Co-evolved ligands to ORF8. Could they reduce SARS-COV-2-excesive inflammation? DOI Creative Commons
Melissa Belló-Pérez, Julio Coll

Published: Dec. 19, 2023

ORF8 is an asymmetric-homodimer SARS-COV-2 accessory protein implicated in excesive human inflammation causing numerous deaths. There no approved drug targeting ORF8, nor it known whether any anti-ORF8 drugs could reduce inflammation. Computationally combining ligand co-evolution of parent molecules with affinity-consensus docking, children candidates for docking to cavities were generated. Targeting the homodimer interface highest affinity scaffolds, hundreds grandchildren predicting nanoMolar affinities, unique high specificities and low toxicity risks Although remaining hypothetical without experimental confirmation, this constitute a new methodological attempt search drug-like interfere SARS-COV-2-dependent excessive

Language: Английский

Regulation of virion production by the ORF8 signal peptide across SARS-CoV-2 variants DOI Creative Commons
Mir M. Khalid, Irene P. Chen,

Frank S Soveg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 6, 2024

The open reading frame 8 (ORF8), an accessory protein of SARS-CoV-2, is prone to deletions and mutations across different viral variants, which was first described in several Singapore variants. reason why evolution favors loss or inactivation ORF8 not fully understood, although the effects on inflammation, immune evasion, disease severity have been described. Here we show using clinical deficient isolates, virus like particles (VLPs) replicons that expression dampens particle production. physically interacts with Spike induces Golgi fragmentation, overall contributing less Using systematic deletions, mapped reducing function its N terminal signal peptide. Interestingly, this part severely truncated recent XBB.1.5 variant, when restored, suppresses production context entire genome. Collectively, our data support model evolutionary pressure exists delete sequence SARS-CoV-2 variants enable

Language: Английский

Citations

3
Coronavirus envelope protein activates TMED10-mediated unconventional secretion of inflammatory factors DOI Creative Commons
Lei Liu,

Lijingyao Zhang,

Xinyan Hao

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 8, 2024

The precise cellular mechanisms underlying heightened proinflammatory cytokine production during coronavirus infection remain incompletely understood. Here we identify the envelope (E) protein in severe coronaviruses (SARS-CoV-2, SARS, or MERS) as a potent inducer of interleukin-1 release, intensifying lung inflammation through activation TMED10-mediated unconventional secretion (UcPS). In contrast, E mild (229E, HKU1, OC43) demonstrates less pronounced effect. contains an SS/DS motif, which is not present milder strains and facilitates interaction with TMED10. This enhances TMED10-oligomerization, facilitating UcPS cargo translocation into ER-Golgi intermediate compartment (ERGIC)-a pivotal step UcPS. Progesterone analogues were identified compounds inhibiting E-enhanced release factors Mouse Hepatitis Virus (MHV) model. These findings elucidate molecular mechanism driving coronavirus-induced hyperinflammation, proposing E-TMED10 potential therapeutic target to counteract adverse effects inflammation.

Language: Английский

Citations

2
Genomic surveillance and vaccine response to the dominant SARS-CoV-2 XBB lineage in Rio Grande do Sul DOI Creative Commons

Bruna Candia Piccoli,

Thaís Regina y Castro, Luíza Funck Tessele

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 22, 2024

The COVID-19 pandemic has been marked by novel viral variants, posing challenges to global public health. Recombination, a evolution mechanism, is implicated in SARS-CoV-2's ongoing evolution. XBB recombinant lineage, known for evading antibody-mediated immunity, exhibits higher transmissibility without increased disease severity. We investigated the prevalence and genomic features of SARS-CoV-2-positive cases Rio Grande do Sul (RS), Brazil. sequenced 357 samples from epidemiological weeks (EW) 47/2022 17/2023, included 389 publicly available sequences. Clinical data were obtained DATASUS, e-SUS, SIVEP GRIPE (data recording systems Brazilian Ministry Health). Of these, 143 classified as 586 other Omicron lineages. In March 2023 (EW 10), became dominant, accounting 83.3% cases. 97.7% XBB-infected patients successfully recovered infection, with low mortality rate (2.3%). Even after receiving three vaccine doses having previously infected, 59.5% experienced reinfection XBB. However, 54% individuals, interval between their infection last dose exceeded one year, potentially leading decline antibody levels. addition, we identified 90 mutations RS circulating XBB, spread throughout genome, notably Spike protein region associated immune resistance. This study provides insights into dynamics impact variant becoming predominant first time state. Continued surveillance SARS-CoV-2 crucial effective health management.

