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

SARS-CoV-2 and innate immunity: the good, the bad, and the “goldilocks” DOI Creative Commons
Benjamín L. Sievers, Mark T. K. Cheng,

Kata Csiba

et al.

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 21(2), P. 171 - 183

Published: Nov. 20, 2023

Abstract An ancient conflict between hosts and pathogens has driven the innate adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that be leveraged therapeutically. The humoral response to SARS-CoV-2 infection been focus intense research, role immune system received significantly less attention. Here, we review current knowledge various means employs evade defense systems. We consider immunity in vaccines phenomenon long COVID.

Language: Английский

Citations

51

Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion DOI Creative Commons
Harriet V Mears, George R. Young, Theo Sanderson

et al.

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(1), P. e3002982 - e3002982

Published: Jan. 21, 2025

Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5′ genomic leader upstream each body open reading frame. In SARS-CoV-2, TRS has consensus AAACGAAC; upon searching for emergence this motif global SARS-CoV-2 sequences, we find that it evolves frequently, especially 3′ end genome. We show well-supported examples Spike gene—within nsp16 coding region ORF1b—which expressed during human infection, canonical Envelope gene TRS, both which have evolved convergently multiple lineages. The most frequent neo-TRS within Nucleocapsid gene, present virtually all viruses from B.1.1 lineage, including variants concern Alpha, Gamma, Omicron descendants thereof. Here, demonstrate leads to expression novel mRNA encoding truncated C-terminal portion Nucleocapsid, an antagonist type I interferon production contributes viral fitness infection. observe distinct phenotypes when sequence mutated compared alone ablated. Our findings undergoing evolutionary changes at functional RNA level addition amino acid level.

Language: Английский

Citations

1

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.

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

Published: April 13, 2024

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

8

SARS-CoV-2 ORF8 as a Modulator of Cytokine Induction: Evidence and Search for Molecular Mechanisms DOI Creative Commons
Marília Inês Móvio,

Giovana Waner Carneiro de Almeida,

Isabella das Graças Lopes Martines

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(1), P. 161 - 161

Published: Jan. 22, 2024

Severe cases of SARS-CoV-2 infection are characterized by an immune response that leads to the overproduction pro-inflammatory cytokines, resulting in lung damage, cardiovascular symptoms, hematologic acute kidney injury and multiple organ failure can lead death. This remarkable increase cytokines other inflammatory molecules is primarily caused viral proteins, particular interest has been given ORF8, a unique accessory protein specific SARS-CoV-2. Despite plenty research, precise mechanisms which ORF8 induces proinflammatory not clear. Our investigations demonstrated augments production IL-6 induced Poly(I:C) human embryonic (HEK)-293 monocyte-derived dendritic cells (mono-DCs). We discuss our findings multifaceted roles as modulator cytokine response, focusing on type I interferon IL-6, key component In addition, we explore hypothesis may act through pattern recognition receptors dsRNA such TLRs.

Language: Английский

Citations

7

Comprehensive genomic analysis of the SARS-CoV-2 Omicron variant BA.2.76 in Jining City, China, 2022 DOI Creative Commons
Qiang Yin, Wei Liu,

Yajuan Jiang

et al.

BMC Genomics, Journal Year: 2024, Volume and Issue: 25(1)

Published: April 17, 2024

Abstract Objective This study aims to analyze the molecular characteristics of novel coronavirus (SARS-CoV-2) Omicron variant BA.2.76 in Jining City, China. Methods Whole-genome sequencing was performed on 87 cases SARS-CoV-2 infection. Evolutionary trees were constructed using bioinformatics software sequence homology, sites, N-glycosylation and phosphorylation sites. Results All whole-genome sequences classified under evolutionary branch BA.2.76. Their similarity reference strain Wuhan-Hu-1 ranged from 99.72 99.74%. In comparison Wuhan-Hu-1, exhibited 77–84 nucleotide differences 27 deletions. A total 69 amino acid 9 deletions, 1 stop codon mutation identified across 18 proteins. Among them, spike (S) protein highest number ORF8 showed a Q27 mutation. Multiple proteins displayed variations glycosylation Conclusion continues evolve, giving rise new strains with enhanced transmission, stronger immune evasion capabilities, reduced pathogenicity. The application high-throughput technologies epidemic prevention control COVID-19 provides crucial insights into virus at genomic level, thereby holding significant implications for pandemic.

Language: Английский

Citations

5

SARS-CoV-2 ORF8 Mediates Signals in Macrophages and Monocytes through MyD88 Independently of the IL-17 Receptor DOI Open Access
Nicole O. Ponde, Karsen E. Shoger, Mst Shamima Khatun

et al.

