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Journal ArticleDOI

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19.

TL;DR: It is proposed that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
About: This article is published in Cell.The article was published on 2020-05-28 and is currently open access. It has received 3286 citations till now.
Citations
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Journal ArticleDOI
13 Jul 2020-Science
TL;DR: The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections.
Abstract: 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.

2,171 citations

Journal ArticleDOI
05 Feb 2021-Science
TL;DR: This article analyzed multiple compartments of circulating immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months after infection.
Abstract: Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

1,980 citations

Journal ArticleDOI
Paul Bastard1, Paul Bastard2, Paul Bastard3, Lindsey B. Rosen4, Qian Zhang1, Eleftherios Michailidis1, Hans-Heinrich Hoffmann1, Yu Zhang4, Karim Dorgham3, Quentin Philippot3, Quentin Philippot2, Jérémie Rosain2, Jérémie Rosain3, Vivien Béziat1, Vivien Béziat3, Vivien Béziat2, Jeremy Manry3, Jeremy Manry2, Elana Shaw4, Liis Haljasmägi5, Pärt Peterson5, Lazaro Lorenzo2, Lazaro Lorenzo3, Lucy Bizien2, Lucy Bizien3, Sophie Trouillet-Assant6, Kerry Dobbs4, Adriana Almeida de Jesus4, Alexandre Belot6, Anne Kallaste7, Emilie Catherinot, Yacine Tandjaoui-Lambiotte2, Jérémie Le Pen1, Gaspard Kerner2, Gaspard Kerner3, Benedetta Bigio1, Yoann Seeleuthner3, Yoann Seeleuthner2, Rui Yang1, Alexandre Bolze, András N Spaan1, András N Spaan8, Ottavia M. Delmonte4, Michael S. Abers4, Alessandro Aiuti9, Giorgio Casari9, Vito Lampasona9, Lorenzo Piemonti9, Fabio Ciceri9, Kaya Bilguvar10, Richard P. Lifton1, Richard P. Lifton10, Marc Vasse, David M. Smadja3, Mélanie Migaud3, Mélanie Migaud2, Jérôme Hadjadj3, Benjamin Terrier3, Darragh Duffy11, Lluis Quintana-Murci11, Lluis Quintana-Murci12, Diederik van de Beek13, Lucie Roussel14, Donald C. Vinh14, Stuart G. Tangye15, Stuart G. Tangye16, Filomeen Haerynck17, David Dalmau18, Javier Martinez-Picado19, Javier Martinez-Picado20, Petter Brodin21, Petter Brodin22, Michel C. Nussenzweig23, Michel C. Nussenzweig1, Stéphanie Boisson-Dupuis1, Stéphanie Boisson-Dupuis3, Stéphanie Boisson-Dupuis2, Carlos Rodríguez-Gallego, Guillaume Vogt3, Trine H. Mogensen24, Trine H. Mogensen25, Andrew J. Oler4, Jingwen Gu4, Peter D. Burbelo4, Jeffrey I. Cohen4, Andrea Biondi26, Laura Rachele Bettini26, Mariella D'Angiò26, Paolo Bonfanti26, Patrick Rossignol27, Julien Mayaux3, Frédéric Rieux-Laucat3, Eystein S. Husebye28, Eystein S. Husebye29, Eystein S. Husebye30, Francesca Fusco, Matilde Valeria Ursini, Luisa Imberti31, Alessandra Sottini31, Simone Paghera31, Eugenia Quiros-Roldan32, Camillo Rossi, Riccardo Castagnoli33, Daniela Montagna33, Amelia Licari33, Gian Luigi Marseglia33, Xavier Duval, Jade Ghosn3, Hgid Lab4, Covid Clinicians5, Covid-Storm Clinicians§4, CoV-Contact Cohort§3, Amsterdam Umc Covid Biobank2, Amsterdam Umc Covid Biobank3, Amsterdam Umc Covid Biobank1, Covid Human Genetic Effort1, John S. Tsang4, Raphaela Goldbach-Mansky4, Kai Kisand5, Michail S. Lionakis4, Anne Puel1, Anne Puel2, Anne Puel3, Shen-Ying Zhang2, Shen-Ying Zhang3, Shen-Ying Zhang1, Steven M. Holland4, Guy Gorochov3, Emmanuelle Jouanguy1, Emmanuelle Jouanguy2, Emmanuelle Jouanguy3, Charles M. Rice1, Aurélie Cobat3, Aurélie Cobat1, Aurélie Cobat2, Luigi D. Notarangelo4, Laurent Abel1, Laurent Abel3, Laurent Abel2, Helen C. Su4, Jean-Laurent Casanova 
23 Oct 2020-Science
TL;DR: A means by which individuals at highest risk of life-threatening COVID-19 can be identified is identified, and the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical CO VID-19 is tested.
Abstract: Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

