scholarly journals The Discovery of a Recombinant SARS2-like CoV Strain Provides Insight Into SARS and COVID-19 Pandemics

2020 ◽  
Author(s):  
Xin Li ◽  
Xiufeng Jin ◽  
Shunmei Chen ◽  
Liangge Wang ◽  
Tung On Yau ◽  
...  
Keyword(s):  
Junction Region ◽  
Entry Site ◽  
Furin Cleavage ◽  
Internal Ribosome Entry ◽  
Spike Gene ◽  
Furin Cleavage Site ◽  
Gene Level ◽  
First Time ◽  
Insight Into

Abstract Background: In December 2019, the world awoke to a new zoonotic strain of coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).Results: In the present study, we classified betacoronavirus subgroup B into the SARS-CoV-2, SARS-CoV and SARS-like CoV clusters, and the ORF8 genes of these three clusters into types 1, 2 and 3, respectively. One important result of our study is that we reported—for the first time—a recombination event of ORF8 at the whole-gene level in a bat, which had been co-infected by two betacoronavirus strains. This result provides substantial proof for long-existing hypotheses regarding the recombination and biological functions of ORF8. Based on the analysis of recombination events in the Spike gene, we propose that the Spike protein of SARS-CoV-2 may have more than one specific receptor for its function as gp120 of HIV has CD4 and CCR5. In the present study, we also found that the ancestor of betacoronavirus had a strong first Internal Ribosome Entry Site (IRES) and at least one furin cleavage site (FCS) in the junction region between S1 and S2 subunits.Conclusions: We concluded that the junction FCS in SARS-CoV-2 may increase the efficiency of its entry into cells, while the type 2 ORF8 acquired by SARS-CoV may increase its replication efficiency. These two most critical events provide the most likely explanation for SARS and COVID-19 pandemics.

scholarly journals The discovery of a recombinant SARS2-like CoV strain provides insights into SARS and COVID-19 pandemics

2020 ◽  
Author(s):  
Xin Li ◽  
Xiufeng Jin ◽  
Shunmei Chen ◽  
Liangge Wang ◽  
Tung On Yau ◽  
...  
Keyword(s):  
Viral Entry ◽  
Binding Sites ◽  
Cleavage Sites ◽  
Specific Receptor ◽  
Furin Cleavage ◽  
Translational Initiation ◽  
Ribosome Binding Sites ◽  
Gene Level ◽  
Main Factors ◽  
First Time

AbstractIn December 2019, the world awoke to a new zoonotic strain of coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the present study, we identified key recombination regions and mutation sites cross the SARS-CoV-2, SARS-CoV and SARS-like CoV clusters of betacoronavirus subgroup B. Based on the analysis of these recombination events, we proposed that the Spike protein of SARS-CoV-2 may have more than one specific receptor for its function. In addition, we reported—for the first time—a recombination event of ORF8 at the whole-gene level in a bat and ultimately determined that ORF8 enhances the viral replication. In conjunction with our previous discoveries, we found that receptor binding abilities, junction furin cleavage sites (FCSs), strong first ribosome binding sites (RBSs) and enhanced ORF8s are main factors contributing to transmission, virulence and host adaptability of CoVs. Junction FCSs and enhanced ORF8s increase the efficiencies in viral entry into cells and replication, respectively while strong first RBSs enhance the translational initiation. The strong recombination ability of CoVs integrated these factors to generate multiple recombinant strains, two of which evolved into SARS-CoV and SARS-CoV-2 by nature selection, resulting in the SARS and COVID-19 pandemics.

scholarly journals The Double-Stranded RNA Binding Protein 76:NF45 Heterodimer Inhibits Translation Initiation at the Rhinovirus Type 2 Internal Ribosome Entry Site

2006 ◽  
Vol 80 (14) ◽  
pp. 6936-6942 ◽  
Author(s):  
Melinda K. Merrill ◽  
Matthias Gromeier
Keyword(s):  
Translation Initiation ◽  
Internal Ribosome Entry Site ◽  
Rna Binding ◽  
Neuronal Cells ◽  
Rna Binding Protein ◽  
Glioma Cells ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Double Stranded Rna

