scholarly journals Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chase W Nelson ◽  
Zachary Ardern ◽  
Tony L Goldberg ◽  
Chen Meng ◽  
Chen-Hao Kuo ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Protein Sequence ◽  
Evolutionary Analysis ◽  
Overlapping Genes ◽  
Emerging Viruses ◽  
Consensus Sequences ◽  
Overlapping Gene ◽  
Strong Antibody Response ◽  
Accessory Genes

Understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics but are still widely overlooked. We identify and characterize ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples). ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. Our results liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.

scholarly journals Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

2020 ◽  
Author(s):  
Chase W. Nelson ◽  
Zachary Ardern ◽  
Tony L. Goldberg ◽  
Chen Meng ◽  
Chen-Hao Kuo ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Protein Sequence ◽  
Evolutionary Analysis ◽  
Overlapping Genes ◽  
Emerging Viruses ◽  
Consensus Sequences ◽  
Overlapping Gene ◽  
Strong Antibody Response ◽  
Accessory Genes

AbstractUnderstanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics, but are still widely overlooked. We identify and characterize ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples). ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. Our results liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.

scholarly journals Immunological imprinting of the antibody response in COVID-19 patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Teresa Aydillo ◽  
Alexander Rombauts ◽  
Daniel Stadlbauer ◽  
Sadaf Aslam ◽  
Gabriela Abelenda-Alonso ◽  
...  
Keyword(s):  
Immune Response ◽  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Humoral Immune Response ◽  
Nucleocapsid Protein ◽  
Spike Protein ◽  
Ongoing Research ◽  
Variable Regions ◽  
Humoral Immune ◽  
Human Coronaviruses

AbstractIn addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.

scholarly journals AlphaFold at CASP13

2019 ◽  
Vol 35 (22) ◽  
pp. 4862-4865 ◽  
Author(s):  
Mohammed AlQuraishi
Keyword(s):  
Protein Structure ◽  
Protein Sequence ◽  
Structure Prediction ◽  
Computational Prediction ◽  
Data Bank ◽  
Academic Community ◽  
Physical Contact ◽  
Evolutionary Analysis ◽  
History Of ◽  
First Time

Abstract Summary: Computational prediction of protein structure from sequence is broadly viewed as a foundational problem of biochemistry and one of the most difficult challenges in bioinformatics. Once every two years the Critical Assessment of protein Structure Prediction (CASP) experiments are held to assess the state of the art in the field in a blind fashion, by presenting predictor groups with protein sequences whose structures have been solved but have not yet been made publicly available. The first CASP was organized in 1994, and the latest, CASP13, took place last December, when for the first time the industrial laboratory DeepMind entered the competition. DeepMind's entry, AlphaFold, placed first in the Free Modeling (FM) category, which assesses methods on their ability to predict novel protein folds (the Zhang group placed first in the Template-Based Modeling (TBM) category, which assess methods on predicting proteins whose folds are related to ones already in the Protein Data Bank.) DeepMind's success generated significant public interest. Their approach builds on two ideas developed in the academic community during the preceding decade: (i) the use of co-evolutionary analysis to map residue co-variation in protein sequence to physical contact in protein structure, and (ii) the application of deep neural networks to robustly identify patterns in protein sequence and co-evolutionary couplings and convert them into contact maps. In this Letter, we contextualize the significance of DeepMind's entry within the broader history of CASP, relate AlphaFold's methodological advances to prior work, and speculate on the future of this important problem.

scholarly journals Overlapping protein-coding genes in human genome and their coincidental expression in tissues

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chao-Hsin Chen ◽  
Chao-Yu Pan ◽  
Wen-chang Lin
Keyword(s):  
Human Genome ◽  
Expression Profiles ◽  
Tissue Expression ◽  
Human Protein ◽  
Clear Understanding ◽  
Overlapping Genes ◽  
Genome Sequences ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Overlapping Gene

