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    Altered Sub-Genomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections

    Authors: Matthew D Parker; Benjamin B Lindsey; Dhruv R Shah; Sharon Hsu; Alexander James Keeley; David G Partridge; Shay Leary; Alison Cope; Amy State; Katie Johnson; Nasar Ali; Rasha Raghei; Joe Heffer; Nikki Smith; Peijun Zhang; Marta Gallis; Stavroula F Louka; Max Whiteley; Benjamin H Foulkes; Stella Christou; Paige Wolverson; Manoj Pohare; Sam E Hansford; Luke R Green; Cariad Evans; Mohammad Raza; Dennis Wang; Silvana Gaudieri; Simon Mallal; - The COVID-19 Genomics UK (COG-UK) consortium; Thushan I de Silva

    doi:10.1101/2021.03.02.433156 Date: 2021-03-03 Source: bioRxiv

    SARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome and is a crucial step in the SARS-CoV-2 life cycle. Applying our tool (periscope) to ARTIC Network Oxford Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA expression profiles are significantly increased in B.1.1.7 infections (n=879). This increase is seen over the previous dominant circulating lineage in the UK, B.1.177 (n=943), which is independent of genomic reads, E gene PROTEIN cycle threshold and day of illness when sampling occurred. A noncanonical subgenomic RNA which could represent ORF9b PROTEIN is significantly enriched in B.1.1.7 SARS-CoV-2 infections MESHD, potentially as a result of a triple nucleotide mutation leading to amino acid substitution D3L in nucleocapsid in this lineage which increases complementarity with the genomic leader sequence. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern.

    Antibody landscape against SARS-CoV-2 proteome revealed significant differences between non-structural/ accessory proteins and structural proteins

    Authors: Yang Li; Zhaowei Xu; Qing Lei; Danyun Lai; Hongyan Hou; Hewei Jiang; yunxiao Zheng; Xuening Wang; Jiaoxiang Wu; Mingliang Ma; Bo Zhang; Hong Chen; Caizheng Yu; Junbiao Xue; Nainang Zhang; Huan Qi; Shujuan Guo; Yandi Zhang; Xiaosong Lin; Zongjie Yao; Huiming Sheng; Ziyong Sun; Feng Wang; Xionglin Fan; Sheng-ce Tao

    doi:10.1101/2020.12.08.20246314 Date: 2020-12-11 Source: medRxiv

    The immunogenicity of SARS-CoV-2 proteome is largely unknown, especially for non-structural proteins and accessory proteins. Here we collected 2,360 COVID-19 MESHD sera and 601 control sera. We analyzed these sera on a protein microarray with 20 proteins of SARS-CoV-2, built an antibody response landscape for IgG and IgM. We found that non-structural proteins and accessory proteins NSP1 HGNC, NSP7 PROTEIN, NSP8 PROTEIN, RdRp PROTEIN, ORF3b PROTEIN and ORF9b PROTEIN elicit prevalent IgG responses. The IgG patterns and dynamic of non-structural/ accessory proteins are different from that of S and N protein PROTEIN. The IgG responses against these 6 proteins are associated with disease severity and clinical outcome and declined sharply about 20 days after symptom onset. In non-survivors, sharp decrease of IgG antibodies against S1 and N HGNC N protein PROTEIN before death was observed. The global antibody responses to non-structural/ accessory proteins revealed here may facilitate deeper understanding of SARS-CoV-2 immunology. HighlightsO_LIAn antibody response landscape against SARS-CoV-2 proteome was constructed C_LIO_LINon-structural/accessory proteins elicit prevalent antibody responses but likely through a different mechanism to that of structural proteins C_LIO_LIIgG antibodies against non-structural/accessory proteins are more associated with disease severity and clinical outcome C_LIO_LIFor non-survivors, the levels of IgG antibodies against S1 and N HGNC decline significantly before death C_LI

    Conflicting and Ambiguous Names of Overlapping ORFs in SARS-CoV- 2: A Homology-Based Resolution

