A Prenylated dsRNA Sensor Protects Against Severe COVID-19

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Abstract

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response.

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STAR: ultrafast universal RNA-seq aligner.

Alexander Dobin, Carrie A. Davis, Felix Schlesinger … (2013)

Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

Sven Heinz, Christopher Benner, Nathanael Spann … (2010)

Genome-scale studies have revealed extensive, cell type-specific colocalization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here, we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling, followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs. Copyright 2010 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0404511

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date Nihms-submitted: 07 June 2022

Publication date (Print): 29 October 2021

Publication date (Electronic): 29 October 2021

Publication date PMC-release: 09 June 2022

Volume: 374

Issue: 6567

Page: eabj3624

Affiliations

[1 ]MRC−University of Glasgow Centre for Virus Research (CVR), Institute of Infection, Inflammation and Immunity, University of Glasgow; Glasgow, UK

[2 ]Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK

[3 ]Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK

[4 ]Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge; Cambridge, UK

[5 ]Roslin Institute, University of Edinburgh; Edinburgh, UK

[6 ]laboratory of Tropical Diseases − Prof. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas; Campinas, SP, Brazil

[7 ]Department of Education and Research, Oncology Control Centre of Amazonas State − 5 FCECON; Manaus, AM, Brazil

[8 ]Postgraduate Program in Tropical Medicine, Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, AM, Brazil

[9 ]Edinburgh Clinical Research Facility, University of Edinburgh, Western General Hospital, Edinburgh, UK

[10 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

[12 ]Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow; Glasgow, UK

[13 ]Division of Infection & Immunity, Cardiff University; Cardiff, UK

[14 ]NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

[15 ]Respiratory Medicine, Alder Hey Children’s Hospital, Liverpool, UK

[16 ]National Heart and Lung Institute, Imperial College London, London, UK

[17 ]Imperial College Healthcare NHS Trust London, London, UK

[18 ]Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK

Author notes

[11]

ISARIC4C investigators.

[* ]Corresponding author. sam.wilson@ 123456glasgow.ac.uk

Article

Manuscript ID: EMS145627

DOI: 10.1126/science.abj3624

PMC ID: 7612834

PubMed ID: 34581622

SO-VID: 83f04da1-8a0d-484a-a8da-7321889b1f38

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This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material.

A Prenylated dsRNA Sensor Protects Against Severe COVID-19

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Novel Coronavirus Disease COVID-19

Most cited references 103

STAR: ultrafast universal RNA-seq aligner.

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.

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