1,913 citations

Journal ArticleDOI
TL;DR: The potentially pathological roles of macrophages during SARS-CoV-2 infection are described and ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19 are discussed.
Abstract: The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.

1,840 citations

Journal ArticleDOI
TL;DR: The first discoveries that shape the current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle are summarized and relate that to the knowledge of coronavirus biology.
Abstract: The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus-host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.

1,787 citations

References
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Journal ArticleDOI
TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.
Abstract: In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html .

47,038 citations


"Imbalanced Host Response to SARS-Co..." refers background or methods in this paper

  • ...1.10 Ilumina http://basespace.illumina.com/ dashboard DESeq2 Love et al., 2014 https://bioconductor.org/packages/ release/bioc/html/DESeq2.html STRING Szklarczyk et al., 2019 https://string-db.org/ gplots CRAN https://cran.r-project.org/web/ packages/gplots/index.html PMA Witten et al., 2009 https://cran.r-project.org/web/ packages/PMA/index.html ggplot2 Tidyverse https://ggplot2.tidyverse.org/ Bowtie2 Langmead and Salzberg, 2012 http://bowtie-bio.sourceforge.net/ bowtie2/index.shtml ImmGen Yoshida et al., 2019 http://www.immgen.org/ ll...

    [...]

  • ...1.10 Ilumina http://basespace.illumina.com/ dashboard DESeq2 Love et al., 2014 https://bioconductor.org/packages/ release/bioc/html/DESeq2.html STRING Szklarczyk et al., 2019 https://string-db.org/ gplots CRAN https://cran.r-project.org/web/ packages/gplots/index.html PMA Witten et al., 2009…...

    [...]

  • ...Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2....

    [...]

  • ...Raw reads were aligned to the human genome (hg19) using the RNA-Seq Aligment App on Basespace (Illumina, CA), following differential expression analysis using DESeq2 (Love et al., 2014)....

    [...]

Journal ArticleDOI
TL;DR: Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.

37,898 citations

Book
13 Aug 2009
TL;DR: This book describes ggplot2, a new data visualization package for R that uses the insights from Leland Wilkisons Grammar of Graphics to create a powerful and flexible system for creating data graphics.
Abstract: This book describes ggplot2, a new data visualization package for R that uses the insights from Leland Wilkisons Grammar of Graphics to create a powerful and flexible system for creating data graphics. With ggplot2, its easy to: produce handsome, publication-quality plots, with automatic legends created from the plot specification superpose multiple layers (points, lines, maps, tiles, box plots to name a few) from different data sources, with automatically adjusted common scales add customisable smoothers that use the powerful modelling capabilities of R, such as loess, linear models, generalised additive models and robust regression save any ggplot2 plot (or part thereof) for later modification or reuse create custom themes that capture in-house or journal style requirements, and that can easily be applied to multiple plots approach your graph from a visual perspective, thinking about how each component of the data is represented on the final plot. This book will be useful to everyone who has struggled with displaying their data in an informative and attractive way. You will need some basic knowledge of R (i.e. you should be able to get your data into R), but ggplot2 is a mini-language specifically tailored for producing graphics, and youll learn everything you need in the book. After reading this book youll be able to produce graphics customized precisely for your problems,and youll find it easy to get graphics out of your head and on to the screen or page.

29,504 citations

Journal ArticleDOI
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

21,455 citations

Journal ArticleDOI
TL;DR: Characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia, and further investigation is needed to explore the applicability of the Mu LBSTA scores in predicting the risk of mortality in 2019-nCoV infection.

16,282 citations

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