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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.

    Membrane lectins enhance SARS-CoV-2 infection MESHD and influence the neutralizing activity of different classes of antibodies

    Authors: Florian A. Lempp; Leah Soriaga; Martin Montiel-Ruiz; Fabio Benigni; Julia Noack; Young-Jun Park; Siro Bianchi; Alexandra C. Walls; John E. Bowen; Jiayi Zhou; Hanna Kaiser; Maria Agostini; Marcel Meury; Exequiel Dellota Jr.; Stefano Jaconi; Elisabetta Cameroni; Herbert W. Virgin; Antonio Lanzavecchia; David Veesler; Lisa Purcell; Amalio Telenti; Davide Corti

    doi:10.1101/2021.04.03.438258 Date: 2021-04-04 Source: bioRxiv

    Investigating the mechanisms of SARS-CoV-2 cellular infection MESHD is key to better understand COVID-19 MESHD immunity and pathogenesis. Infection, which involves both cell attachment and membrane fusion, relies on the ACE2 HGNC receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN HGNC and the sialic acid-binding Ig-like lectin 1 HGNC ( SIGLEC1 HGNC) function as auxiliary receptors by enhancing ACE2 HGNC-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain ( NTD HGNC) or to the conserved proteoglycan site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 HGNC over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif ( RBM HGNC), while potently neutralizing infection of ACE2 HGNC over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN HGNC and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2 HGNC-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.

    Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19 MESHD+ Subjects

    Authors: Madelein Jennewein; Anna MacCamey; Nicholas Akins; Junli Feng; Leah Homad; Nicholas Hurlburt; Emily Seydoux; Yu-Hsin Wang; Andrew B Stuart; Venkata Vishwanadh Edara; Katharine Floyd; Abigail Vanderheiden; John R. Mascola; Nicole Doria-Rose; Lingshu Wang; Eun Yang; Helen Chu; Jonathan Torres; Gabriel Ozorowski; Andrew Ward; Rachael Whaley; Kristen Cohen; Marie Pancera; Juliana McElrath; Janet A Englund; Andres Finzi; Mehul Suthar; Andrew McGuire; Leonidas Stamatatos

    doi:10.1101/2021.03.23.436684 Date: 2021-03-24 Source: bioRxiv

    SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterized 198 antibodies isolated from four COVID19 MESHD+ subjects and identified 14 SARS-CoV-2 neutralizing antibodies. One targeted the NTD HGNC, one recognized an epitope in S2 and twelve bound the RBD. Three anti-RBD neutralizing antibodies cross-neutralized SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs MESHD to the ACE2 HGNC receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency rather than the antibody epitope specificity regulates the in vivo protective potential of anti-SARS-CoV-2 antibodies. The anti-S2 antibody also neutralized SARS-CoV-1 and all four cross-neutralizing antibodies neutralized the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.

    The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies that target both the NTD HGNC NTD MESHD and the RBD

    Authors: Fatima Amanat; Mahima Thapa; Tingting Lei; Shaza M. Sayed Ahmed; Daniel C. Adelsberg; Juan Manuel Carreno; Shirin Strohmeier; Aaron J. Schmitz; Sarah Zafar; Julian Q Zhou; Willemijn Rijnink; Hala Alshammary; Nicholas Borcherding; Ana Gonzalez Reiche; Komal Srivastava; Emilia Mia Sordillo; Harm van Bakel; Jackson S. Turner; Goran Bajic; Viviana M Simon; Ali H. Ellebedy; Florian Krammer

    doi:10.1101/2021.03.07.21253098 Date: 2021-03-09 Source: medRxiv

    In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast derived mAbs from subjects who received SARS-CoV-2 spike PROTEIN mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, that the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD HGNC and RBD of SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN and an original antigenic-sin like backboost to seasonal human coronaviruses OC43 and HKU1 spike proteins PROTEIN. Neutralizing activity of NTD HGNC mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD HGNC was abolished, suggesting that a proportion of vaccine induced RBD binding antibodies may provide substantial protection against viral variants carrying E484K.

