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    Genome-wide CRISPR activation screen identifies novel receptors for SARS-CoV-2 entry MESHD

    Authors: Shiyou Zhu; Ying Liu; Zhuo Zhou; Zhiying Zhang; Xia Xiao; Zhiheng Liu; Ang Chen; Xiaojing Dong; Feng Tian; Shihua Chen; Yiyuan Xu; Chunhui Wang; Qiheng Li; Xuran Niu; Qian Pan; Shuo Du; Junyu Xiao; Jianwei Wang; Wensheng Wei

    doi:10.1101/2021.04.08.438924 Date: 2021-04-09 Source: bioRxiv

    The ongoing pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has been endangering worldwide public health and economy. SARS-CoV-2 infects MESHD a variety of tissues where the known receptor ACE2 HGNC is low or almost absent, suggesting the existence of alternative pathways for virus entry. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection MESHD. In addition to known host proteins, i.e PROTEIN. ACE2 HGNC, TMPRSS2 HGNC, and NRP1 HGNC, we identified multiple host components, among which LDLRAD3 HGNC, TMEM30A HGNC, and CLEC4G HGNC were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike's N-terminal domain ( NTD HGNC). Their essential and physiological roles have all been confirmed in either neuron or liver cells. In particular, LDLRAD3 HGNC and CLEC4G HGNC mediate SARS-CoV-2 entry MESHD and infection in a fashion independent of ACE2 HGNC. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of the therapeutic countermeasures against COVID-19 MESHD.

    Host PDZ-containing proteins targeted by SARS-Cov-2

    Authors: Celia Caillet-Saguy; Fabien Durbesson; Veronica V. REZELJ; Gergo Gogl; Quang Dinh Tran; Jean-Claude Twizere; Marco Vignuzzi; Renaud Vincentelli; Nicolas Wolff; Rahaf Alharbi; Mazen Hassanain; Anwar M Hashem; Eugene B. Chang; Glenn Randall; Pablo Penaloza-MacMaster; Bozhi Tian; Maria Lucia Madariaga; Jun Huang; Dirk Jochmans; Birgit Weynand; Johan Neyts

    doi:10.1101/2021.02.01.429176 Date: 2021-02-01 Source: bioRxiv

    Small linear motif targeting protein interacting domains called PDZ have been identified at the C-terminus of the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) proteins E PROTEIN, 3a, and N. Using a high-throughput approach of affinity-profiling against the full human PDZome, we identified sixteen human PDZ binders of SARS-CoV-2 proteins E PROTEIN, 3A and N showing significant interactions with dissociation constants values ranging from 3 M to 82 M. Six of them ( TJP1 HGNC, PTPN13 HGNC, HTRA1 HGNC, PARD3 HGNC, MLLT4 HGNC, LNX2 HGNC) are also recognized by SARS-CoV while three ( NHERF1 HGNC, MAST2 HGNC, RADIL HGNC) are specific to SARS-CoV-2 E protein PROTEIN. Most of these SARS-CoV-2 protein partners are involved in cellular junctions/polarity and could be also linked to evasion mechanisms of the immune responses during viral infection MESHD. Seven of the PDZ-containing proteins among binders of the SARS-CoV-2 proteins E PROTEIN, 3a or N affect significantly viral replication under knock-down gene expression in infected cells. This PDZ profiling identifying human proteins potentially targeted by SARS-CoV-2 can help to understand the multifactorial severity of COVID19 MESHD and to conceive effective anti-coronaviral agents for therapeutic purposes.

    Structure-function investigation of a new VUI-202012/01 SARS-CoV-2 variant

    Authors: Jasdeep Singh; Nasreen Z Ehtesham; Syed Asad Rahman; Yakob G. Tsegay; Daniel S. Abebe; Mesay G. Edo; Endalkachew H. Maru; Wuletaw C. Zewde; Lydia K. Naylor; Dejen F. Semane; Menayit T. Deresse; Bereket B. Tezera; Lovisa Skoglund; Jamil Yousef; Elisa Pin; Wanda Christ; Mikaela Olausson; My Hedhammar; Hanna Tegel; Sara Mangsbo; Mia Phillipson; Anna Manberg; Sophia Hober; Peter Nilsson; Charlotte Thalin; Samuel Bates; Chevaun Morrison-Smith; Benjamin Nicholson; Edmond Wong; Leena El-Mufti; Michael Kann; Anna Bolling; Brooke Fortin; Hayden Ventresca; Wen Zhou; Santiago Pardo; Megan Kwock; Aditi Hazra; Leo Cheng; Rushdy Ahmad; James A. Toombs; Rebecca Larson; Haley Pleskow; Nell Meosky Luo; Christina Samaha; Unnati M. Pandya; Pushpamali De Silva; Sally Zhou; Zakary Ganhadeiro; Sara Yohannes; Rakiesha Gay; Jacqueline Slavik; Shibani S. Mukerji; Petr Jarolim; David R. Walt; Becky C. Carlyle; Lauren L. Ritterhouse; Sara Suliman

