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      Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

      research-article
      1 , 2 , 3 , 4 , 1 , 4 , 5 , 6 , 7 , 1 , 2 , 3 , 4 , 8 , 9 , 1 , 2 , 3 , 4 , 10 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 11 , 12 , 12 , 12 , 12 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 13 , 1 , 2 , 14 , 1 , 2 , 3 , 15 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 1 , 2 , 3 , 15 , 16 , 16 , 16 , 16 , 16 , 16 , 8 , 8 , 10 , 12 , 12 , 12 , 12 , 17 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 18 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 12 , 1 , 2 , 19 , QCRG Structural Biology Consortium 12 , 20 , 20 , 20 , 21 , 22 , 21 , 22 , 21 , 22 , 21 , 22 , 21 , 22 , 23 , 23 , 4 , 4 , 4 , 5 , 7 , 4 , 7 , 5 , 6 , 7 , 5 , 7 , 24 , 25 , 24 , 25 , 16 , 25 , 26 , 27 , 28 , 29 , 30 , 30 , 30 , 30 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 31 , 4 , 4 , Zoonomia Consortium , 32 , 33 , 34 , 34 , 34 , 34 , 4 , 35 , 36 , 1 , 2 , 14 , 19 , 1 , 2 , 12 , 37 , 1 , 2 , 12 , 15 , 37 , 1 , 2 , 12 , 19 , 1 , 2 , 12 , 37 , 1 , 2 , 3 , 12 , 38 , 1 , 2 , 12 , 19 , 39 , 1 , 2 , 12 , 14 , 1 , 12 , 37 , 1 , 2 , 12 , 37 , 31 , 31 , 30 , 29 , 40 , 26 , 27 , 28 , 27 , 1 , 2 , 14 , 4 , 41 , 23 , 1 , 2 , 3 , 15 , 21 , 22 , 42 , 43 , § , 11 , § , 9 , 44 , § , 1 , 2 , 12 , 36 , 37 , 41 , § , 1 , 2 , 12 , 14 , § , 10 , § , 8 , § , 20 , § , 16 , § , 1 , 2 , 3 , 4 , 21 , §
      (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab), (Collab)
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          How lethal coronaviruses engage hosts

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely related to the deadly coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Considerable efforts are focused on developing treatments, and therapies that work across coronaviruses would be particularly valuable. Shedding light on the host factors hijacked by the viruses, Gordon et al. mapped the interactions between viral and human proteins for SARS-CoV-2, SARS-CoV-1, and MERS-CoV; analyzed the localization of viral proteins in human cells; and used genetic screening to identify host factors that either enhance or inhibit viral infection. For a subset of the interactions essential for the virus life cycle, the authors determined the cryo–electron microscopy structures and mined patient data to understand how targeting host factors may be relevant to clinical outcomes.

          Science, this issue p. eabe9403

          Abstract

          Comparison of host interactions of three lethal coronaviruses identifies commonly hijacked pathways and potential drug targets.

          Abstract

          INTRODUCTION

          The emergence of three lethal coronaviruses in <20 years and the urgency of the COVID-19 pandemic have prompted efforts to develop new therapeutic strategies, including by repurposing existing agents. After performing a comparative analysis of the three pathogenic human coronaviruses severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV), we identified shared biology and host-directed drug targets to prioritize therapeutics with potential for rapid deployment against current and future coronavirus outbreaks.

          RATIONALE

          Expanding on our recent SARS-CoV-2 interactome, we mapped the virus-host protein-protein interactions for SARS-CoV-1 and MERS-CoV and assessed the cellular localization of each viral protein across the three strains. We conducted two genetic screens of SARS-CoV-2 interactors to prioritize functionally-relevant host factors and structurally characterized one virus-host interaction. We then tested the clinical relevance of three more host factors by assessing risk in genetic cohorts or observing effectiveness of host factor–targeting drugs in real-world evidence.

          RESULTS

          Quantitative comparison of the 389 interactors of SARS-CoV-2, 366 of SARS-CoV-1, and 296 of MERS-CoV highlighted interactions with host processes that are conserved across all three viruses, including where nonorthologous proteins from different virus strains seem to fill similar roles. We also localized each individually-expressed viral protein by microscopy and then raised and validated antisera against 14 SARS-CoV-2 proteins to determine their localization during infection.

          On the basis of two independent genetic perturbation screens, we identified 73 host factors that, when depleted, caused significant changes in SARS-CoV-2 replication. From this list of potential drug targets, we validated the biological and clinical relevance of Tom70, IL17RA, PGES-2, and SigmaR1.

          A 3-Å cryo–electron microscopy structure of Tom70, a mitochondrial import receptor, in complex with SARS-CoV-2 ORF9b, provides insight into how ORF9b may modulate the host immune response. Using curated genome-wide association study data, we found that individuals with genotypes corresponding to higher soluble IL17RA levels in plasma are at decreased risk of COVID-19 hospitalization.

