JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
File(s)
Published version
Author(s)
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.
Date Issued
2021-01-01
Date Acceptance
2020-10-28
Citation
Science Advances, 2021, 7 (1), pp.1-15
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).
License URL
Sponsor
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000605159200041&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
NIHR-RP-011-053
RDB01 79560
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
RHEUMATOID-ARTHRITIS
FUNCTIONAL RECEPTOR
BARICITINIB
PLACEBO
PROTEIN
INJURY
Publication Status
Published
Article Number
ARTN eabe4724
Date Publish Online
2021-01-01