Early innate immune response and evolution of a SARS-CoV-2 furin cleavage site inactive variant in bat cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1205767 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31875300_1.fastq.gz | Fastqsanger.gz | |||
| SRR31875300_2.fastq.gz | Fastqsanger.gz | |||
| SRR31875301_1.fastq.gz | Fastqsanger.gz | |||
| SRR31875301_2.fastq.gz | Fastqsanger.gz | |||
| SRR31875302_1.fastq.gz | Fastqsanger.gz |
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Project description:SARS-CoV-2 has caused the largest known coronavirus pandemic and is believed to have emerged from insectivorous bats. Little is known about the evolution of these viruses in their reservoir bat species. In this study, we investigated SARS-CoV-2-host interaction using human and bat cells. Bat cells mount a robust and early antiviral response but elicit a dampened pro-inflammatory response upon SARS-CoV-2 infection compared to human cells. Furthermore, an inactivating R685P mutation within the furin cleavage site (FCS) of the SARS-CoV-2 spike protein was naturally selected for in infected bat cells. Taken together, our data demonstrate that insectivorous bat cells have evolved a differential antiviral immune response against SARS-CoV-2 infection, likely to mitigate immunopathology that is observed in humans. Our study sheds light on the evolution of sarbecoviruses in bats and extends molecular evidence to data from field studies that have demonstrated that SARS-CoV-2-related viruses in wild-caught bats lack an intact FCS.
2025-06-04 | GSE285756 | GEO
Project description:Furin cleavage in European SARS-related bat coronaviruses
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Project description:SARS-CoV-2 has caused the largest known coronavirus pandemic and is believed to have emerged from insectivorous bats. Little is known about the evolution of these viruses in their reservoir bat species. In this study, we investigated SARS-CoV-2-host interaction using human and bat cells. Bat cells mount a robust and early antiviral response but elicit a dampened pro-inflammatory response upon SARS-CoV-2 infection compared to human cells.
2025-06-05 | PXD058807 | Pride
Project description:The current pandemic of COVID-19 caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), threatens human health around the world. Of particular concern is that bats are recognized as one of the most potential natural hosts of SARS-CoV-2; however, coronavirus ecology in bats is still nascent. Here, we performed a degenerate primer screening and next-generation sequencing analysis of 112 bats, collected from Hainan Province, China. Three coronaviruses, namely bat betacoronavirus (Bat CoV) CD35, Bat CoV CD36 and bat alphacoronavirus CD30 were identified. Bat CoV CD35 genome had 99.5% identity with Bat CoV CD36, both sharing the highest nucleotide identity with Bat Hp-betacoronavirus Zhejiang2013 (71.4%), followed by SARS-CoV-2 (54.0%). Phylogenetic analysis indicated that Bat CoV CD35 formed a distinct clade, and together with Bat Hp-betacoronavirus Zhejiang2013, was basal to the lineage of SARS-CoV-1 and SARS-CoV-2. Notably, Bat CoV CD35 harbored a canonical furin-like S1/S2 cleavage site that resembles the corresponding sites of SARS-CoV-2. The furin cleavage sites between CD35 and CD36 are identical. In addition, the receptor-binding domain of Bat CoV CD35 showed a highly similar structure to that of SARS-CoV-1 and SARS-CoV-2, especially in one binding loop. In conclusion, this study deepens our understanding of the diversity of coronaviruses and provides clues about the natural origin of the furin cleavage site of SARS-CoV-2.
| S-EPMC10151251 | biostudies-literature
Project description:ABSTRACT: Furin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific furin knockout (βfurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on βfurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βfurKO cells show impaired cleavage of the accessory V-ATPase subunit Ac45, and by blocking this pump in β cells the mTORC1 pathway is activated. Furthermore, βfurKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction. METHOD: Data obtained for the β cell specific knockout (RIP-Cre+/- furin flox/flox) and control (furin flox/flox) samples were compared to investigate the effect of furin loss on the mRNA profile of islets. Although this method does not directly provide furin targets, the notion of differential gene expression might elucidate affected cellular processes, potentially leading to upstream furin substrates.
