Virological characteristics correlating with SARS-CoV-2 spike protein fusogenicity

Frontiers in Virology, Год журнала: 2024, Номер 4

Опубликована: Март 14, 2024

Introduction The severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike (S) protein is essential in mediating membrane fusion of the virus with target cells. Several reports demonstrated that SARS-CoV-2 S fusogenicity reportedly closely associated intrinsic pathogenicity determined using hamster models. However, association between and other virological parameters remains elusive. Methods In this study, we investigated (e.g., S1/S2 cleavage efficiency, plaque size, pseudoviral infectivity, pseudovirus entry viral replication kinetics) eleven previous variants concern (VOCs) interest (VOIs) correlating fusogenicity. Results discussion was found to be strongly correlated efficiency size formed by clinical isolates. less kinetics. Taken together, our results suggest could potential indicators predict newly emerged variants.

Язык: Английский

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SARS-CoV-2 Evolution: Implications for Diagnosis, Treatment, Vaccine Effectiveness and Development

Vaccines, Год журнала: 2024, Номер 13(1), С. 17 - 17

Опубликована: Дек. 28, 2024

The COVID-19 pandemic, driven by the rapid evolution of SARS-CoV-2 virus, presents ongoing challenges to global public health. is characterized rapidly evolving mutations, especially in (but not limited to) spike protein, complicating predictions about its evolutionary trajectory. These mutations have significantly affected transmissibility, immune evasion, and vaccine efficacy, leading multiple pandemic waves with over half a billion cases seven million deaths globally. Despite several strategies, from development administration design availability antivirals, including monoclonal antibodies, already having been employed, persistent circulation virus emergence new variants continue result high case numbers fatalities. In past four years, immense research efforts contributed much our understanding viral pathogenesis mechanism, syndrome, host-microbe interactions, effective vaccines, diagnostic tools, treatments. focus this review provide comprehensive analysis functional impact on diagnosis, treatments, effectiveness. We further discuss safety pregnancy implications hybrid immunity long-term protection against infection, as well latest developments pan-coronavirus nasal formulations, emphasizing need for continued surveillance, research, adaptive health strategies response race.

Язык: Английский

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A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 11, 2025

Abstract Coronaviruses (CoV) encode sixteen non-structural proteins (nsps), most of which form the replication-transcription complex (RTC). The RTC contains a core composed one nsp12 RNA-dependent RNA polymerase (RdRp), two nsp8s and nsp7. recruits other nsps to synthesize all viral RNAs within infected cell. While essential for replication, mechanism by assembles into processive remains poorly understood. We show that preferentially first having nsp12-polymerase bind template, followed subsequent association nsp7 nsp8. Once assembled on requires hundreds seconds undergo conformational change enables elongation. In absence RNA, (apo-)RTC several hours adopt its elongation-competent conformation. propose this obligatory activation step facilitates recruitment additional nsp’s efficient synthesis may represent promising target therapeutic interventions.

Язык: Английский

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A phylogenetic method identifies candidate drivers of the evolution of the SARS-CoV-2 mutation spectrum

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 20, 2025

Abstract The molecular processes that generate new mutations evolve, but the causal mechanisms are largely unknown. In particular, relative rates of mutation types ( e . g ., C>T), spectrum, sometimes vary among closely related species and populations. I present an algorithm for subdividing a phylogeny into distinct spectra. By applying this approach to SARS-CoV-2 comprising approximately eight million genome sequences, identify 10 shifts in spectrum. find strong enrichment consistent with candidate amino-acid substitutions polymerase, strikingly three appearances same homoplasious substitution each associated decreased C>T rates. With rapidly growing genomic datasets, future extensions promises insights evolution mutational processes.

Язык: Английский

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The impact of remdesivir on SARS-CoV-2 evolution in vivo

JCI Insight, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

The impact of remdesivir on SARS-CoV-2 diversity and evolution in vivo has remained unclear. In this single-center, retrospective cohort study, we assessed diversification over time a hospitalized patients who did or not receive remdesivir. Whole genome sequencing was performed 98 paired specimens collected from 49 before after administration. Genetic divergence between significantly different what observed the drug. However, when comparing minority variants, several positions showed preferential treatment, which were associated with variants concern. Most notably, administration resulted strong selection for nonsynonymous mutation nsp12, G671S, previously enhanced viral fitness. This same found enriched second 143 inpatients compared to controls. Only one other implicated resistance (nsp12:V792I) be preferentially selected These data suggest that replicative fitness may presence antiviral therapy as an indirect means overcome selective pressure.

Язык: Английский

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A comprehensive review of current insights into the virulence factors of SARS-CoV-2

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

ABSTRACT The evolution of SARS-CoV-2 pathogenicity has been a major focus attention. However, the determinants are still unclear. Various hypotheses have attempted to elucidate mechanisms underlying viral pathogenicity, but definitive conclusion yet be reached. Here, we review potential impact all proteins in on pathogenic process and analyze effects their mutations evolution. We aim summarize which virus-encoded crucial influencing defined as disease severity following infection. Mutations these key proteins, virulence factors SARS-CoV-2, may driving forces behind pathogenicity. S protein can entry fusogenicity. such NSP2, NSP5, NSP14, ORF7a alter virus’s ability suppress host synthesis innate immunity. NSP3, NSP4, NSP6, N protein, NSP12 replication efficiency. combined NSP6 significantly reduce replication. In addition, various including ORF3a, ORF8, Spike E directly participate inflammatory process. modulate levels inflammation Collectively, influence by impacting immune evasion, capacity, level mediated conclusion, is likely determined multiple factors.