    Authors: Irwin Jungreis; Chase W. Nelson; Zachary Ardern; Yaara Finkel; Nevan J. Krogan; Kei Sato; John Ziebuhr; Noam Stern-Ginossar; Angelo Pavesi; Andrew E. Firth; Alexander E. Gorbalenya; Manolis Kellis

    id:10.20944/preprints202012.0048.v1 Date: 2020-12-02 Source: Preprints.org

    At least six small alternate-frame open reading frames (ORFs) overlapping well-characterized SARS-CoV-2 genes have been hypothesized to encode accessory proteins. Researchers have used different names for the same ORF or the same name for different ORFs, resulting in erroneous homological and functional inferences. We propose standard names for these ORFs and their shorter isoforms, developed in consultation with the Coronaviridae Study Group of the ICTV. We recommend calling the 39 codon Spike-overlapping ORF ORF2b; the 41, 57, and 22 codon ORF3a PROTEIN-overlapping ORFs ORF3c, ORF3d, and ORF3b PROTEIN; the 33 codon ORF3d isoform ORF3d-2; and the 97 and 73 codon Nucleocapsid-overlapping ORFs ORF9b PROTEIN and ORF9c PROTEIN. Finally, we document conflicting usage of the name ORF3b PROTEIN in 32 studies, and consequent erroneous inferences, stressing the importance of reserving identical names for homologs. We recommend that authors referring to these ORFs provide lengths and coordinates to minimize ambiguity due to prior usage of alternative names.

    Proteo-genomic analysis of SARS-CoV-2: A clinical landscape of SNPs, COVID-19 MESHD proteome and host responses

    Authors: Sheetal Tushir; Sathisha Kamanna; Sujith S Nath; Aishwarya Bhat; Steffimol Rose; Advait R Aithal; Utpal Tatu

    doi:10.1101/2020.11.27.20237032 Date: 2020-11-30 Source: medRxiv

    A novel severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is the causative agent of COVID-19 MESHD and continues to be a global health challenge. To understand viral disease biology, we have carried out proteo-genomic analysis using next generation sequencing (NGS) and mass-spectrometry on nasopharyngeal swabs of COVID-19 MESHD patients to examine clinical genome and proteome. Our study confirms the hyper mutability of SARS-CoV-2 showing multiple SNPs. NGS analysis detected 27 mutations of which 14 are synonymous, 11 are missense and 2 are extragenic in nature. Phylogenetic analysis of SARS-CoV-2 isolates indicated their close relation to Bangladesh isolate and multiple origins of isolates within a country. Our proteomic analysis, for the first time identified 13 different SARS-CoV-2 proteins from the clinical swabs. Of the total 41 peptides captured by HRMS, 8 matched to nucleocapsid protein PROTEIN, 2 to ORF9b PROTEIN, 1 to spike glycoprotein PROTEIN and ORF3a PROTEIN, with remaining mapping to ORF1ab PROTEIN polyprotein. Additionally, host proteome analysis revealed several key host proteins to be uniquely expressed in COVID-19 MESHD patients. Pathway analysis of these proteins points towards modulation in immune response, especially involving neutrophil and IL-12 mediated signaling. Besides revealing the aspects of host-virus pathogenesis, our study opens new avenues to develop better diagnostic markers and therapeutics.

    Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19 MESHD-associated mechanisms