2020-05-12 | GSE150312 | GEO
Project description:Analysis of T-cells lacking the proprotein convertase furin. Proprotein convertases promote the proteolytic maturation of proproteins. Furin is induced in activated T-cells. Results provide insight into the function of furin in T-cells. CD4+CD62L+CD44- naive, CD4+CD62L-CD44+ memory and CD4+CD25+FoxP3+ regulatory T cells were isolated from Fur flox/flox and CD4 cre Fur flox/flox mice. Naive T cells were activated via TCR. Total RNA was extracted from all cells and hybridized to Affymetrix microarrays.
2015-08-05 | E-GEOD-67884 | biostudies-arrayexpress
Project description:Analysis of T-cells lacking the proprotein convertase furin. Proprotein convertases promote the proteolytic maturation of proproteins. Furin is induced in activated T-cells. Results provide insight into the function of furin in T-cells.
2015-08-05 | GSE67884 | GEO
Project description:Direct RNA sequencing using an Oxford Nanopore MinION characterised the transcriptome of SARS-CoV-2 grown in Vero E6 cells. This cell line is being widely used to propagate the novel coronavirus. The viral transcriptome was analysed using a recently developed ORF-centric pipeline. This revealed the pattern of viral transcripts, (i.e. subgenomic mRNAs), generally fitted the predicted replication and transcription model for coronaviruses. A 24 nt in-frame deletion was detected in subgenomic mRNAs encoding the spike (S) glycoprotein. This feature was identified in over half of the mapped transcripts and was predicted to remove a proposed furin cleavage site from the S glycoprotein. This motif directs cleavage of the S glycoprotein into functional subunits during virus entry or exit. Cleavage of the S glycoprotein can be a barrier to zoonotic coronavirus transmission and affect viral pathogenicity. Allied to this transcriptome analysis, tandem mass spectrometry was used to identify over 500 viral peptides and 44 phosphopeptides, covering almost all of the proteins predicted to be encoded by the SARS-CoV-2 genome, including peptides unique to the deleted variant of the S glycoprotein. Detection of an apparently viable deletion in the furin cleavage site of the S glycoprotein reinforces the point that this and other regions of SARS-CoV-2 proteins may readily mutate. This is of clear significance given the interest in the S glycoprotein as a potential vaccine target and the observation that the furin cleavage site likely contributes strongly to the pathogenesis and zoonosis of this virus. The viral genome sequence should be carefully monitored during the growth of viral stocks for research, animal challenge models and, potentially, in clinical samples. Such variations may result in different levels of virulence, morbidity and mortality.
2020-03-31 | PXD018241 | Pride
Project description:The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1β levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-β1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.
2016-12-30 | GSE84117 | GEO
Project description:The multibasic furin cleavage site at the S1/S2 boundary of the spike protein (S protein) is a hallmark of SARS-CoV-2 and plays an crucial role in viral infection. O-glycosylation near the furin site catalyzed by host cell glycosyltransferases can theoretically hinder spike protein processing and impede viral infection, but so far such a hypothesis has not been tested with authentic viruses. The mechanism underlying furin activation also remains poorly understood. In this study, we have discovered that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the multibasic S1/S2 boundary region. These O-glycosylations inhibit furin processing of the spike protein and surprisingly suppress the incorporation of S protein into virus-like-particles (VLPs). Mechanistic analysis revealed that the assembly of spike protein into VLPs relies on protein-protein interaction between the furin-cleaved S protein and a double aspartic motif on the membrane protein of SARS-CoV-2, suggesting a novel mechanism for furin activation of the S protein. Interestingly, a point mutation at P681, found in the alpha and delta variants of SARS-CoV-2, confers resistance to glycosylation by GalNAc-T3 and T7, thereby diminishing the inhibitory effect against furin processing. However, an additional mutation at N679 in the most recent omicron variant reverses this resistance, rendering it susceptible to glycosylation in vitro and sensitive to the expression of GalNAc-T3 and T7 in human lung cells. Together, our findings suggest a glycosylation-based defense mechanism employed by host cells against SARS-CoV-2 and unveil the intricate interplay between the host and pathogen at this critical “battlefield” as the virus initially evades and currently succumbs to host cell glycosylation..
2024-03-21 | PXD049110 | Pride