    Homologous and heterologous serological response to the N-terminal domain of SARS-CoV-2

    Authors: Huibin Lv; Owen Tak-Yin Tsang; Ray T. Y. So; Yiquan Wang; Hejun Liu; Garrick K. Yip; Qi Wen Teo; Yihan Lin; Weiwen Liang; Jinlin Wang; Wilson W. Ng; Ian A. Wilson; Malik Peiris; Nicholas C. Wu; Chris K. P. Mok

    doi:10.1101/2021.02.17.431722 Date: 2021-02-18 Source: bioRxiv

    The increasing numbers of infected cases of coronavirus disease 2019 MESHD ( COVID-19 MESHD) caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) poses serious threats to public health and the global economy. Most SARS-CoV-2 neutralizing antibodies target the receptor binding domain (RBD) and some the N-terminal domain ( NTD HGNC) of the spike protein PROTEIN, which is the major antigen of SARS-CoV-2. While the antibody response to RBD has been extensively characterized, the antigenicity and immunogenicity of the NTD HGNC protein are less well studied. Using 227 plasma samples from COVID-19 MESHD patients, we showed that SARS-CoV-2 NTD HGNC-specific antibodies could be induced during infection. As compared to the serological response to SARS-CoV-2 RBD, the SARS-CoV-2 NTD HGNC response is less cross-reactive with SARS-CoV MESHD. Furthermore, neutralizing antibodies are rarely elicited in a mice model when NTD HGNC is used as an immunogen. We subsequently demonstrate that NTD HGNC has an altered antigenicity when expressed alone. Overall, our results suggest that while NTD HGNC offers an alternative strategy for serology testing, it may not be suitable as an immunogen for vaccine development.

    Exploring the Regulatory Function of the N-terminal Domain of SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD Protein Through Molecular Dynamics Simulation

    Authors: Yao Li; Tong Wang; Juanrong Zhang; Bin Shao; Haipeng Gong; Yusong Wang; Siyuan Liu; Tie-Yan Liu

    id:2101.01884v1 Date: 2021-01-06 Source: arXiv

    SARS-CoV-2 is what has caused the COVID-19 pandemic MESHD. Early viral infection MESHD is mediated by the SARS-CoV-2 homo-trimeric Spike (S) protein PROTEIN with its receptor binding domains (RBDs) in the receptor-accessible state. We performed molecular dynamics simulation on the S protein PROTEIN with a focus on the function of its N-terminal domains (NTDs). Our study reveals that the NTD HGNC acts as a "wedge" and plays a crucial regulatory role in the conformational changes of the S protein PROTEIN. The complete RBD structural transition is allowed only when the neighboring NTD HGNC that typically prohibits the RBD's movements as a wedge detaches and swings away. Based on this NTD HGNC "wedge" model, we propose that the NTD-RBD interface should be a potential drug target.

    Differential Dynamic Behavior of Prefusion Spike Proteins PROTEIN of SARS Coronaviruses 1 and 2

    Authors: Vivek Govind Kumar; Dylan S Ogden; Ugochi Isu; Adithya Polasa; James Losey; Mahmoud Moradi; Pallavi Roja Rani; Gyan Ranjan; Paras Sehgal; Pulala Chandrasekhar; S Afsar; J Vijaya Lakshmi; A Surekha; Sridhar Sivasubbu; Vinod Scaria; Paolo Bonfanti; Cor H van der Leest; Nidhi Rohatgi; Lothar Wiese; Charles Edouard Luyt; Farrah Kheradmand; Ivan O Rosas; Fang Cai; Panteleimon Tsiamalos; Konstantinos Syrigos; George Chrysos; Thomas Nitsotolis; Haralampos Milionis; Garyphallia Poulakou; Evangelos Giamarellos-Bourboulis