    Authors: Estelle MN Laurent; Yorgos Sofianatos; Anastassia Komarova; Jean-Pascal Gimeno; Payman Samavarchi Tehrani; Dae-Kyum Kim; Hala Abdouni; Marie Duhamel; Patricia Cassonnet; Jennifer J Knapp; Da Kuang; Aditya Chawla; Dayag Sheykhkarimli; Ashyad Rayhan; Roujia Li; Oxana Pogoutse; David E Hill; Mike E Calderwood; Pascal Falter-Braun; Patrick Aloy; Ulrich Stelzl; Marc Vidal; Anne-Claude Gingras; Georgios A Pavlopoulos; Sylvie Van Der Werf; Isabelle Fournier; Frederick P Roth; Michel Salzet; Caroline Demeret; Yves Jacob; Etienne Coyaud; Joseph Newman; Amin S Asfor; Alison Burman; Sylvia Crossley; John Hammond; Elma Tchilian; Bryan Charleston; Dalan Bailey; Tobias J Tuthill; Simon Graham; Tomas Malinauskas; Jiandong Huo; Julia Tree; Karen Buttigieg; Ray Owens; Miles Carroll; Rod Daniels; John McCauley; Kuan-Ying A Huang; Mark Howarth; Alain Townsend

    doi:10.1101/2020.08.28.272955 Date: 2020-08-29 Source: bioRxiv

    The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 MESHD disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a PROTEIN and ORF7b PROTEIN protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b PROTEIN with MAVS HGNC and ISG20 HGNC; N with PKR HGNC and TARB2; NSP2 PROTEIN NSP2 HGNC with RIG-I HGNC and STAT1 HGNC; NSP16 PROTEIN with PARP9 HGNC- DTX3L HGNC. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

    SARS-CoV-2 ORF9 HGNC ORF9 PROTEINb Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I HGNC/ MDA-5 HGNC- MAVS HGNC, TLR3 HGNC- TRIF HGNC, and cGAS- STING HGNC Signaling Pathways

    Authors: Lulu Han; Meng-Wei Zhuang; Yi Zheng; Jing Zhang; Mei-Ling Nan; Pei-Hui Wang; Chengjiang Gao; Katie G Beauregard; Ying Zhang; Megan Cleary; Samantha Xu; Xiao Yao; Purvish P Patel; Tatiana Plavina; David H Wilson; Lei Chang; Kim M Kaiser; Jacob Natterman; Susanne V Schmidt; Eicke Latz; Kevin Hrusovsky; Dawn Mattoon; Andrew J Ball; Saurabh Gombar; Robert Tibshirani; Benjamin A Pinsky; Scott D Boyd

    doi:10.1101/2020.08.16.252973 Date: 2020-08-17 Source: bioRxiv

    Severe acute respiratory syndrome MESHD corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease 2019 MESHD ( COVID-19 MESHD), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19 MESHD. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b ( ORF9b PROTEIN) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b PROTEIN impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b PROTEIN inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I HGNC/ MDA5 HGNC- MAVS HGNC signaling, including RIG-I HGNC, MDA-5 HGNC, MAVS HGNC, TBK1 HGNC, and IKK{varepsilon} rather than IRF3-5D, the active form of IRF3 HGNC. SARS-CoV-2 ORF9b PROTEIN also suppressed the induction of type I and III IFNs by TRIF HGNC and STING HGNC, the adaptor protein of endosome RNA-sensing pathway of TLR3 HGNC- TRIF HGNC signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS- STING HGNC signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b PROTEIN protein interacts with RIG-I HGNC, MDA-5 HGNC, MAVS HGNC, TRIF HGNC, STING HGNC, TBK1 HGNC, and prevents TBK1 HGNC phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 HGNC activation. Overexpression of SARS-CoV-2 ORF9b PROTEIN facilitates the replication of the vesicular stomatitis virus MESHD. Therefore, SARS-CoV-2 ORF9b PROTEIN negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19 MESHD.

