ADAM10 and ADAM17 promote SARS‐CoV‐2 cell entry and spike protein‐mediated lung cell fusion DOI Creative Commons
Georg Jocher, Vincent Grass,

Sarah K. Tschirner

et al.

EMBO Reports, Journal Year: 2022, Volume and Issue: 23(6)

Published: May 8, 2022

The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify metalloprotease ADAM17 as a facilitator SARS-CoV-2 entry and ADAM10 factor required for lung syncytia formation, hallmark pathology. ADAM17, which are broadly expressed in human lung, cleave spike protein (S) vitro, indicating that contribute priming S, an essential step viral fusion. ADAM protease-targeted inhibitors severely impair infection by variants concern alpha, beta, delta, omicron also reduce primary cells TMPRSS2 protease-independent manner. Our study establishes formation defines both proteases potential targets antiviral drug development.

Language: Английский

Large-Scale Multi-omic Analysis of COVID-19 Severity DOI Creative Commons
Katherine A. Overmyer, Evgenia Shishkova, Ian Miller

et al.

Cell Systems, Journal Year: 2020, Volume and Issue: 12(1), P. 23 - 40.e7

Published: Oct. 8, 2020

We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive COVID-19-negative patients with diverse disease severities outcomes. Quantified transcripts, proteins, metabolites, lipids were associated clinical outcomes in a curated relational database, uniquely enabling systems analysis cross-ome correlations to molecules patient prognoses. mapped 219 molecular features high significance COVID-19 status severity, many of which involved complement activation, dysregulated lipid transport, neutrophil activation. identified sets covarying molecules, e.g., protein gelsolin metabolite citrate or plasmalogens apolipoproteins, offering pathophysiological insights therapeutic suggestions. The observed dysregulation platelet function, coagulation, acute phase response, endotheliopathy further illuminated the unique phenotype. present web-based tool (covid-omics.app) interactive exploration our compendium illustrate its utility through machine learning approach for prediction severity.

Language: Английский

Citations

544
The cGAS–STING pathway drives type I IFN immunopathology in COVID-19 DOI Creative Commons
Jérémy Di Domizio, Muhammet F. Gülen, Fanny Saidoune

et al.

Nature, Journal Year: 2022, Volume and Issue: 603(7899), P. 145 - 151

Published: Jan. 19, 2022

Abstract COVID-19, which is caused by infection with SARS-CoV-2, characterized lung pathology and extrapulmonary complications 1,2 . Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3–5 ). Although rapid induction type IFNs limits virus propagation, a sustained increase levels late phase associated aberrant inflammation poor clinical outcome 5–17 Here we show that cyclic GMP-AMP synthase (cGAS)–stimulator interferon genes (STING) pathway, controls immunity to cytosolic DNA, critical driver IFN responses (ref. 18 Profiling skin manifestations, uncover STING-dependent signature primarily mediated macrophages adjacent areas endothelial cell damage. Moreover, cGAS–STING activity was detected samples from patients prominent tissue destruction, responses. A lung-on-chip model revealed that, addition macrophages, SARS-CoV-2 activates signalling cells through mitochondrial DNA release, leads death production. In mice, pharmacological inhibition STING reduces severe induced improves disease outcome. Collectively, our study establishes mechanistic basis pathological reveals principle for development host-directed therapeutics.

Language: Английский

Citations

423
Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses DOI Creative Commons
Ruofan Wang, Camille R. Simoneau, Jessie Kulsuptrakul

et al.

Cell, Journal Year: 2020, Volume and Issue: 184(1), P. 106 - 119.e14

Published: Dec. 9, 2020

Language: Английский

Citations

405
Phosphoregulation of Phase Separation by the SARS-CoV-2 N Protein Suggests a Biophysical Basis for its Dual Functions DOI Creative Commons
Christopher R. Carlson, Jonathan B Asfaha, Chloe M. Ghent

et al.

Molecular Cell, Journal Year: 2020, Volume and Issue: 80(6), P. 1092 - 1103.e4

Published: Nov. 20, 2020

Language: Английский

Citations

338
Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium DOI Open Access
Diana A. Gorog, Robert F. Storey, Paul A. Gurbel

et al.

