat shock proteins (HSPs) are a large group of chaperones found in most eukaryotes and bacteria. They responsible for the correct protein folding, protection cell against stressors, presenting immune inflammatory cytokines; furthermore, they important factors regulating differentiation, survival death. Although biological function HSPs is to maintain homeostasis, some them can be used by viruses both fold their increase chances unfavorable host conditions. Folding viral as well replicating many different carried out by, among others, from HSP70 HSP90 families. In cases, family directly interact with polymerase enhance replication or facilitate formation complex and/or stability proteins. It known that expression genes at transcriptional translational levels. Both these form and, consequently, entry virus into cell. Current studies have shown significance course infection SARS-CoV-2. A comprehensive understanding chaperone use during will provide new insight mechanisms therapeutic potential. The aim this study describe molecular basis participation infections potential antiviral therapy.

Language: Английский

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Animal models for COVID-19: advances, gaps and perspectives

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 7, 2022

Abstract COVID-19, caused by SARS-CoV-2, is the most consequential pandemic of this century. Since outbreak in late 2019, animal models have been playing crucial roles aiding rapid development vaccines/drugs for prevention and therapy, as well understanding pathogenesis SARS-CoV-2 infection immune responses hosts. However, current some deficits there an urgent need novel to evaluate virulence variants concerns (VOC), antibody-dependent enhancement (ADE), various comorbidities COVID-19. This review summarizes clinical features COVID-19 different populations, characteristics major including those naturally susceptible animals, such non-human primates, Syrian hamster, ferret, minks, poultry, livestock, mouse sensitized genetically modified, AAV/adenoviral transduced, mouse-adapted strain engraftment human tissues or cells. host receptors proteases essential designing advanced modified models, successful studies on are also reviewed. Several improved alternatives future proposed, reselection alternative receptor genes multiple gene combinations, use transgenic knock-in method, strains establishing next generation mice.

Language: Английский

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Spatiotemporal, optogenetic control of gene expression in organoids

Nature Methods, Journal Year: 2023, Volume and Issue: 20(10), P. 1544 - 1552

Published: Sept. 21, 2023

Organoids derived from stem cells have become an increasingly important tool for studying human development and modeling disease. However, methods are still needed to control study spatiotemporal patterns of gene expression in organoids. Here we combined optogenetics perturbation technologies activate or knock-down RNA target genes programmable patterns. To illustrate the usefulness our approach, locally activated Sonic Hedgehog (SHH) signaling organoid model neurodevelopment. Spatial single-cell transcriptomic analyses showed that this local induction was sufficient generate stereotypically patterned organoids revealed new insights into SHH's contribution regulation With study, propose optogenetic perturbations combination with spatial transcriptomics as a powerful technology reprogram cell fates tissue patterning

Language: Английский

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Prediction and Analysis of SARS-CoV-2-Targeting MicroRNA in Human Lung Epithelium

Genes, Journal Year: 2020, Volume and Issue: 11(9), P. 1002 - 1002

Published: Aug. 26, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus, is responsible for the disease 2019 (COVID-19) pandemic of 2020. Experimental evidence suggests that microRNA can mediate intracellular defence mechanism against some viruses. The purpose this study was to identify with predicted binding sites in SARS-CoV-2 genome, compare these their expression profiles lung epithelial tissue and make inference towards possible roles mitigating infection. We hypothesize high specific coronavirus-targeting epithelia may protect infection viral propagation, conversely, low confer susceptibility have identified 128 human potential target most which very epithelia. Six are differentially expressed upon vitro SARS-CoV-2. Additionally, 28 also SARS-CoV genome while 23 MERS-CoV genome. found a number commonly two other studies. Further research into identifying bona fide targeting will be useful understanding importance as cellular pathogenic infections.

Language: Английский

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ACE2 Interaction Networks in COVID-19: A Physiological Framework for Prediction of Outcome in Patients with Cardiovascular Risk Factors

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(11), P. 3743 - 3743

Published: Nov. 21, 2020

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcomes in patients cardiovascular (CVD). The aim of the study was to characterize interaction between SARS-CoV-2 and Angiotensin-Converting Enzyme (ACE2) functional networks a focus on CVD. Methods: Using network medicine approach publicly available datasets, we investigated ACE2 tissue expression described that could be affected by heart, lungs nervous system. We compared them changes ACE-2 following analyzing public data human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This analysis performed using Network Relative Importance (NERI) algorithm, which integrates protein-protein co-expression networks. also miRNA-target predictions identify miRNAs regulate ACE2-related play role COVID19 outcome. Finally, enrichment for identifying main COVID-19 risk groups. Results: found similar confidence levels systems, supporting heart potential target SARS-CoV-2. Analysis infected hiPSC-CMs identified multiple hub genes corrupted signaling can responsible symptoms. most were EGFR (Epidermal Growth Factor Receptor), FN1 (Fibronectin 1), TP53, HSP90AA1, APP (Amyloid Beta Precursor Protein), while interactions MAST2 CALM1 (Calmodulin 1). Enrichment revealed diseases ACE2, especially cancerous diseases, obesity, hypertensive disease, Alzheimer’s non-insulin-dependent diabetes mellitus, congestive failure. Among ACE2-network components connected SARS-Cov-2 interactome, AGT (Angiotensinogen), CAT (Catalase), DPP4 (Dipeptidyl Peptidase 4), CCL2 (C-C Motif Chemokine Ligand 2), TFRC (Transferrin Receptor) CAV1 (Caveolin-1), factors. first time common regulators virus-related proteins all analyzed datasets. top regulating miR-27a-3p, miR-26b-5p, miR-10b-5p, miR-302c-5p, hsa-miR-587, hsa-miR-1305, hsa-miR-200b-3p, hsa-miR-124-3p, hsa-miR-16-5p. Conclusion: Our provides complete mechanistic framework investigating validated data. predicted groups, including established ones, thus providing reliable novel information regarding complexity pathways It used personalized diagnosis COVID-19.

Language: Английский

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