    doi:10.1101/2021.01.01.425028 Date: 2021-01-04 Source: bioRxiv

    The SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus MESHD) has accumulated multiple mutations during its global circulation. Recently, a new strain of SARS-CoV-2 (VUI 202012/01) had been identified leading to sudden spike in COVID-19 MESHD cases in South-East England. The strain has accumulated 23 mutations which have been linked to its immune evasion and higher transmission capabilities. Here, we have highlighted structural-function impact of crucial mutations occurring in spike (S), ORF8 PROTEIN and nucleocapsid (N) protein PROTEIN of SARS-CoV-2. Some of these mutations might confer higher fitness to SARS-CoV-2 MESHD. SummarySince initial outbreak of COVID-19 MESHD in Wuhan city of central China, its causative agent; SARS-CoV-2 virus has claimed more than 1.7 million lives out of 77 million populations and still counting. As a result of global research efforts involving public-private-partnerships, more than 0.2 million complete genome sequences have been made available through Global Initiative on Sharing All Influenza Data (GISAID). Similar to previously characterized coronaviruses (CoVs), the positive-sense single-stranded RNA SARS-CoV-2 genome codes for ORF1ab PROTEIN non-structural proteins (nsp(s)) followed by ten or more structural/nsps [1, 2]. The structural proteins include crucial spike (S), nucleocapsid (N PROTEIN), membrane (M), and envelope (E) proteins PROTEIN. The S protein PROTEIN mediates initial contacts with human hosts while the E and M proteins PROTEIN function in viral assembly and budding. In recent reports on evolution of SARS-CoV-2, three lineage defining non-synonymous mutations; namely D614G in S protein PROTEIN (Clade G), G251V in ORF3a PROTEIN (Clade V) and L84S in ORF 8 (Clade S) were observed [2-4]. The latest pioneering works by Plante et al and Hou et al have shown that compared to ancestral strain, the ubiquitous D614G variant (clade G) of SARS-CoV-2 exhibits efficient replication in upper respiratory tract epithelial cells and transmission, thereby conferring higher fitness MESHD [5, 6]. As per latest WHO reports on COVID-19 MESHD, a new strain referred as SARS-CoV-2 VUI 202012/01 (Variant Under Investigation, year 2020, month 12, variant 01) had been identified as a part of virological and epidemiological analysis, due to sudden rise MESHD in COVID-19 MESHD detected cases in South-East England [7]. Preliminary reports from UK suggested higher transmissibility (increase by 40-70%) of this strain, escalating Ro (basic reproduction number) of virus to 1.5-1.7 [7, 8]. This apparent fast spreading variant inculcates 23 mutations; 13 non-synonymous, 6 synonymous and 4 amino acid deletions [7]. In the current scenario, where immunization programs have already commenced in nations highly affected by COVID-19 MESHD, advent of this new strain variant has raised concerns worldwide on its possible role in disease severity and antibody responses. The mutations also could also have significant impact on diagnostic assays owing to S gene target failures.

    Binding of SARS-CoV-2 spike PROTEIN protein to ACE2 HGNC is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection MESHD studies.

    Authors: Kritika Khanna; Wilfred Raymond; Annabelle R Charbit; Jing Jin; Irina Gitlin; Monica Tang; Hannah S Sperber; Sergej Franz; Satish Pillai; Graham Simmons; John V Fahy; Suparerk Borwornpinyo; Arunee Thitithanyanont; Suradej Hongeng; Casey Barton Behravesh; Rebecca Fischer; Gabriel L Hamer; Marion Frankenberger; Lorenz Nowak; Katharina Heinig; Ina Koch; Mircea G Stoleriu; Anne Hilgendorff; Juergen Behr; Andreas Pichlmair; Benjamin Schubert; Fabian J Theis; Dirk H Busch; Herbert B Schiller; Kilian Schober; Evangelos J Giamarellos-Bourboulis; Timothy E Sweeney