Abstract The completion of human genome sequences and the advancement of next-generation sequencing technologies have engendered a clear understanding of all human genes. Overlapping genes are usually observed in compact genomes, such as those of bacteria and viruses. Notably, overlapping protein-coding genes do exist in human genome sequences. Accordingly, we used the current Ensembl gene annotations to identify overlapping human protein-coding genes. We analysed 19,200 well-annotated protein-coding genes and determined that 4,951 protein-coding genes overlapped with their adjacent genes. Approximately a quarter of all human protein-coding genes were overlapping genes. We observed different clusters of overlapping protein-coding genes, ranging from two genes (paired overlapping genes) to 22 genes. We also divided the paired overlapping protein-coding gene groups into four subtypes. We found that the divergent overlapping gene subtype had a stronger expression association than did the subtypes of 5ʹ-tandem overlapping and 3ʹ-tandem overlapping genes. The majority of paired overlapping genes exhibited comparable coincidental tissue expression profiles; however, a few overlapping gene pairs displayed distinctive tissue expression association patterns. In summary, we have carefully examined the genomic features and distributions about human overlapping protein-coding genes and found coincidental expression in tissues for most overlapping protein-coding genes.

scholarly journals Differences in Antibody Kinetics and Functionality Between Severe and Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infections

2020 ◽  
Vol 222 (8) ◽  
pp. 1265-1269 ◽  
Author(s):  
Ger Rijkers ◽  
Jean-Luc Murk ◽  
Bas Wintermans ◽  
Bieke van Looy ◽  
Marcel van den Berge ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Geometric Mean ◽  
Severe Disease ◽  
Immunoglobulin A ◽  
Virus Neutralization ◽  
Neutralization Titer ◽  
Humoral Immune ◽  
Leave Of Absence ◽  
Antibody Kinetics

Abstract We determined and compared the humoral immune response in patients with severe (hospitalized) and mild (nonhospitalized) coronavirus disease 2019 (COVID-19). Patients with severe disease (n = 38) develop a robust antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including immunoglobulin G and immunoglobulin A antibodies. The geometric mean 50% virus neutralization titer is 1:240. SARS-CoV-2 infection was found in hospital personnel (n = 24), who developed mild symptoms necessitating leave of absence and self-isolation, but not hospitalization; 75% developed antibodies, but with low/absent virus neutralization (60% with titers <1:20). While severe COVID-19 patients develop a strong antibody response, mild SARS-CoV-2 infections induce a modest antibody response. Long-term monitoring will show whether these responses predict protection against future infections.

scholarly journals Genomic Characterization of Severe Acute Respiratory Syndrome-Related Coronavirus in European Bats and Classification of Coronaviruses Based on Partial RNA-Dependent RNA Polymerase Gene Sequences

2010 ◽  
Vol 84 (21) ◽  
pp. 11336-11349 ◽  
Author(s):  
Jan Felix Drexler ◽  
Florian Gloza-Rausch ◽  
Jörg Glende ◽  
Victor Max Corman ◽  
Doreen Muth ◽  
...  
Keyword(s):  
Amino Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Surface Expression ◽  
Emerging Viruses ◽  
Reading Frame ◽  
High Frequencies ◽  
Nyctalus Leisleri ◽  
Genomic Characterization

ABSTRACT Bats may host emerging viruses, including coronaviruses (CoV). We conducted an evaluation of CoV in rhinolophid and vespertilionid bat species common in Europe. Rhinolophids carried severe acute respiratory syndrome (SARS)-related CoV at high frequencies and concentrations (26% of animals are positive; up to 2.4 × 108 copies per gram of feces), as well as two Alphacoronavirus clades, one novel and one related to the HKU2 clade. All three clades present in Miniopterus bats in China (HKU7, HKU8, and 1A related) were also present in European Miniopterus bats. An additional novel Alphacoronavirus clade (bat CoV [BtCoV]/BNM98-30) was detected in Nyctalus leisleri. A CoV grouping criterion was developed by comparing amino acid identities across an 816-bp fragment of the RNA-dependent RNA polymerases (RdRp) of all accepted mammalian CoV species (RdRp-based grouping units [RGU]). Criteria for defining separate RGU in mammalian CoV were a >4.8% amino acid distance for alphacoronaviruses and a >6.3% distance for betacoronaviruses. All the above-mentioned novel clades represented independent RGU. Strict associations between CoV RGU and host bat genera were confirmed for six independent RGU represented simultaneously in China and Europe. A SARS-related virus (BtCoV/BM48-31/Bulgaria/2008) from a Rhinolophus blasii (Rhi bla) bat was fully sequenced. It is predicted that proteins 3b and 6 were highly divergent from those proteins in all known SARS-related CoV. Open reading frame 8 (ORF8) was surprisingly absent. Surface expression of spike and staining with sera of SARS survivors suggested low antigenic overlap with SARS CoV. However, the receptor binding domain of SARS CoV showed higher similarity with that of BtCoV/BM48-31/Bulgaria/2008 than with that of any Chinese bat-borne CoV. Critical spike domains 472 and 487 were identical and similar, respectively. This study underlines the importance of assessments of the zoonotic potential of widely distributed bat-borne CoV.