The Journal of Immunology, Journal Year: 2023, Volume and Issue: 211(2), P. 252 - 260

Published: June 2, 2023

Abstract SARS-CoV-2 has caused an estimated 7 million deaths worldwide to date. A secreted accessory protein, known as open reading frame 8 (ORF8), elicits inflammatory pulmonary cytokine responses and is associated with disease severity in COVID-19 patients. Recent reports proposed that ORF8 mediates downstream signals macrophages monocytes through the IL-17 receptor complex (IL-17RA, IL-17RC). However, generally are found be restricted nonhematopoietic compartment, thought due rate-limiting expression of IL-17RC. Accordingly, we revisited capacity induce gene mouse human monocytes. In SARS-CoV-2–infected lungs, IL17RC mRNA was undetectable monocyte/macrophage populations. cultured macrophages, but not led elevated target cytokines. ORF8-induced signaling fully preserved presence anti–IL-17RA/RC neutralizing Abs Il17ra−/− cells. also operative Il1r1−/− bone marrow–derived macrophages. TLR/IL-1R family adaptor MyD88, which dispensable for IL-17R signaling, required activity yet MyD88 signaling. Thus, conclude transduces via independently IL-17R.

Language: Английский

Citations

12

Genomic Surveillance and Mutation Analysis of SARS-CoV-2 Variants among Patients in Saudi Arabia DOI Creative Commons
Feda A. Alsuwairi, Asma N. Alsaleh, Dalia Obeid

et al.

Microorganisms, Journal Year: 2024, Volume and Issue: 12(3), P. 467 - 467

Published: Feb. 26, 2024

The genome of severe acute respiratory coronavirus-2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has undergone a rapid evolution, resulting in emergence multiple SARS-CoV-2 variants with amino acid changes. This study aimed to sequence whole and detect present specimens from Saudi Arabia. Furthermore, we sought analyze characterize changes various proteins identified variants. A total 1161 samples patients diagnosed COVID-19 Arabia, between 1 April 2021 31 July 2023, were analyzed. Whole sequencing was employed variant identification mutation analysis. statistical analysis performed using Statistical Analytical Software SAS, version 9.4, GraphPad, 9.0. twenty-three subvariants within population, Omicron BA.1 (21K) (37.0%) Delta (21J) (12%) being most frequently detected. Notably, exhibited higher mean rate. Amino mutations observed twelve proteins. Among these, spike (S), ORF1a, nucleocapsid (N), ORF1b showed frequency compared other viral S protein highest incidence (47.6%). Conversely, ORF3a, ORF8, ORF7a, ORF6, ORF7b appeared more conserved, demonstrating lowest percentage mutations. investigation structural regions revealed N-terminal S1 subunit harbor mutations, while domain envelope (E) displayed frequency. provides insights into genetic diversity SARS-CoV-2, underscoring need further research comprehend its evolution occurrence These findings are pertinent development testing approaches, therapeutics, vaccine strategies.

Language: Английский

Citations

4

Dissecting the COVID‐19 Immune Response: Unraveling the Pathways of Innate Sensing and Response to SARSCoV‐2 Structural Proteins DOI Open Access
María Guadalupe Vizoso-Pinto, Leonardo de Paula Pereira,

Ana Luiza Pessoa de Mendonça Angelo

et al.

Journal of Molecular Recognition, Journal Year: 2025, Volume and Issue: 38(2)

Published: Feb. 5, 2025

ABSTRACT Severe acute respiratory syndrome coronavirus (SARS‐CoV), the virus responsible for COVID‐19, interacts with host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining disease's severity host's ability to clear virus. Given virus's substantial socioeconomic impact, high morbidity mortality rates, public health importance, understanding these is essential. This article examines diverse responses triggered by SARS‐CoV‐2's structural proteins, including spike (S), membrane (M), envelope (E), nucleocapsid (N) along nonstructural proteins (NSPs) open reading frames. play pivotal roles modulation, facilitating viral replication, evading detection, contributing severe inflammatory such as cytokine storms distress (ARDS). The employs strategies like suppressing type I interferon production disrupting key antiviral pathways, MAVS, OAS‐RNase‐L, PKR. study also explores pathways govern activation suppression of throughout COVID‐19. By analyzing sensing receptors initiated upon recognizing SARS‐CoV‐2 this review elucidates associated response Understanding offers valuable insights therapeutic interventions informs strategies, a deeper COVID‐19 immunopathogenesis.

Language: Английский

Citations

0

Impact of SARS-CoV-2 Wuhan and Omicron Variant Proteins on Type I Interferon Response DOI Creative Commons
Marija Janevska,

Evelien Naessens,

Bruno Verhasselt

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 569 - 569

Published: April 15, 2025

SARS-CoV-2 has demonstrated a remarkable capacity for immune evasion. While initial studies focused on the Wuhan variant and adaptive immunity, later emerging strains such as Omicron exhibit mutations that may alter their immune-modulatory properties. We performed comprehensive review of evasion mechanisms associated with viral proteins to focus evolutionary dynamics modulation. systematically analyzed compared impact all currently known type I interferon (IFN) responses using dual-luciferase reporter assay carrying an interferon-inducible promoter. Results revealed Nsp1, Nsp5, Nsp14, ORF6 are potent IFN inhibitors conserved across strains. Notably, we identified strain-specific differences, Nsp6 Spike exhibiting enhanced suppression in Omicron, whereas Envelope protein largely retained this function. To extend these findings, investigated selected primary human endothelial cells also observed differences response higher expressing strain variant, suggesting Omicron’s adaptational contribute damped course pandemic’s trajectory.

Language: Английский

Citations

0

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