    doi:10.1101/2020.12.08.415505 Date: 2020-12-08 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), and the SARS-CoV-2 spike PROTEIN protein is an envelope PROTEIN glycoprotein that binds angiotensin converting enzyme 2 as an entry receptor. The capacity of enveloped viruses to infect host MESHD cells depends on a precise thiol/disulfide balance in their surface glycoprotein complexes. To determine if cystines MESHD in the SARS-CoV-2 spike PROTEIN protein maintain a native binding interface that can be disrupted by drugs that cleave cystines, we tested if thiol-based drugs have efficacy in receptor binding and cell infection assays. We found that thiol-based drugs, cysteamine and WR-1065 (the active metabolite of amifostine) in particular, decrease binding of SARS-CoV-2 spike PROTEIN protein to its receptor, decrease the entry efficiency of SARS-CoV-2 spike PROTEIN pseudotyped virus, and inhibit SARS-CoV-2 live virus infection MESHD. Our findings uncover a vulnerability of SARS-CoV-2 to thiol-based drugs and provide rationale to test thiol-based drugs, especially cysteamine and amifostine, as novel treatments for COVID-19 MESHD. One Sentence SummaryThiol-based drugs decrease binding of SARS-CoV-2 spike PROTEIN protein to its receptor and inhibit SARS-CoV-2 cell entry.

    Identification of key genes and pathways in the hPSC-derived lungs infected by the SARS-CoV-2

    Authors: Hanming Gu; Gongsheng Yuan

    doi:10.21203/rs.3.rs-114578/v1 Date: 2020-11-23 Source: ResearchSquare

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), which has led to numerous infections MESHD and deaths MESHD in the world. Our research is to explore the differentially expressed genes (DEGs) and signaling pathways in hPSC-derived lungs by using a bioinformatics method to clarify their potential pathogenesis. The gene expression profile of GSE155241 dataset was originally created by using an Illumina NovaSeq 6000 (Homo sapiens) platform. Functional categories and significant pathways were identified by the KEGG and GO analysis. The results suggested that brain disorders MESHD and mitochondrial dysfunctions MESHD are the main signaling pathways affected by the SARS-CoV-2 infection MESHD. Furthermore, key genes e PROTEIN.g. CDC20 HGNC, NCBP1 HGNC and inhibitors e.g. MEK1 HGNC-2-inhibitor, tivozanib may paly critical roles in COVID-19 MESHD. Therefore, our study provides insights into the treatment of COVID-19 MESHD and related disorders.

    Fully automated detection and differentiation of pandemic and endemic coronaviruses (NL63, 229E, HKU1, OC43 and SARS-CoV-2) on the Hologic Panther Fusion

    Authors: Anne K Cordes; William M Rehrauer; Molly A Accola; Benno Woelk; Birgitta Hilfrich; Albert Heim

    doi:10.1101/2020.08.31.20185074 Date: 2020-09-02 Source: medRxiv

    The Hologic Panther Fusion (PF) platform provides fully automated CE marked diagnostics for respiratory viruses, including recently SARS-coronavirus MESHD 2 by a transcription mediated amplification (TMA) assay, but not for the endemic human coronaviruses (hCoV). Therefore, a laboratory developed multiplexed RT-PCR protocol (LDT) that detects and differentiates the four hCoV NL63, 229E, HKU1 and OC43 was adapted on the PF. The novel CE marked Aptima SARS-CoV-2 TMA MESHD and the LDT for hCoV were validated with 321 diagnostic specimens from the upper and lower respiratory tract in comparison to two SARS-CoV-2 RT-PCRs (PF E-gene PROTEIN LDT and genesig RT-PCR, 157 specimens) or the R-GENE hCoV / hParaFlu RT-PCR (164 specimens), respectively. For the endemic hCoV, results were 96.3% concordant with two specimens discordantly positive in the PF and four specimens discordantly positive in the R-GENE assay. All discordantly positive samples had Ct values between 33 and 39. The PF hCoV LDT identified 23 hCoV positive specimens as NL63, 15 as 229E, 15 as HKU1 and 25 as OC43. The Aptima SARS-CoV-2 TMA gave 99.4 % concordant results compared to the consensus results with a single specimen discordantly positive. Moreover, 36 samples from proficiency testing panels were detected and typed correctly by both novel methods. In conclusion, the SARS-CoV-2 TMA MESHD and the LDT for hCoV enhanced the diagnostic spectrum of the PF for all coronaviruses circulating globally for a multitude of diagnostic materials from the upper and lower respiratory tract.