Language: Английский

Citations

2
Ligands docking to ORF8 by co-evolution. Could they reduce the inflammation levels induced by SARS-COV-2 infections? DOI Creative Commons
Melissa Belló-Pérez, Julio Coll

Published: Nov. 23, 2023

The unique ORF8 is an asymmetric homodimer accessory protein of SARS-COV-2 implicated in pathogenesis by activating excesive human inflammation causing numerous deaths. There no approved drug targeting ORF8, nor it known whether any anti-ORF8 drugs could reduce coronavirus-induced inflammation. Computationally combining ligand co-evolution parent molecules with affinity-ranking consensus docking, children candidates for cavities and ligands were generated. Targeting the interface cavity highest affinity scaffolds, hundreds grandchildren generated specificity-toxicity controlled additional co-evolutions to predict nanoMolar affinities, high specificities low toxicity risks. Although remaining hypothetical without experimental confirmation, these constitute a new methodological attempt search drug-like interfere SARS-COV-2-dependent excessive

Language: Английский

Citations

4
Comparative Pathogenesis of Severe Acute Respiratory Syndrome Coronaviruses DOI Creative Commons
Jingshu Zhang, Melanie Rissmann, Thijs Kuiken

et al.

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2023, Volume and Issue: 19(1), P. 423 - 451

Published: Oct. 13, 2023

Over the last two decades world has witnessed global spread of genetically related highly pathogenic coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. However, impact these outbreaks differed significantly with respect to hospitalizations fatalities seen worldwide. While many studies have been performed recently on SARS-CoV-2, a comparative pathogenesis analysis SARS-CoV may further provide critical insights into mechanisms disease that drive coronavirus-induced disease. In this review, we comprehensively describe clinical experimental observations transmission SARS-CoV-2 in comparison SARS-CoV, focusing human, animal, vitro studies. By deciphering similarities disparities terms mechanisms, offer divergent characteristics viruses. This information also be relevant assessing potential novel introductions coronaviruses.

Language: Английский

Citations

3
Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution DOI Creative Commons
Cassia Wagner, Kathryn E. Kistler, Garrett A. Perchetti

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 23, 2023

Abstract Knockout of the ORF8 protein has repeatedly spread through global viral population during SARS-CoV-2 evolution. Here we use both regional and pathogen sequencing to explore selection pressures underlying its loss. In Washington State, identified transmission clusters with knockout throughout evolution, not just on novel, high fitness backbones. Indeed, is truncated more frequently knockouts circulate for longer than any other gene. Using a phylogeny, find evidence positive explain this phenomenon: nonsense mutations resulting in shortened products occur are associated faster clade growth rates synonymous ORF8. Loss also reduced clinical severity, highlighting diverse impacts

Language: Английский

Citations

2
A neonatal mouse model characterizes transmissibility of SARS-CoV-2 variants and reveals a role for ORF8 DOI Open Access
Bruno A. Rodriguez-Rodriguez, Grace O. Ciabattoni, Ralf Duerr

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 4, 2022

Abstract Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets 1, 2 . Mice advantages low cost, wide availability, less regulatory and husbandry challenges, existence versatile reagent genetic toolbox. However, adult mice do not robustly transmit 3 Here we establish model based on neonatal that allows transmission clinical isolates. We characterize tropism, respiratory tract replication ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 BQ.1.1. identify inter-variant differences in timing magnitude infectious particle shedding from index mice, both which shape contact mice. Furthermore, two recombinant lacking either ORF6 ORF8 host antagonists. The removal shifts viral towards lower tract, resulting significantly delayed reduced our model. Our results demonstrate potential mouse determinants while revealing first time role an accessory protein this context.

Language: Английский

Citations

3
Electroacupuncture Alleviates Lung Injury in CpG1826-Challenged Mice via Modulating CD39-NLRP3 Pathway DOI Creative Commons
Jiasi Wu, Xin Xiong,

Xiumin Hu

et al.