    doi:10.1101/2020.12.25.424008 Date: 2020-12-26 Source: bioRxiv

    Within the last two decades, severe acute respiratory syndrome MESHD (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks. For reasons yet to be fully understood the COVID-19 MESHD outbreak caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic MESHD caused by SARS-CoV-1, despite striking similarities between the two viruses. One of the most variable genes differentiating SARS-CoV-1 and SARS-CoV-2 is the S gene that encodes the spike glycoprotein PROTEIN. This protein mediates a crucial step in the infection, i.e., host cell recognition and viral entry, which starts with binding to the host cell angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) protein for both viruses. Recent structural and functional studies have shed light on the differential binding behavior of the SARS-CoV-1 and SARS-CoV-2 spike PROTEIN proteins. In particular, cryogenic electron microscopy (cryo-EM) studies show that ACE2 HGNC binding is preceded by a large-scale conformational change in the spike protein PROTEIN to expose the receptor binding domain (RBD) to its binding partner. Unfortunately, these studies do not provide detailed information on the dynamics of this activation process. Here, we have used an extensive set of unbiased and biased microsecond-timescale all-atom molecular dynamics ( MD MESHD) simulations of SARS-CoV-1 and SARS-CoV-2 spike PROTEIN protein ectodomains in explicit solvent to determine the differential behavior of spike protein PROTEIN activation in the two viruses. Our results based on nearly 50 microseconds of equilibrium and nonequilibrium MD simulations indicate that the active form of the SARS-CoV-2 spike PROTEIN protein is considerably more stable than the active SARS-CoV-1 spike protein PROTEIN. Unlike the active SARS-CoV-2 spike PROTEIN, the active SARS-CoV-1 spike spontaneously undergoes a large-scale conformational transition to a pseudo-inactive state, which occurs in part due to interactions between the N-terminal domain ( NTD HGNC) and RBD that are absent in the SARS-CoV-2 spike PROTEIN protein. Steered MD (SMD) simulations indicate that the energy barriers between active and inactive states are comparatively lower for the SARS-CoV-1 spike protein PROTEIN. Based on these results, we hypothesize that the greater propensity of the SARS-CoV-2 spike PROTEIN protein to remain in the active conformation contributes to the higher transmissibility of SARS-CoV-2 in comparison to SARS-CoV-1. These results strongly suggest that the differential binding behavior of the active SARS-CoV-1 and 2 spike proteins PROTEIN is not merely due to differences in their RBDs as other domains of the spike protein PROTEIN such as the NTD HGNC could play a crucial role in the effective binding process, which involves the pre-binding activation. Therefore, our hypothesis predicts that mutations in regions such as the NTD HGNC, which is not directly involved in binding, may lead to a change in the effective binding behavior of the coronavirus.

    The N-terminal domain of spike glycoprotein PROTEIN mediates SARS-CoV-2 infection MESHD by associating with L-SIGN HGNC and DC-SIGN

    Authors: Wai Tuck Soh; Yafei Liu; Emi E Nakayama; Chikako Ono; Shiho Torii; Hironori Nakagami; Yoshiharu Matsuura; Tatsuo Shioda; Hisashi Arase; Reid Simon; Ivan Grishagin; Laura Brovold; Ewy A Mathé; Matthew D Hall; Samuel G Michael; Alexander G Godfrey; Jordi Mestres; Lars J Jensen; Tudor I Oprea; Isabel Crooker; Sara Y Del Valle; Guido Espana; Geoffrey Fairchild; Richard C Gerkin; Timothy C Germann; Quanquan Gu; Xiangyang Guan; Lihong Guo; Gregory R Hart; Thomas J Hladish; Nathaniel Hupert; Daniel Janies; Cliff C Kerr; Daniel J Klein; Eili Klein; Gary Lin; Carrie Manore; Lauren Ancel Meyers; John Mittler; Kunpeng Mu; Rafael C NUNez; Rachel Oidtman; Remy Pasco; Ana Pastore y Piontti Pastore y Piontti; Rajib Paul; Carl AB Pearson; Dianela Perdomo; T Alex Perkins; Kelly Pierce; Alexander N Pillai; Rosalyn Cherie Rael; Katherine Rosenfeld; Chrysm Watson Ross; Julie A Spencer; Arlin B Stoltzfus; Kok Ben Toh; Shashaank Vattikuti; Alessandro Vespignani; Lingxiao Wang; Lisa White; Pan Xu; Yupeng Yang; Osman N Yogurtcu; Weitong Zhang; Yanting Zhao; Difan Zou; Matthew Ferrari; David Pannell; Michael Tildesley; Jack Seifarth; Elyse Johnson; Matthew Biggerstaff; Michael Johansson; Rachel B Slayton; John Levander; Jeff Stazer; Jessica Salermo; Michael C Runge

    doi:10.1101/2020.11.05.369264 Date: 2020-11-05 Source: bioRxiv

    The widespread occurrence of SARS-CoV-2 has had a profound effect on society and a vaccine is currently being developed. Angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) is the primary host cell receptor that interacts with the receptor-binding domain (RBD) of the SARS-CoV-2 spike PROTEIN protein. Although pneumonia MESHD is the main symptom in severe cases of SARS-CoV-2 infection MESHD, the expression levels of ACE2 HGNC in the lung is low, suggesting the presence of another receptor for the spike protein PROTEIN. In order to identify the additional receptors for the spike protein PROTEIN, we screened a receptor for the SARS-CoV-2 spike PROTEIN protein from the lung cDNA library. We cloned L-SIGN HGNC as a specific receptor for the N-terminal domain ( NTD HGNC) of the SARS-CoV-2 spike PROTEIN protein. The RBD of the spike protein PROTEIN did not bind to L-SIGN HGNC. In addition, not only L-SIGN HGNC but also DC-SIGN, a closely related C-type lectin receptor HGNC to L-SIGN HGNC, bound to the NTD HGNC of the SARS-CoV-2 spike PROTEIN protein. Importantly, cells expressing L-SIGN HGNC and DC-SIGN were both infected by SARS-CoV-2. Furthermore, L-SIGN HGNC and DC-SIGN induced membrane fusion by associating with the SARS-CoV-2 spike PROTEIN protein. Serum antibodies from infected patients and a patient-derived monoclonal antibody against NTD HGNC inhibited SARS-CoV-2 infection of L-SIGN MESHD L-SIGN HGNC or DC-SIGN expressing cells. Our results highlight the important role of NTD HGNC in SARS-CoV-2 dissemination through L-SIGN HGNC and DC-SIGN and the significance of having anti- NTD HGNC neutralizing antibodies in antibody-based therapeutics.