ABSTRACT Poliovirus (PV) plus-strand RNA genomes initiate translation in a cap-independent manner via an internal ribosome entry site (IRES) in their 5′ untranslated region. Viral translation is codetermined by cellular IRES trans-acting factors, which can influence viral propagation in a cell-type-specific manner. Engineering of a poliovirus recombinant devoid of neuropathogenic properties but highly lytic in malignant glioma cells was accomplished by exchange of the cognate poliovirus IRES with its counterpart from human rhinovirus type 2 (HRV2), generating PV-RIPO. Neuroblast:glioma heterokaryon analyses revealed that loss of neurovirulence is due to trans-dominant repression of PV-RIPO propagation in neuronal cells. The double-stranded RNA binding protein 76 (DRBP76) was previously identified to bind to the HRV2 IRES in neuronal cells and to inhibit PV-RIPO translation and propagation (M. Merrill, E. Dobrikova, and M. Gromeier, J. Virol. 80:3347-3356, 2006). The results of size exclusion chromatography indicate that DRBP76 heterodimerizes with nuclear factor of activated T cells, 45 kDa (NF45), in neuronal but not in glioma cells. The DRBP76:NF45 heterodimer binds to the HRV2 IRES in neuronal but not in glioma cells. Ribosomal profile analyses show that the heterodimer preferentially associates with the translation apparatus in neuronal cells and arrests translation at the HRV2 IRES, preventing PV-RIPO RNA assembly into polysomes. Results of this study suggest that the DRBP76:NF45 heterodimer selectively blocks HRV2 IRES-driven translation initiation in neuron-derived cells.

scholarly journals Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

Science ◽  
2020 ◽  
Vol 370 (6518) ◽  
pp. 856-860 ◽  
Author(s):  
Ludovico Cantuti-Castelvetri ◽  
Ravi Ojha ◽  
Liliana D. Pedro ◽  
Minou Djannatian ◽  
Jonas Franz ◽  
...  
Keyword(s):  
Cell Entry ◽  
Host Cells ◽  
Tissue Tropism ◽  
Furin Cleavage ◽  
Blocking Antibody ◽  
Pathological Analysis ◽  
Furin Cleavage Site ◽  
Neuropilin 1 ◽  
Virus Receptors ◽  
Insight Into

The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.

scholarly journals Flavivirus RNA methylation

2014 ◽  
Vol 95 (4) ◽  
pp. 763-778 ◽  
Author(s):  
Hongping Dong ◽  
Katja Fink ◽  
Roland Züst ◽  
Siew Pheng Lim ◽  
Cheng-Feng Qin ◽  
...  
Keyword(s):  
Immune Response ◽  
Rna Structure ◽  
Innate Immune ◽  
Viral Rna ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Viral Translation ◽  
Rna Capping

The 5′ end of eukaryotic mRNA contains the type-1 (m7GpppNm) or type-2 (m7GpppNmNm) cap structure. Many viruses have evolved various mechanisms to develop their own capping enzymes (e.g. flavivirus and coronavirus) or to ‘steal’ caps from host mRNAs (e.g. influenza virus). Other viruses have developed ‘cap-mimicking’ mechanisms by attaching a peptide to the 5′ end of viral RNA (e.g. picornavirus and calicivirus) or by having a complex 5′ RNA structure (internal ribosome entry site) for translation initiation (e.g. picornavirus, pestivirus and hepacivirus). Here we review the diverse viral RNA capping mechanisms. Using flavivirus as a model, we summarize how a single methyltransferase catalyses two distinct N-7 and 2′-O methylations of viral RNA cap in a sequential manner. For antiviral development, a structural feature unique to the flavivirus methyltransferase was successfully used to design selective inhibitors that block viral methyltransferase without affecting host methyltransferases. Functionally, capping is essential for prevention of triphosphate-triggered innate immune activation; N-7 methylation is critical for enhancement of viral translation; and 2′-O methylation is important for subversion of innate immune response during viral infection. Flaviviruses defective in 2′-O methyltransferase are replicative, but their viral RNAs lack 2′-O methylation and are recognized and eliminated by the host immune response. Such mutant viruses could be rationally designed as live attenuated vaccines. This concept has recently been proved with Japanese encephalitis virus and dengue virus. The findings obtained with flavivirus should be applicable to other RNA viruses.

