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      Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

      research-article
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      American Association for the Advancement of Science

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          The genetics underlying severe COVID-19

          The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified.

          Science, this issue p. eabd4570, p. [Related article:]eabd4585; see also p. [Related article:]404

          Abstract

          A large immunological and genomics study of COVID-19 patients reveals excess mutations in the type I IFN pathway.

          Abstract

          INTRODUCTION

          Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost biological and medical importance.

          RATIONALE

          We established the COVID Human Genetic Effort ( www.covidhge.com) to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance. We sequenced the exome or genome of 659 patients of various ancestries with life-threatening COVID-19 pneumonia and 534 subjects with asymptomatic or benign infection. We tested the specific hypothesis that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity that underlie life-threatening influenza pneumonia also underlie life-threatening COVID-19 pneumonia. We considered three loci identified as mutated in patients with life-threatening influenza: TLR3, IRF7, and IRF9. We also considered 10 loci mutated in patients with other viral illnesses but directly connected to the three core genes conferring influenza susceptibility: TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG from the TLR3-dependent type I IFN induction pathway, and IFNAR1, IFNAR2, STAT1, and STAT2 from the IRF7- and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes of inheritance at these 13 loci.

          RESULTS

          We found an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, at the 13 candidate loci in the 659 patients with life-threatening COVID-19 pneumonia relative to the 534 subjects with asymptomatic or benign infection ( P = 0.01). Experimental tests for all 118 rare nonsynonymous variants (including both pLOF and other variants) of these 13 genes found in patients with critical disease identified 23 patients (3.5%), aged 17 to 77 years, carrying 24 deleterious variants of eight genes. These variants underlie autosomal-recessive (AR) deficiencies ( IRF7 and IFNAR1) and autosomal-dominant (AD) deficiencies ( TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2) in four and 19 patients, respectively. These patients had never been hospitalized for other life-threatening viral illness. Plasmacytoid dendritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and TLR3 −/−, TLR3 +/−, IRF7 −/−, and IFNAR1 −/− fibroblasts were susceptible to SARS-CoV-2 infection in vitro.

          CONCLUSION

          At least 3.5% of patients with life-threatening COVID-19 pneumonia had known (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiencies) genetic defects at eight of the 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential roles for both the double-stranded RNA sensor TLR3 and type I IFN cell-intrinsic immunity in the control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection.

          Inborn errors of TLR3- and IRF7-dependent type I IFN production and amplification underlie life-threatening COVID-19 pneumonia.

          Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Molecules represented in bold are encoded by genes with variants that also underlie critical COVID-19 pneumonia.

          Abstract

          Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

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          Most cited references41

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          Is Open Access

          Fast and accurate short read alignment with Burrows–Wheeler transform

          Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
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            A framework for variation discovery and genotyping using next-generation DNA sequencing data

            Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.
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              • Record: found
              • Abstract: found
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              Is Open Access

              Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

              Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
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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
                23 October 2020
                24 September 2020
                : 370
                : 6515
                : eabd4570
                Affiliations
                [1 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
                [2 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
                [3 ]University of Paris, Imagine Institute, Paris, France.
                [4 ]Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
                [5 ]Department of Paediatric Infectious Diseases & Virology, Imperial College London, London, UK.
                [6 ]Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
                [7 ]Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
                [8 ]Helix, San Mateo, CA, USA.
                [9 ]Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia.
                [10 ]School of Microbiology, University of Antioquia UdeA, Medellin, Colombia.
                [11 ]Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
                [12 ]NIAID Clinical Genomics Program, NIH, Bethesda, MD, USA.
                [13 ]Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, Paris, France.
                [14 ]Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR 7212, Université de Paris, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France.
                [15 ]Sorbonne Université, Inserm, Centre d’Immunologie et des Maladies Infectieuses–Paris (CIMI PARIS), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Pitié-Salpêtrière, Paris, France.
                [16 ]Translational Immunology Lab, Institut Pasteur, Paris, France.
                [17 ]Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
                [18 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [19 ]Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
                [20 ]Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
                [21 ]Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
                [22 ]Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
                [23 ]School of Life sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
                [24 ]Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
                [25 ]Swiss Institue of Bioinformatics, Lausanne, Switzerland.
                [26 ]Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada.
                [27 ]Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
                [28 ]Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium.
                [29 ]Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
                [30 ]Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
                [31 ]The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of, Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti, University of Medical Sciences, Tehran, Iran.
                [32 ]Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti, Iran.
                [33 ]National Center of Genomics Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
                [34 ]Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Kuwait.
                [35 ]Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
                [36 ]Translational Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Misery of National Guard Health Affairs, Riyadh, Saudi Arabia.
                [37 ]Cancer & Blood Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
                [38 ]Amsterdam UMC, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands.
                [39 ]Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
                [40 ]Department of Infectious Diseases, San Gerardo Hospital–University of Milano-Bicocca, Monza, Italy.
                [41 ]CREA Laboratory, Diagnostic Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy.
                [42 ]Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy.
                [43 ]Chief Medical Officer, ASST Spedali Civili di Brescia, Brescia, Italy.
                [44 ]Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA.
                [45 ]PRIMER, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
                [46 ]Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
                [47 ]Department of Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
                [48 ]Fonds de la Recherche Scientifique (FNRS) and Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
                [49 ]Department of Paediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Lab, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium.
                [50 ]Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
                [51 ]Immunology Division, Genetics Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute, Vall d’Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain.
                [52 ]Aix Marseille Univ, INSERM, INRAE, C2VN, CHU Timone, Marseille, France.
                [53 ]Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey.
                [54 ]Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey.
                [55 ]Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey.
                [56 ]Departments of Infectious Diseases and Clinical Microbiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
                [57 ]Department of Immunology, Hospital Universitario de G.C. Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
                [58 ]University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
                [59 ]Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Rome, Italy.
                [60 ]Intensive Care Unit, AP-HM, Marseille, France.
                [61 ]Avicenne Hospital Intensive Care Unit, APHP, Bobigny, INSERM U1272 Hypoxia & Lung, Paris, France.
                [62 ]PH Réanimation CHU Avicenne, Bobigny, INSERM U1272 Hypoxie & Poumon, Paris, France.
                [63 ]Université de Paris, IAME UMR-S 1137, INSERM, Paris, France.
                [64 ]Inserm CIC 1425, Paris, France.
                [65 ]AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France.
                [66 ]Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
                [67 ]Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
                [68 ]Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University, New York, USA.
                [69 ]Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
                [70 ]Department of Biomedicine, Aarhus University, Aarhus, Denmark.
                [71 ]College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
                [72 ]Department of Medical Microbiology, Utrecht UMC, Utrecht, Netherlands.
                [73 ]Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
                [74 ]Turnstone Biologics, New York, NY, USA.
                [75 ]Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
                [76 ]New York Genome Center, New York, NY, USA.
                [77 ]AP-HP, Hôpital Saint-Louis, Laboratoire d’Immunologie, Paris, France.
                [78 ]Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA.
                [79 ]Howard Hughes Medical Institute, New York, NY, USA.
                [80 ]Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [81 ]Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [82 ]The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [83 ]Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA.
                [84 ]Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
                [85 ]Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
                [86 ]Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                All collaborators and their affiliations appear at the end of this paper.

                [‡]

                These authors contributed equally to this work.

                [§]

                These authors contributed equally to this work.

                []Corresponding author. Email: casanova@ 123456rockefeller.edu
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                Article
                abd4570
                10.1126/science.abd4570
                7857407
                32972995
                a33d8acc-c016-4548-be92-d5b110f22947
                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
                : 22 June 2020
                : 16 September 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01AI088364
                Funded by: doi http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Funded by: doi http://dx.doi.org/10.13039/100002350, ST. GILES FOUNDATION;
                Funded by: doi http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;
                Funded by: doi http://dx.doi.org/10.13039/100012007, Rockefeller University;
                Funded by: French National Research Agency;
                Award ID: ANR-10-IAHU-01
                Funded by: the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence;
                Award ID: ANR-10-LABX-62-IBEID
                Funded by: National Human Genome Research Institute (NHGRI);
                Award ID: UM1HG006504 and U24HG008956
                Funded by: the French Foundation for Medical Research (FRM);
                Award ID: EQU201903007798
                Funded by: NIH Clinical and Translational Science Award;
                Award ID: UL1 TR001866
                Funded by: Emergent Ventures;
                Award ID: fast grant
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                Laura Zahn
                Suzanne White
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