    Rapid host response to an infection with Coronavirus. Study of transcriptional responses with Porcine Epidemic Diarrhea Virus

    Authors: Wei Hou; Fei Liu; Wim H.M. van der Poel; Marcel M Hulst

    doi:10.1101/2020.07.28.224576 Date: 2020-07-28 Source: bioRxiv

    The transcriptional response in Vero cells (ATCC(R) CCL-81) infected with the coronavirus Porcine Epidemic Diarrhea Virus MESHD (PEDV) was measured by RNAseq analysis 4 and 6 hours after infection. Differential expressed genes (DEGs) in PEDV infected cells were compared to DEGs responding in Vero cells infected with Mammalian Orthoreovirus (MRV). Functional analysis of MRV and PEDV DEGs showed that MRV increased the expression level of several cytokines and chemokines (e.g. IL6, CXCL10 HGNC, IL1A HGNC, CXCL8 [alias IL8 HGNC]) and antiviral genes (e PROTEIN.g. IFI44, IFIT1, MX1, OASL), whereas for PEDV no enhanced expression was observed for these "hallmark" antiviral and immune effector genes. Pathway and Gene Ontology "enrichment analysis" revealed that PEDV infection did not stimulate expression of genes able to activate an acquired immune response, whereas MRV did so within 6h. Instead, PEDV down-regulated the expression of a set of zinc finger proteins with putative antiviral activity and enhanced the expression of the transmembrane serine protease gene TMPRSS13 (alias MSPL) to support its own infection by virus-cell membrane fusion (Shi et al, 2017, Viruses, 9(5):114). PEDV also down-regulated expression of Ectodysplasin A, a cytokine of the TNF-family able to activate the canonical NFKB-pathway responsible for transcription of inflammatory genes like IL1B, TNF, CXCL8 and PTGS2. The only 2 cytokine genes found up-regulated by PEDV were Cardiotrophin-1, an IL6-type cytokine with pleiotropic functions on different tissues and types of cells, and Endothelin 2, a neuroactive peptide with vasoconstrictive properties. Furthermore, by comprehensive datamining in biological and chemical databases and consulting related literature we identified sets of PEDV-response genes with potential to influence i) the metabolism of biogenic amines (e.g. histamine), ii) the formation of cilia and "synaptic clefts" between cells, iii) epithelial mucus production, iv) platelets activation, and v) physiological processes in the body regulated by androgenic hormones (like blood pressure, salt/water balance and energy homeostasis). The information in this study describing a "very early" response of epithelial cells to an infection with a coronavirus may provide pharmacologists, immunological and medical specialists additional insights in the underlying mechanisms of coronavirus associated severe clinical symptoms including those induced by SARS-CoV-2. This may help them to fine-tune therapeutic treatments and apply specific approved drugs to treat COVID-19 MESHD patients.

    Witnessing Evolution of SARS-CoV-2 through Comparative Phylogenomics: The Proximate Origin is Guangdong, not Wuhan

    Authors: Özgül Doğan; Ertan Mahir Korkmaz; Mahir Budak; Battal Çıplak; Hasan Hüseyin Başıbüyük

    id:10.20944/preprints202005.0332.v2 Date: 2020-06-21 Source: Preprints.org

    A new form of coronavirus called severe acute respiratory disease coronavirus type 2 MESHD (SARS-CoV-2) is currently causing a pandemic. A six-month evolutionary history of SARS-CoV-2 is witnessed by characterising the total genome of 821 samples using comparative phylogenomic approaches. Our analyses produced striking inclusive results that may guide scientists/professionals for the past/future of pandemic. Phylogenetic and time estimation analyses suggest the proximate origin of pandemic strain as Guangdong and the origin time as first half of September 2019, not Wuhan and December 2019, respectively. The viral genome experienced a substitution rate similar to other RNA viruses, but it is particularly high in some of the peptides encoding sequences such as leader protein, E PROTEIN gene, orf8, orf10, nsp10, N gene PROTEIN, S gene and M gene and nsp4 HGNC, while low in nsp11, orf7a PROTEIN, 3C-like proteinase, nsp9, nsp8 and endoRNase. Most strikingly, the divergence rate of amino acid sequences is high proportional to nucleotide divergence. Additionally, specific non-synonymous mutations in nsp3 HGNC and nsp6 evolved under positive selection. The exponential growth rate (r), doubling time (Td) and R0 were estimated to be 47.43 per year, 5.39 days and 2.72, respectively. Comparison of synapomorphies distinguishing the SARS-CoV-2 and the candidate ancestor bat coronavirus indicates that mutation pattern in nsp3 HGNC and S gene enabled the new strain to invade human and become a pandemic strain. We arrive at the following main conclusions: (i) six months evolution of viral genome is nearly neutral, (ii) origin of pandemic is not Wuhan and predates formal reports, (iii) although viral population is ongoing an exponential growth, the doubling time is evolving towards shortening, and (iv) divergence rate of total genome is similar to other RNA viruses, but it is prominently high in some genes while low in some others and evolution in these genes should be closely monitored as their protein products intervening to pathogenicity, virulence and immune response.