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(7), P. 475 - 495

Published: Jan. 13, 2022

Language: Английский

Citations

258
SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals DOI Creative Commons
Nils C. Gassen, Jan Papies, Thomas Bajaj

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 21, 2021

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated might lead to excessive inflammatory autoimmune responses as observed in severe long COVID-19 patients. Here we show that SARS-CoV-2 modulates reduces Accordingly, compound-driven induction of autophagy limits propagation. In detail, SARS-CoV-2-infected cells accumulation key metabolites, activation inhibitors (AKT1, SKP2) reduction proteins responsible for initiation (AMPK, TSC2, ULK1), membrane nucleation, phagophore formation (BECN1, VPS34, ATG14), well autophagosome-lysosome fusion ATG14 oligomers). Consequently, phagophore-incorporated markers LC3B-II P62 accumulate, which confirm a hamster model lung samples Single-nucleus single-cell sequencing patient-derived mucosal differential transcriptional regulation immune genes depending on cell type, disease duration, replication levels. Targeting autophagic pathways by exogenous administration the polyamines spermidine spermine, selective AKT1 inhibitor MK-2206, BECN1-stabilizing anthelmintic drug niclosamide inhibit propagation vitro with IC

Language: Английский

Citations

237
Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities DOI Creative Commons
Manuel Hayn, Maximilian Hirschenberger, Lennart Koepke

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 35(7), P. 109126 - 109126

Published: April 27, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) and autophagy. We show that synergize counteract anti-viral responses. For example, Nsp14 targets type I IFN receptor for lysosomal degradation, ORF3a prevents fusion autophagosomes lysosomes, ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, Nsp15 antagonizes signaling less efficiently than orthologs closely related RaTG13-CoV SARS-CoV-1. Overall, autophagy more II or III signaling, infection experiments confirm potent inhibition by IFN-γ -λ1. Our results define repertoire selected mechanisms antagonists also reveal vulnerability help develop safe effective approaches.

Language: Английский

Citations

212
Morphological, cellular, and molecular basis of brain infection in COVID-19 patients DOI Creative Commons
Fernanda Crunfli, Victor Corasolla Carregari, Flávio P. Veras

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 11, 2022

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum cerebral impact acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranging from alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to damage confirmed brain tissue samples extracted orbitofrontal region (via endonasal transethmoidal access) who died COVID-19. In an independent cohort 26 COVID-19, we used histopathological signs a guide for possible SARS-CoV-2 infection found that among 5 exhibited those signs, all them had genetic material virus brain. Brain these five patients also foci replication, particularly astrocytes. Supporting hypothesis astrocyte neural stem cell-derived human astrocytes vitro are susceptible through noncanonical mechanism involves spike-NRP1 interaction. SARS-CoV-2-infected manifested changes energy metabolism key proteins metabolites fuel neurons, well biogenesis neurotransmitters. Moreover, elicits secretory phenotype reduces neuronal viability. Our data support model which reaches brain, infects astrocytes, consequently, leads death or dysfunction. These deregulated processes could contribute structural functional seen brains patients.

Language: Английский

Citations

208
Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells DOI Creative Commons
Mario Witkowski, Caroline Tizian, Marta Ferreira‐Gomes

et al.

Nature, Journal Year: 2021, Volume and Issue: 600(7888), P. 295 - 301

Published: Oct. 25, 2021

Language: Английский

Citations

203
Skeletal muscle alterations in patients with acute Covid‐19 and post‐acute sequelae of Covid‐19 DOI Creative Commons

M Soares,

Moritz Eggelbusch, Elie Naddaf

et al.

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2022, Volume and Issue: 13(1), P. 11 - 22

Published: Jan. 7, 2022

Abstract Skeletal muscle‐related symptoms are common in both acute coronavirus disease (Covid)‐19 and post‐acute sequelae of Covid‐19 (PASC). In this narrative review, we discuss cellular molecular pathways that affected consider these regard to skeletal muscle involvement other conditions, such as respiratory distress syndrome, critical illness myopathy, post‐viral fatigue syndrome. Patients with severe PASC suffer from weakness exercise intolerance. Histological sections present fibre atrophy, metabolic alterations, immune cell infiltration. Contributing factors patients include systemic inflammation, disuse, hypoxaemia, malnutrition. These also contribute post‐intensive care unit (ICU) syndrome ICU‐acquired likely explain a substantial part Covid‐19‐acquired weakness. The intolerance associated more obscure. Direct (SARS‐CoV)‐2 viral infiltration into or an aberrant system contribute. Similarities between alterations chronic deserve further study. Both SARS‐CoV‐2‐specific generic consequences underlie the observed PASC.

Language: Английский

Citations

199