          To demonstrate the value of our data for drug repurposing, we identified SARS-CoV-2 patients who were prescribed drugs against prioritized targets and asked how they fared compared with carefully matched patients treated with clinically similar drugs that do not inhibit SARS-CoV-2. Both indomethacin, an inhibitor of host factor PGES-2, and typical antipsychotics, selected for their interaction with sigma receptors, showed effectiveness against COVID-19 compared with celecoxib and atypical antipsychotics, respectively.

          CONCLUSION

          By employing an integrative and collaborative approach, we identified conserved mechanisms across three pathogenic coronavirus strains and further investigated potential drug targets. This versatile approach is broadly applicable to other infectious agents and disease areas.

          Overview of the approaches taken for systemic and functional comparison of pathogenic human coronaviruses.

          (Left) Viral-human protein-protein interaction network mapping, viral protein localization studies, and functional genetic screens provide key insights into the shared and individual characteristics of each virus. (Right) Structural studies and hypothesis testing in clinical datasets demonstrate the utility of this approach for prioritizing therapeutic strategies. Nsp, nonstructural protein; ORF, open reading frame; ER, endoplasmic reticulum.

          Abstract

          The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo–electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

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          Most cited references99

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

            Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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              clusterProfiler: an R package for comparing biological themes among gene clusters.

              Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.
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                Author and article information

                Journal
                Science
                Science
                SCIENCE
                science
                Science (New York, N.y.)
                American Association for the Advancement of Science
                0036-8075
                1095-9203
                04 December 2020
                15 October 2020
                : 370
                : 6521
                : eabe9403
                Affiliations
                [1 ]Quantitative Biosciences Institute (QBI) COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA.
                [2 ]QBI, University of California, San Francisco, CA 94158, USA.
                [3 ]Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
                [4 ]J. David Gladstone Institutes, San Francisco, CA 94158, USA.
                [5 ]Medical Scientist Training Program, University of California, San Francisco, CA 94143, USA.
                [6 ]Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.
                [7 ]Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
                [8 ]Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, 75724, Paris, cedex 15, France.
                [9 ]Institute for Clinical and Experimental Pharmacology and Toxicology I, University of Freiburg, 79104 Freiburg, Germany.
                [10 ]Center for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
                [11 ]Aetion, Inc., New York, NY 10001, USA.
                [12 ]QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, CA 94158, USA.
                [13 ]Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
                [14 ]Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
                [15 ]Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
                [16 ]European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
                [17 ]Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
                [18 ]Beam Therapeutics, Cambridge, MA 02139, USA.
                [19 ]Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA.
                [20 ]Department of Biomedical Science, Centre for Membrane Interactions and Dynamics, University of Sheffield, Firth Court, Sheffield S10 2TN, UK.
                [21 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [22 ]Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [23 ]MRC–University of Glasgow Centre for Virus Research, Glasgow G61 1QH, Scotland, UK.
                [24 ]Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
                [25 ]Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
                [26 ]Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ‘ALDO MORO’, Via Orabona, 4 70125, Bari, Italy.
                [27 ]Institute of Virology, Medical Center–University of Freiburg, 79104 Freiburg, Germany.
                [28 ]Département de Virologie, CNRS UMR 3569, Institut Pasteur, Paris 75015, France.
                [29 ]Department of Medicine, University of California, San Diego, CA 92093, USA.
                [30 ]Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
                [31 ]MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
                [32 ]HealthVerity, Philadelphia, PA 19103, USA.
                [33 ]Department of Neurology, University of California, San Francisco, CA 94143, USA.
                [34 ]Synthego Corporation, Redwood City, CA 94063, USA.
                [35 ]Department of Epidemiology & Biostatistics, University of California, San Francisco, CA 94158, USA.
                [36 ]Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA.
                [37 ]Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
                [38 ]Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.
                [39 ]The University of California, Berkeley–University of California, San Francisco Graduate Program in Bioengineering, University of California, San Francisco, CA 94158, USA.
                [40 ]Department to Bioengineering, University of California, San Diego, CA 92093, USA.
                [41 ]Department of Medicine, University of California, San Francisco, CA 94143, USA.
                [42 ]Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [43 ]The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
                [44 ]Centre for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, 79104 Freiburg, Germany.
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                The QCRG Structural Biology Consortium collaborators and their affiliations are listed in the supplementary materials.

                [‡]

                The Zoonomia Consortium collaborators and their affiliations are listed in the supplementary materials.