    Interaction network of SARS-CoV-2 with host receptome through spike protein PROTEIN

    Authors: Yunqing Gu; Jun Cao; Xinyu Zhang; Hai Gao; Yuyan Wang; Jia Wang; Jinlan Zhang; Guanghui Shen; Xiaoyi Jiang; Jie Yang; Xichen Zheng; Jianqing Xu; Cheng Cheng Zhang; Fei Lan; Di Qu; Yun Zhao; Guoliang Xu; Youhua Xie; Min Luo; Zhigang Lu; Khatendra Reang; Akadiri Olalekan; Sarah H Carl; Ali Doga Yucel; Ozgur Can; Serena Ozabrahamyan; Alpsu Olkan; Ece Erdemoglu; Fulya Aksit; Gokhan Haci Tanisali; Oleksandr M. Yefanov; Anton Barty; Alexandra Tolstikova; Gihan K. Ketawala; Sabine Botha; E. Han Dao; Brandon Hayes; Mengning Liang; Matthew H Seaberg; Mark S. Hunter; Alex Batyuk; Valerio Mariani; Zhen Su; Frederic Poitevin; Chun Hong Yoon; Christopher J. Kupitz; Raymond G. Sierra; Edward H Snell; Hasan DeMirci

    doi:10.1101/2020.09.09.287508 Date: 2020-09-09 Source: bioRxiv

    Host cellular receptors are key determinants of virus tropism MESHD and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2 HGNC, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 HGNC cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV MESHD. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein PROTEIN as the target. Twelve receptors were identified, including ACE2 HGNC. Most receptors bind at least two domains on S protein PROTEIN, the receptor-binding-domain (RBD) and the N-terminal-domain ( NTD HGNC), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 HGNC or KREMEN1 HGNC is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV MESHD and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 MESHD patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2 HGNC, KREMEN1 HGNC and ASGR1 HGNC respectively, and ACE2 HGNC/ ASGR1 HGNC/ KREMEN1 HGNC (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism MESHD and provided potential explanations for various COVID-19 MESHD symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 HGNC and KREMEN1 HGNC as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 MESHD investigation.

    Cryo-electron microscopy structure of the SADS-CoV spike glycoprotein PROTEIN provides insights into an evolution of unique coronavirus spike proteins PROTEIN

    Authors: Songying Ouyang

    doi:10.1101/2020.03.04.976258 Date: 2020-03-07 Source: bioRxiv

    The current outbreak of Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) by a novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has aroused great public health concern. Coronavirus has a history of causing epidemics in human and animals. In 2017 an outbreak in piglets by a novel coronavirus was emerged designated as swine acute diarrhea syndrome coronavirus (SADS-CoV MESHD) which is originated from the same genus of horseshoe bats (Rhinolophus) as Severe Acute Respiratory Syndrome CoV (SARS-CoV MESHD) having a broad species tropism. In addition to human cells, it can also infect cell lines from diverse species. Coronavirus host range is determined by its spike glycoprotein PROTEIN (S). Given the importance of S protein PROTEIN in viral entry to cells and host immune responses, here we report the cryo-EM structure of the SADS-CoV S MESHD in the prefusion conformation at a resolution of 3.55 [A]. Our study reveals that SADS-CoV S MESHD structure takes an intra-subunit quaternary packing mode where the NTD HGNC and CTD from the same subunit pack together by facing each other. The comparison of NTD HGNC and CTD with that of the other four genera suggests the evolutionary process of the SADS-CoV S MESHD. Moreover, SADS-CoV S MESHD has several characteristic structural features, such as more compact architecture of S trimer, and masking of epitopes by glycan shielding, which may facilitate viral immune evasion. These data provide new insights into the evolutionary relationships of SADS-CoV S MESHD and would extend our understanding of structural and functional diversity, which will facilitate to vaccine development.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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