Язык: Английский

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Enhanced RNA replication and pathogenesis in recent SARS-CoV-2 variants harboring the L260F mutation in NSP6

PLoS Pathogens, Год журнала: 2025, Номер 21(3), С. e1013020 - e1013020

Опубликована: Март 31, 2025

The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape. Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across entire viral genome their functional impact is not well understood. To address contribution of these mutations, we reconstructed genomes recent Omicron disabled expression (replicons) to systematically compare RNA replication capabilities independently Spike. We also used a single reference replicon complemented it various variant proteins quantify entry single-round infection assays. Viral were negatively correlated, suggesting that as evolve reduced functions under growing pressure on Spike, increases compensatory mechanism. identified multiple replication. NSP6 emerged hotspot distinct L260F mutation arising BQ.1.1 XBB.1.16 variants. Using mutant revertant clones, was validated enhance cells increase pathogenesis mice. Notably, this host lipid droplet content NSP6. Collectively, systematic analysis defined NSP6’s key role provides insight into evolutionary trajectories possible therapeutic implications.

Язык: Английский

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Overview of SARS-CoV-2 variants in the federation of Bosnia and Herzegovina throughout four waves of the pandemic

Technology and Health Care, Год журнала: 2025, Номер unknown

Опубликована: Апрель 11, 2025

Aim COVID-19 pandemic, caused by SARS-CoV-2, has had a profound impact on global health, including in Bosnia and Herzegovina, which faced unique challenges due to limited testing high mortality rates. This analysis aimed identify mutations detect different SARS-CoV-2 lineages across four pandemic waves. Methodology A total of 127 samples were collected sequenced from patients the Federation providing comprehensive overview viral genetic diversity this region. Two sequencing platforms, Ion Torrent Illumina, used, whereby 37 platform, while others Illumina platform. Results study presents genomic variants circulating Herzegovina over distinct waves, spanning March 2020 April 2023. Examination variations these waves revealed key associated with transmission potential virulence. Conclusion These insights into evolution emphasizes importance continuous surveillance understand strengthen public health responses future pandemics.

Язык: Английский

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Allosteric Signal within the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein Mediated by a Class 3 Monoclonal Antibody Revealed through Molecular Dynamics Simulations and Protein Residue Networks

ACS Omega, Год журнала: 2024, Номер 9(4), С. 4684 - 4694

Опубликована: Янв. 18, 2024

This study investigated the allosteric action within receptor-binding domain (RBD) of SARS-CoV-2 spike protein caused by class 3 monoclonal antibody (mAb) binding. As emergence variants has raised concerns about effectiveness treatments antibodies, targeting highly conserved epitopes become an alternative strategy design. Simulations explicitly solvated RBD BA.2.75 omicron subvariants were carried out both in presence and absence bebtelovimab, as a model example antibodies against protein. The comparative analysis showed that bebtelovimab's binding on two α helices at epitope region disrupted nearby interaction network, which triggered denser network formation opposite side motif (RBM) resulted "close" conformation could prevent ACE2 A better understanding this lead to development mAbs for further concern. In terms computational techniques, communicability matrix serve tool visualize effects allostery, pairs amino acids or secondary structures with high pinpoint possible sites transfer signal. Additionally, gain/loss help elucidate consequences actions, be employed along other allostery quantification techniques some previous studies.

Язык: Английский

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Substitution-Mutation Rate Ratio (c/µ) As Molecular Adaptation Test Beyond Ka/Ks: A SARS-COV-2 Case Study

Journal of Molecular Evolution, Год журнала: 2025, Номер unknown

Опубликована: Май 3, 2025

Abstract The Ka/Ks ratio test, which assesses nonsynonymous versus synonymous substitution rates in Translated Region (TR) of a genome, is widely used to quantify fitness changes due mutations but its critical limits are be addressed. can categorize the total change as neutral (Ka/Ks = 1), beneficial > or deleterious < only if neutral. Otherwise, provides protein sequence change. This neutrality assumption also renders this test inapplicable sites non-protein-coding UnTranslated (UTR). Our previous work introduced substitution-mutation rate (c/µ) per nucleotide site (c: UTR/TR mean value Ka and Ks TR; µ: mutation rate) generalized alternative detect selection pressure, offering broader application without forementioned presumptions. paper derives general equation linking c/µ with weighted Ks/µ Ka/µ (c/µ Ps*(Ks/μ) + Pa*(Ka/μ), Ps Pa: proportions under model codon table), demonstrating that infers same does (i.e. 1). might provide different assignment from test. Indeed, our comparative analysis tests across 25 proteins SARS-COV-2 using three independent genomic datasets shows inaccurately reports type for 7 proteins. findings advocate complement traditional pressure at genome.

Язык: Английский

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