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                https://orcid.org/0000-0002-6098-7367
                https://orcid.org/0000-0002-5697-1274
                https://orcid.org/0000-0001-7007-4070
                https://orcid.org/0000-0001-8590-7741
                https://orcid.org/0000-0002-6551-1827
                https://orcid.org/0000-0003-4369-7381
                https://orcid.org/0000-0002-5736-4388
                https://orcid.org/0000-0002-2238-8590
                https://orcid.org/0000-0003-4195-425X
                https://orcid.org/0000-0002-4400-771X
                https://orcid.org/0000-0003-0144-7712
                https://orcid.org/0000-0002-2724-7703
                https://orcid.org/0000-0003-4902-337X
                Article
                abe9403
                10.1126/science.abe9403
                7808408
                33060197
                c8fe2382-d265-492e-b979-c9bce40a9df0
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 September 2020
                : 12 October 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Award ID: 1650113
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P01AI063302, P50AI150476, R01AI120694, R01AI122747, R01AI143292, U19AI135972, U19AI135990
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P01AI120943, R01AI143292
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: U19AI135990
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R35GM122481
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: U19AI135972
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01AI128214
                Funded by: doi http://dx.doi.org/10.13039/100000051, National Human Genome Research Institute;
                Award ID: R01 HG009979
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: K99GM138753
                Funded by: doi http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award ID: None
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: T32GM007618
                Funded by: doi http://dx.doi.org/10.13039/100000052, NIH Office of the Director;
                Award ID: AI150476
                Funded by: doi http://dx.doi.org/10.13039/100000005, U.S. Department of Defense;
                Award ID: W81XWH-20-1-0270
                Funded by: doi http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: F32GM137463
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: F32CA239333
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: F32 CA239336
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: T32GM007618
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: F30AI143401
                Funded by: doi http://dx.doi.org/10.13039/100014989, Chan Zuckerberg Initiative;
                Funded by: doi http://dx.doi.org/10.13039/100013349, LABoratoires d’EXcellence ARCANE;
                Funded by: doi http://dx.doi.org/10.13039/100012399, Biomedical Advanced Research and Development Authority;
                Award ID: ASPR-20-01495
                Funded by: doi http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: INV-006099
                Funded by: doi http://dx.doi.org/10.13039/100000185, Defense Advanced Research Projects Agency;
                Award ID: HR0011-20-2-0040
                Funded by: doi http://dx.doi.org/10.13039/100006502, Defense Sciences Office, DARPA;
                Award ID: HR0011-19-2-0020
                Funded by: doi http://dx.doi.org/10.13039/100016127, Fast Grants;
                Award ID: COVID19 grant
                Funded by: doi http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MC PC 19026
                Funded by: doi http://dx.doi.org/10.13039/100006502, Defense Sciences Office, DARPA;
                Award ID: HR0011-19-2-0020
                Funded by: doi http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MC_UU_12016/2
                Funded by: doi http://dx.doi.org/10.13039/100006502, Defense Sciences Office, DARPA;
                Award ID: HR0011-19-2-0020
                Funded by: doi http://dx.doi.org/10.13039/100006502, Defense Sciences Office, DARPA;
                Award ID: HR0011-19-2-0020
                Funded by: doi http://dx.doi.org/10.13039/100007013, Hoffman-La Roche;
                Funded by: doi http://dx.doi.org/10.13039/100016127, Fast Grants;
                Award ID: COVID19 grant
                Funded by: doi http://dx.doi.org/10.13039/100008072, Gladstone Institutes;
                Funded by: doi http://dx.doi.org/10.13039/100009724, Roddenberry Foundation;
                Funded by: doi http://dx.doi.org/10.13039/100006502, Defense Sciences Office, DARPA;
                Award ID: HR0011-19-2-0020
                Funded by: doi http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;
                Award ID: R01 NS089713
                Funded by: doi http://dx.doi.org/10.13039/100014895, Open Philanthropy Project;
                Funded by: doi http://dx.doi.org/10.13039/100007457, JPB Foundation;
                Funded by: doi http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: HHSN272201400008C
                Funded by: doi http://dx.doi.org/10.13039/100006502, Defense Sciences Office, DARPA;
                Award ID: HR0011-19-2-0020
                Funded by: doi http://dx.doi.org/10.13039/100001021, Damon Runyon Cancer Research Foundation;
                Award ID: DRG-2402-20
                Funded by: doi http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Award ID: 1019894
                Funded by: Laboratory for Genomics Research;
                Award ID: Excellence in Research Award COVID19
                Funded by: URGENCE COVID-19 Institut Pasteur fundraising campaign;
                Funded by: FastGrants;
                Award ID: COVID19 grant
                Funded by: The Augusta University-Georgia State University Seed Grant;
                Funded by: doi http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MC_UU_12016/2
                Funded by: Vir Biotechnology;
                Funded by: The Ron Conway Family;
                Funded by: The Laboratory for Genomics Research;
                Award ID: Excellence in Research Award, 133122P
                Funded by: DFG under Germany’s Excellence Strategy;
                Award ID: EXC-2189, project ID 390939984
                Funded by: Chan Zuckerberg Biohub;
                Award ID: None
                Funded by: NIGMS;
                Award ID: R01 GM24485
                Funded by: Laboratory for Genomics Research;
                Award ID: Excellence in Research Award
                Funded by: URGENCE COVID-19 Institut Pasteur fundraising campaign;
                Funded by: BBSRC;
                Award ID: BB/S009566/1, BB/L002841/1
                Funded by: BBSRC;
                Award ID: BB/S009566/1, BB/L002841/1
                Funded by: doi http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;
                Award ID: BB/J014443/1
                Funded by: The Laboratory for Genomics Research;
                Award ID: Excellence in Research Award, 133122P
                Categories
                Research Article
                Research Articles
                R-Articles
                Engineering
                Microbio
                Online
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                Valda Vinson
                Julia Katris

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