scholarly journals Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)-associated coronavirus infection

2004 ◽  
Vol 53 (5) ◽  
pp. 435-438 ◽  
Author(s):  
Weijun Chen ◽  
Zuyuan Xu ◽  
Jingsong Mu ◽  
Ling Yang ◽  
Haixue Gan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Time Course ◽  
Recovery Phase ◽  
Antibody Responses ◽  
Igg Antibodies ◽  
Rt Pcr ◽  
Blood Samples ◽  
Convalescent Phase ◽  
Coronavirus Infection

To understand the time-course of viraemia and antibody responses to severe acute respiratory syndrome-associated coronavirus (SARS-CoV), RT-PCR and ELISA were used to assay 376 blood samples from 135 SARS patients at various stages of the illness, including samples from patients who were in their early convalescent phase. The results showed that IgM antibodies decreased and became undetectable 11 weeks into the recovery phase. IgG antibodies, however, remained detectable for a period beyond 11 weeks and were found in 100 % of patients in the early convalescent phase. SARS-CoV viraemia mainly appeared 1 week after the onset of illness and then decreased over a period of 1 month, becoming undetectable in the blood samples of the convalescent patients. At the peak of viraemia, viral RNA was detectable in 75 % of blood samples from patients who were clinically diagnosed with SARS 1 or 2 weeks before the test.

scholarly journals A Fluorescence-based High Throughput-Screening assay for the SARS-CoV RNA synthesis complex

2020 ◽  
Author(s):  
Cecilia Eydoux ◽  
Veronique Fattorini ◽  
Ashleigh Shannon ◽  
Thi-Tuyet-Nhung Le ◽  
Bruno Didier ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rna Synthesis ◽  
Drug Repositioning ◽  
List Type ◽  
Emerging Viruses ◽  
Screening Assay ◽  
Highly Active ◽  
High Throughput Screening Assay

AbstractThe Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire antiviral strategies, as conserved viral enzymes (eg., viral proteases and RNA-dependent RNA polymerases) represent targets of choice. Since 2003, much effort has been expended in the characterization of the SARS-CoV replication/transcription machinery. Until recently, a pure and highly active preparation of SARS-CoV recombinant RNA synthesis machinery was not available, impeding target-based high throughput screening of drug candidates against this viral family. The current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic revealed a new pathogen whose RNA synthesis machinery is highly (>96% aa identity) homologous to SARS-CoV. This phylogenetic relatedness highlights the potential use of conserved replication enzymes to discover inhibitors against this significant pathogen, which in turn, contributes to scientific preparedness against emerging viruses. Here, we report the use of a purified and highly active SARS-CoV replication/transcription complex (RTC) to set-up a high-throughput screening of Coronavirus RNA synthesis inhibitors. The screening of a small (1,520 compounds) chemical library of FDA-approved drugs demonstrates the robustness of our assay and will allow to speed-up drug repositioning or novel drug discovery against the SARS-CoV-2.Principle of SARS-CoV RNA synthesis detection by a fluorescence-based high throughput screening assayHighlights- A new SARS-CoV non radioactive RNA polymerase assay is described- The robotized assay is suitable to identify RdRp inhibitors based on HTS

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