SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity

mBio, Год журнала: 2021, Номер 12(4)

Опубликована: Авг. 24, 2021

SARS-CoV-2 uses its spike protein to enter target cells. The is cleaved by a host protease, and this event facilitates viral entry broadens cell tropism.

Язык: Английский

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Emerging SARS‐CoV‐2 variants can potentially break set epidemiological barriers in COVID‐19

Journal of Medical Virology, Год журнала: 2021, Номер 94(4), С. 1300 - 1314

Опубликована: Ноя. 23, 2021

Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new and/or increased disease severity. Demographic trends from recent coronavirus 2019 waves, which believed to be driven by newer severe acute respiratory syndrome 2 (SARS-CoV-2) variants, indicate that aforementioned being breached a larger number younger healthy individuals developing disease. The SARS-CoV-2 variants have key mutations can induce significant changes in virus-host interactions. Recent studies report that, some these mutations, singly group, enhance mechanisms, such as binding receptor-binding domain (RBD) viral spike protein with angiotensin-converting enzyme (ACE2) receptor host-cells, increase glycosylation at antigenic sites, proteolytic cleavage protein, thus leading improved host-cell entry replication virus. putative interactions imparted RBD sequence potentially reason behind breach observed barriers. Susceptibility outcomes influenced expressions ACE2 other proteases. act more efficiently, even lesser availability entry-receptor associated proteases, efficient greater resulting high loads prolonged shedding, widespread tissue-injury, inflammation transmissibility lethality. Furthermore, accumulating evidence shows multiple reduced neutralization both, natural vaccine-acquired antibodies, indicating repeated vaccine breakthrough infections may arise serious health concerns ongoing pandemic.

Язык: Английский

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CPC-containing oral rinses inactivate SARS-CoV-2 variants and are active in the presence of human saliva

Journal of Medical Microbiology, Год журнала: 2022, Номер 71(2)

Опубликована: Фев. 18, 2022

Introduction. The importance of human saliva in aerosol-based transmission SARS-CoV-2 is now widely recognized. However, little known about the efficacy virucidal mouthwash formulations against emergent variants concern and presence saliva.Hypothesis. Mouthwashes containing actives will have similar inactivation effects multiple retain saliva.Aim. To examine vitro to inactivate variants.Methodology. Inactivation by or absence was assayed using ASTM International Standard E1052-20 methodology.Results. Appropriately formulated mouthwashes 0.07 % cetylpyridinium chloride but not 0.2 chlorhexidine completely inactivated (USA-WA1/2020, Alpha, Beta, Gamma, Delta) up limit detection suspension assays. Tests USA-WA1/2020 indicates that maintained saliva.Conclusions. Together these data suggest chloride-based are effective at inactivating variants. This potential reduce viral load oral cavity mitigate via salivary aerosols.

Язык: Английский

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Cryo-EM reveals binding of linoleic acid to SARS-CoV-2 spike glycoprotein, suggesting an antiviral treatment strategy

Acta Crystallographica Section D Structural Biology, Год журнала: 2023, Номер 79(2), С. 111 - 121

Опубликована: Янв. 20, 2023

The COVID-19 pandemic and concomitant lockdowns presented a global health challenge triggered unprecedented research efforts to elucidate the molecular mechanisms pathogenicity of SARS-CoV-2. spike glycoprotein decorating surface SARS-CoV-2 virions is prime target for vaccine development, antibody therapy serology as it binds host cell receptor central viral entry. electron cryo-microscopy structure protein revealed hydrophobic pocket in receptor-binding domain that occupied by an essential fatty acid, linoleic acid (LA). LA-bound adopts non-infectious locked conformation which more stable than infectious form shields important immunogenic epitopes. Here, impact LA binding on infectivity replication, evolutionary conservation other highly pathogenic coronaviruses, including variants concern (VOCs), are reviewed. importance metabolic products, eicosanoids, regulating human immune response inflammation highlighted. Lipid fatty-acid proteins virion appears be broader strategy employed viruses, picornaviruses Zika virus. Ligand stabilizes their assembly, downregulates infectivity. In case rhinoviruses, this has been exploited develop small-molecule antiviral drugs bind pocket. results suggest treatment based LA-binding

Язык: Английский

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Cell culture systems for isolation of SARS-CoV-2 clinical isolates and generation of recombinant virus

iScience, Год журнала: 2023, Номер 26(5), С. 106634 - 106634

Опубликована: Апрель 10, 2023

A simple and robust cell culture system is essential for generating authentic SARS-CoV-2 stocks evaluation of viral pathogenicity, screening antiviral compounds, preparation inactivated vaccines. Evidence suggests that Vero E6, a line commonly used in the field to grow SARS-CoV-2, does not support efficient propagation new variants triggers rapid adaptation virus. We generated panel 17 human lines overexpressing entry factors tested their ability infection. Two lines, Caco-2/AT HuH-6/AT, demonstrated exceptional susceptibility, yielding highly concentrated virus stocks. Notably, these were more sensitive than E6 cells recovering from clinical specimens. Further, provided platform producing genetically reliable recombinant through reverse genetics system. These cellular models are valuable tool study its continuously emerging variants.