Journal of Inflammation Research, Journal Year: 2023, Volume and Issue: Volume 16, P. 3245 - 3258

Published: Aug. 1, 2023

Cytokine storm secondary lung injury (CSSLI) is the leading death cause in COVID-19 virus infection, and CD39-dominated purinergic brake drives NLRP3 inflammasome activation pyroptosis, which plays a crucial role pathogenesis of CSSLI. Though electroacupuncture (EA) can alleviate caused by variety inducers, its effect on CSSLI underlying mechanism needs further investigation.We established widely recognized mice model with CpG1826 (CpG), TLR-9 agonist agent. Luminex liquid chip was employed to detect serum levels 12 cytokines/chemokines evaluate cytokine formation. H+E staining transmission electron microscope were applied examine pulmonary pathological alveolar macrophage structure, respectively. IL-1β, IL-18, IL-1α, HMGB-1 BAL fluid determined ELISA kits. mRNA protein CD39 assessed qRT-PCR Western blotting. An vitro also incubating PMA-differentiated THP-1 cells samples obtained from relevant group mice.Repeated CpG induced together elevation 11 including GM-CSF, IL-16, MCP-1, IL-2, IL-10, CCL3, TNF-α, IL-6, IL-17A, though not IFN-γ, reduced EA pretreatment different extent. alleviated recovered structure. Moreover, enhanced IL-1β IL-18 level fluid, promoted NLRP3, while suppressing expression lung, all reversed pretreatment. Of note, failed decrease when A438079, selective inhibitor P2X7, administered. However, both are dispensable for decreasing multi-cytokine secretion serum-incubated CpG-stimulated cells. Taken together, CpG-challenged regulating CD39-NLRP3 pathway P2X7-dependent way.EA demonstrated potential be treatment.

Language: Английский

Citations

1
Oligomer formation of SARS-CoV-2 ORF8 through 73YIDI76 motifs regulates immune response and non-infusion antiviral interactions DOI Creative Commons
Mohammad Assadizadeh, Maryam Azimzadeh Irani

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: Nov. 29, 2023

Introduction: Open Reading Frame 8 (ORF8) is a 121 amino acid length SARS-CoV-2 specific accessory protein that plays crucial roles in viral infectivity, and pathogenesis. Current treatments focus on spike or RNA-dependent RNA polymerase proteins. Hence, directing attention to ORF8 yields substantial benefits for innovative non-infusional therapeutics. Functional proposed form oligomers via crystallographic contact centered by 73YIDI76 motifs. Methods: the structure atomistic interactions of trimeric tetrameric oligomeric forms were modeled means thorough molecular modeling dynamics simulations. Results: Results show are stabilized interaction β4-β5 (47-83) loops. motifs involved obtaining oligomerization interfaces. It shown tetramers which resemble doughnut-like construction most forms. Where four loops interfaces between two dimers. Each monomer links others through covalent Cys20-Cys20 bridge. Epitope mapping, binding site predictions, solvent-accessible surface area analyses different B-cell, MHC-I, drug epitopes stay exposed Discussion: Approving infectivity expanded upon regions can be considered as therapeutic targets.

Language: Английский

Citations

1
SARS‐COV‐2 ORF8 as a Modulator of Cytokine Induction: Evidence and Search for Molecular Mechanisms DOI Open Access
Marília Inês Móvio,

Giovana Carneiro,

Isabella Lopes Martines

et al.

Published: Nov. 30, 2023

Severe cases of SARS-CoV-2 infection are characterized by an immune response that leads to the overproduction pro-inflammatory cytokines, resulting in damage lungs and other organs. This remarkable increase cytokines inflammatory molecules is primary caused viral proteins, particular ORF8, a unique accessory protein specific SARS-CoV-2. In addition its role cytokine induction, ORF8 attributed with various functions, including ability evade type I interferon responses. Despite evidence, mechanisms through which exerts these functions remains subject controversy. this mini review, we discuss multifaceted roles as modulator response, focusing on IL-6. We also data from our studies indicating augments production IL-6 induced Poly(I:C) human embryonic kidney (HEK)-293 monocyte-derived dendritic cells (mono-DCs).

Language: Английский

Citations

1