    Sarbecovirus comparative genomics elucidates gene content of SARS-CoV-2 and functional impact of COVID-19 pandemic MESHD COVID-19 pandemic MESHD mutations

    Authors: Irwin Jungreis; Rachel Sealfon; Manolis Kellis

    doi:10.1101/2020.06.02.130955 Date: 2020-06-03 Source: bioRxiv

    Despite its overwhelming clinical importance for understanding and mitigating the COVID-19 pandemic MESHD COVID-19 pandemic MESHD, the protein-coding gene content of the SARS-CoV-2 genome remains unresolved, with the function and even protein-coding status of many hypothetical proteins unknown and often conflicting among different annotations, thus hindering efforts for systematic dissection of its biology and the impact of recent mutations. Comparative genomics is a powerful approach for distinguishing protein-coding versus non-coding functional elements, based on their characteristic patterns of change, which we previously used to annotate protein-coding genes in human, fly, and other species. Here, we use comparative genomics to provide a high-confidence set of SARS-CoV-2 protein-coding genes, to characterize their protein-level and nucleotide-level evolutionary constraint, and to interpret the functional implications for SARS-CoV-2 mutations acquired during the current pandemic. We select 44 complete Sarbecovirus genomes at evolutionary distances well-suited for protein-coding and non-coding element identification, create whole-genome alignments spanning all named and putative genes, and quantify their protein-coding evolutionary signatures using PhyloCSF and their overlapping constraint using FRESCo. We find strong protein-coding signatures for all named genes and for hypothetical ORFs 3a, 6, 7a, 7b, and 8, indicating protein-coding roles, and provide strong evidence of protein-coding status for a recently-proposed alternate-frame novel ORF within 3a. By contrast, ORF10 PROTEIN shows no protein-coding signatures but shows unusually-high nucleotide-level constraint, indicating it has important but non-coding functions, and ORF14 and SARS-CoV-1 ORF3b PROTEIN, which overlap other genes, lack evolutionary signatures expected for dual-coding regions, indicating they do not produce functional proteins. ORF9b PROTEIN has ambiguous protein-coding signatures, preventing us from resolving its protein-coding status. ORF8 PROTEIN shows extremely fast nucleotide-level evolution, lacks a known function, and was deactivated in SARS-CoV-1, but shows clear signatures indicating protein-coding function worthy of further investigation given its rapid evolution and potential role in replication. SARS-CoV-2 mutations are preferentially excluded from evolutionarily-constrained amino acid residues and synonymously-constrained nucleotides, indicating purifying constraint acting at both coding and non-coding levels. In contrast, we find a conserved region in the nucleocapsid that is enriched for recent mutations, which could indicate a selective signal, and find that several spike-protein PROTEIN mutations previously identified as candidates for increased transmission and several mutations in isolates found to generate higher viral load in-vitro disrupt otherwise-perfectly-conserved amino-acids, consistent with adaptations for human-to-human transmission.

    Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray

    Authors: He-wei Jiang; Yang Li; Hai-nan Zhang; Wei Wang; Dong Men; Xiao Yang; Huan Qi; Jie Zhou; Sheng-ce Tao

    doi:10.1101/2020.03.20.20039495 Date: 2020-03-27 Source: medRxiv

    COVID-19 MESHD is caused by SARS-CoV-2, and has become a global pandemic. There is no highly effective medicine or vaccine, most of the patients were recovered by their own immune response, especially the virus specific IgG and IgM responses. However, the IgG/ IgM responses is barely known. To enable the global understanding of SARS-CoV-2 specific IgG/ IgM responses, a SARS-CoV-2 proteome microarray with 18 out of the 28 predicted proteins was constructed. The microarray was applied to profile the IgG/ IgM responses with 29 convalescent sera. The results suggest that at the convalescent phase 100% of patients had IgG/ IgM responses to SARS-CoV-2, especially to protein N PROTEIN, S1 but not S2. S1 purified from mammalian cell demonstrated the highest performance to differentiate COVID-19 MESHD patients from controls. Besides protein N PROTEIN and S1, significant antibody responses to ORF9b PROTEIN and NSP5 PROTEIN NSP5 HGNC were also identified. In-depth analysis showed that the level of S1 IgG positively correlate to age and the level of LDH (lactate dehydrogenase), especially for women, while the level of S1 IgG negatively correlate to Ly% (Lymphocyte percentage). This study presents the first whole picture of the SARS-CoV-2 specific IgG/ IgM responses, and provides insights to develop precise immuno-diagnostics, effective treatment and vaccine.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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