    Temporal evolution and adaptation of SARS-COV 2 codon usage

    Authors: Maddalena Dilucca; Sergio Forcelloni; Andrea Giansanti; Alexandros Georgakilas; Athanasia Pavlopoulou

    doi:10.1101/2020.05.29.123976 Date: 2020-06-03 Source: bioRxiv

    The outbreak of severe acute respiratory syndrome-coronavirus-2 MESHD (SARS-CoV-2) has caused an unprecedented pandemic. Since the first sequenced whole-genome of SARS-CoV-2 on January 2020, the identification of its genetic variants has become crucial in tracking and evaluating their spread across the globe. In this study, we compared 15,259 SARS-CoV-2 genomes isolated from 60 countries since the outbreak of this novel coronavirus with the first sequenced genome in Wuhan to quantify the evolutionary divergence of SARS-CoV-2. Thus, we compared the codon usage patterns, every two weeks, of 13 of SARS-CoV-2 genes encoding for the membrane protein (M PROTEIN), envelope (E), spike surface glycoprotein (S PROTEIN), nucleoprotein (N PROTEIN), non-structural 3C-like proteinase ( 3CLpro PROTEIN), ssRNA-binding protein ( RBP HGNC), 2-O-ribose methyltransferase (OMT), endoRNase (RNase), helicase HGNC, RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN), Nsp7, Nsp8, and exonuclease ExoN. As a general rule, we find that SARS-CoV-2 genome tends to diverge over time by accumulating mutations on its genome and, specifically, on the coding sequences for proteins N PROTEIN and S. Interestingly, different patterns of codon usage were observed among these genes. Genes S, Nsp7, NSp8, tend to use a norrower set of synonymous codons that are better optimized to the human host. Conversely, genes E PROTEIN and M consistently use a broader set of synonymous codons, which does not vary with respect to the reference genome. We identified key SARS-CoV-2 genes (S, N, ExoN, RNase, RdRp PROTEIN, Nsp7 and Nsp8) suggested to be causally implicated in the virus adaptation to the human host.

    Computational Study of Ions and Water Permeation and Transportation Mechanisms of the SARS-CoV-2 Pentameric E Protein PROTEIN Channel

    Authors: Yipeng Cao; Rui Yang; Wei Wang; Imshik Lee; Ruiping Zhang; Wenwen Zhang; Jiana Sun; Bo Xu; Xiangfei Meng

    doi:10.1101/2020.05.17.099143 Date: 2020-05-17 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by a novel coronavirus (SARS-CoV-2) and represents the causative agent of a potentially fatal disease that is of public health emergency of international concern. Coronaviruses, including SARS-CoV-2, encode an envelope (E) protein PROTEIN, which is a small, hydrophobic membrane protein; the E PROTEIN protein of SARS-CoV-2 has high homology with that of severe acute respiratory syndrome coronavirus MESHD. ( SARS-CoV MESHD) In this study, we provide insights into the function of the SARS-CoV-2 E protein PROTEIN channel and the ion and water permeation mechanisms on the basis of combined in silico methods. Our results suggest that the pentameric E protein PROTEIN promotes the penetration of monovalent ions through the channel. Analysis of the potential mean force (PMF), pore radius and diffusion coefficient reveals that Leu10 and Phe19 are the hydrophobic gates of the channel. In addition, the pore demonstrated a clear wetting/dewetting transition with monovalent cation selectivity under transmembrane voltage, which indicates that it is a hydrophobic voltage-dependent channel. Overall, these results provide structural-basis insights and molecular-dynamic information that are needed to understand the regulatory mechanisms of ion permeability in the pentameric SARS-CoV-2 E protein PROTEIN channel.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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