Язык: Английский

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Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

Organoids, Год журнала: 2022, Номер 1(1), С. 2 - 27

Опубликована: Март 2, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes disease 2019 (COVID-19), which was classified as a pandemic in March 2020. As of 22 January 2022, globally more than 347 million cases COVID-19 have been diagnosed, with 5.6 deaths, making it the deadliest since influenza 1918. The clinical presentation COVID-19-related illness spans from asymptomatic to mild symptoms akin infection symptoms, including pneumonia necessitating hospitalisation and admission intensive care units. starts upper tract lungs but severe can also involve heart, blood vessels, brain, liver, kidneys intestine. increasing global health economic burden necessitates an urgent response. Understanding functional characteristics cellular tropism SARS-CoV-2, pathogenesis that leads multi-organ failure death, has prompted unprecedented adoption organoid models. Successful drug discovery vaccine development rely on pre-clinical models faithfully recapitulate viral life cycle host cell response infection. Human stem cell-derived organoids fulfill these criteria. Here we highlight role study SARS-CoV-2 modelling pathogenesis.

Язык: Английский

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Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Авг. 24, 2022

Class 1 and 2 monoclonal antibodies inhibit SARS-CoV-2 entry by blocking the interaction of viral receptor-binding domain with angiotensin-converting enzyme (ACE2), while class 3 target a highly conserved epitope outside ACE2 binding site. We aimed to investigate plasticity spike protein propagating wild-type in presence antibody S309. After 12 weeks, we obtained strain that was completely resistant inhibition S309, due successively evolving amino acid exchanges R346S P337L located paratope The lost affinity domains carrying or both exchanges, not affected. replicated efficiently human CaCo-2 cells more susceptible fusion than original strain. Overall, escaped S309 through slow, but targeted evolution enabling immune escape altering cell entry. This immune-driven enhancement infectivity pathogenicity could play an important role future SARS-CoV-2, which is under increasing immunological pressure from vaccination previous infections.

Язык: Английский

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Phosphoproteomic profiling of influenza virus entry reveals infection-triggered filopodia induction counteracted by dynamic cortactin phosphorylation

Cell Reports, Год журнала: 2022, Номер 38(4), С. 110306 - 110306

Опубликована: Янв. 1, 2022

Binding of influenza virus to its receptor triggers signaling cascades that reprogram the cell for infection. To elucidate global virus-induced changes cellular landscape, we conducted a quantitative phosphoproteomic screen with human and avian viruses. Proteins functions in adhesion cytoskeletal remodeling are overrepresented among hits, majority factors undergoing phosphorylation have significant impact on infection efficiency. We show induces formation filopodia through Cdc42 signaling, which results enhanced endocytosis. The host counteracts this mechanism cortactin, regulator actin polymerization becomes phosphorylated response binding translocates cortex, where it limits uptake. Overall, our study reveals induced by engagement uncovers is counteracted cell.

Язык: Английский

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Genome-Wide Analysis of the Indispensable Role of Non-structural Proteins in the Replication of SARS-CoV-2

Frontiers in Microbiology, Год журнала: 2022, Номер 13

Опубликована: Июнь 1, 2022

Understanding the process of replication and transcription SARS-CoV-2 is essential for antiviral strategy development. The replicase polyprotein indispensable viral replication. However, whether all nsps derived from are not fully understood. In this study, we utilized replicon as system to investigate role each nsp in We found that except nsp16, deletions drastically impair replicon, nsp14 could recover deficiency caused by its deletion replicon. Due unsuccessful expressions nsp1, nsp3, draw a conclusion about their trans-rescue functions. Our study provided new angle understand transcription, helping evaluation target drug

Язык: Английский

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Immunoinformatic exploration of a multi-epitope-based peptide vaccine candidate targeting emerging variants of SARS-CoV-2

Frontiers in Microbiology, Год журнала: 2023, Номер 14

Опубликована: Окт. 17, 2023

Many countries around the world are facing severe challenges due to recently emerging variants of SARS-CoV-2. Over last few months, scientists have been developing treatments, drugs, and vaccines subdue virus prevent its transmission. In this context, a peptide-based vaccine construct containing pathogenic proteins known elicit an immune response was constructed. An analysis spike protein-based epitopes allowed us design "epitope-based subunit vaccine" against coronavirus using approaches "reverse vaccinology" "immunoinformatics." Computational experimentation systematic, comprehensive protocol were followed with aim develop multi-epitope-based peptide (MEBP) candidate. Our study attempted predict MEBP by introducing mutations SARS-CoV-2 (Delta, Lambda, Iota, Omicron, Kappa) in Spike glycoprotein predicting dual-purpose (B-cell T-cell). This screening selected based on antigenicity, allergenicity, population coverage constructing them into linkers adjuvants. The analyzed for physicochemical properties secondary structure prediction, 3D built, refined, validated. Furthermore, peptide-protein interaction Toll-like receptor (TLR) molecules performed. Immune profiling performed check response. Codon optimization obtain GC content before cloning it E. coli genome, facilitating progression vector. Finally, in-silico simulation vaccine-protein complex comprehend stability conformational behavior.

Язык: Английский

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