5
IRUS Total
Downloads
  Altmetric

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

File Description SizeFormat 
sciadv.abe4724.full.pdfPublished version2 MBAdobe PDFView/Open
Title: JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
Authors: Stebbing, J
Nievas, GS
Falcone, M
Youhanna, S
Richardson, P
Ottaviani, S
Shen, JX
Sommerauer, C
Tiseo, G
Ghiadoni, L
Virdis, A
Monzani, F
Rizos, LR
Forfori, F
Avendano-Cespedes, A
De Marco, S
Carrozzi, L
Lena, F
Sanchez-Jurado, PM
Lacerenza, LG
Cesira, N
Caldevilla-Bernardo, D
Perrella, A
Niccoli, L
Mendez, LS
Matarrese, D
Goletti, D
Tan, Y-J
Monteil, V
Dranitsaris, G
Cantini, F
Farcomeni, A
Dutta, S
Burley, SK
Zhang, H
Pistello, M
Li, W
Romero, MM
Pretel, FA
Simon-Talero, RS
Garcia-Molina, R
Kutter, C
Felce, JH
Nizami, ZF
Miklosi, AG
Penninger, JM
Menichetti, F
Mirazimi, A
Abizanda, P
Lauschke, VM
Item Type: Journal Article
Abstract: Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.
Issue Date: 1-Jan-2021
Date of Acceptance: 28-Oct-2020
URI: http://hdl.handle.net/10044/1/84015
DOI: 10.1126/sciadv.abe4724
ISSN: 2375-2548
Publisher: American Association for the Advancement of Science
Start Page: 1
End Page: 15
Journal / Book Title: Science Advances
Volume: 7
Issue: 1
Copyright Statement: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Sponsor/Funder: National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: NIHR-RP-011-053
RDB01 79560
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
RHEUMATOID-ARTHRITIS
FUNCTIONAL RECEPTOR
BARICITINIB
PLACEBO
PROTEIN
INJURY
Adult
Aged
Aged, 80 and over
Antiviral Agents
Azetidines
COVID-19
Cytokine Release Syndrome
Cytokines
Drug Evaluation, Preclinical
Enzyme Inhibitors
Female
Gene Expression Profiling
Humans
Interferon alpha-2
Italy
Janus Kinases
Liver
Male
Middle Aged
Patient Safety
Platelet Activation
Proportional Hazards Models
Purines
Pyrazoles
RNA-Seq
SARS-CoV-2
Spain
Sulfonamides
Virus Internalization
Liver
Humans
Sulfonamides
Azetidines
Pyrazoles
Purines
Cytokines
Enzyme Inhibitors
Antiviral Agents
Proportional Hazards Models
Drug Evaluation, Preclinical
Gene Expression Profiling
Platelet Activation
Adult
Aged
Aged, 80 and over
Middle Aged
Italy
Spain
Female
Male
Janus Kinases
Virus Internalization
Patient Safety
Interferon alpha-2
Cytokine Release Syndrome
RNA-Seq
COVID-19
SARS-CoV-2
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
RHEUMATOID-ARTHRITIS
FUNCTIONAL RECEPTOR
BARICITINIB
PLACEBO
PROTEIN
INJURY
Publication Status: Published
Article Number: ARTN eabe4724
Online Publication Date: 2021-01-01
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine
Imperial College London COVID-19



This item is licensed under a Creative Commons License Creative Commons