scholarly journals Insights into the secondary and tertiary structure of the Bovine Viral Diarrhea Virus Internal Ribosome Entry Site

2021 ◽  
Author(s):  
Devadatta Gosavi ◽  
Iwona Wower ◽  
Irene Beckmann ◽  
Ivo L. Hofacker ◽  
Jacek Wower ◽  
...  
Keyword(s):  
Internal Ribosome Entry Site ◽  
Tertiary Structure ◽  
Bovine Viral Diarrhea ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Viral Diarrhea Virus ◽  
Insight Into ◽  
Independent Translation

The Internal Ribosome Entry Site (IRES) RNA of Bovine viral diarrhea virus (BVDV), an economically significant Pestivirus, is required for the cap-independent translation of viral genomic RNA. Thus, it is essential for viral replication and pathogenesis. We applied a combination of high-throughput biochemical RNA structure probing (SHAPE-MaP) and in silico modeling approaches to gain insight into the secondary and tertiary structures of BVDV IRES RNA. Our study demonstrated that BVDV IRES RNA forms in solution a modular architecture composed of three distinct structural domains (I-III). Two regions within domain III are engaged in tertiary interactions to form an H-type pseudoknot. Computational modeling of the pseudoknot motif provided a fine-grained picture of the tertiary structure and local arrangement of helices in the BVDV IRES. Furthermore, comparative genomics and consensus structure predictions revealed that the pseudoknot is evolutionarily conserved among many Pestivirus species. These studies provide detailed insight into the structural arrangement of BVDV IRES RNA H-type pseudoknot and encompassing motifs that likely contribute to the optimal functionality of viral cap-independent translation element.

scholarly journals An in vitro and in vivo approach for the isolation of Omicron variant from human clinical specimens

2022 ◽  
Author(s):  
Pragya D Yadav ◽  
Nivedita Gupta ◽  
Varsha Potdar ◽  
Sreelekshmy Mohandas ◽  
Rima R Sahay ◽  
...  
Keyword(s):  
Virus Isolation ◽  
Clinical Specimen ◽  
Furin Cleavage ◽  
Clinical Specimens ◽  
Future Studies ◽  
Spike Gene ◽  
Furin Cleavage Site ◽  
Human Clinical Specimen

Due to failure of virus isolation of Omicron variant in Vero CCL-81 from the clinical specimens of COVID-19 cases, we infected Syrian hamsters and then passage into Vero CCL-81 cells. The Omicron sequences were studied to assess if hamster could incorporate any mutation to changes its susceptibility. L212C mutation, Tyrosine 69 deletion, and C25000T nucleotide change in spike gene and absence of V17I mutation in E gene was observed in sequences of hamster passage unlike human clinical specimen and Vero CCL-81 passages. No change was observed in the furin cleavage site in any of the specimen sequence which suggests usefulness of these isolates in future studies.

Aleksey Peshkov as an editor of Samarskaya Gazeta

2020 ◽  
pp. 128-138
Author(s):  
A. S. Bik-Bulatov
Keyword(s):  
Local History ◽  
Organizational Skills ◽  
First Time ◽  
New Evidence ◽  
Insight Into ◽  
Shed Light

The article uses little known letters of M. Gorky, many of which were published for the first time in 1997, as well as findings of Samara-based experts in local history to shed light on the writer’s work as editor-in-chief of the Samarskaya Gazeta newspaper in 1895. The researcher introduces hitherto unstudied reminiscences of the journalist D. Linyov (Dalin) about this period, which reference a letter by Gorky, now lost. The paper details a newly discovered episode of Gorky’s professional biography as a journalist: it concerns his campaign against a Samara ‘she-wolf,’ the madam of a local brothel A. Neucheva. Linyov’s reminiscences turn out to be an important and interesting source, offering an insight into the daily grind of the young editor Gorky, providing new evidence of his excellent organizational skills, and describing his moral and social stance. The author presents his work in the context of a recently initiated broader discussion about the need to map out all Russian periodicals for the period until 1917, as well as all research devoted to individual publications.

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