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JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
- Source :
-
Science advances [Sci Adv] 2021 Jan 01; Vol. 7 (1). Date of Electronic Publication: 2021 Jan 01 (Print Publication: 2021). - Publication Year :
- 2021
-
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.<br /> (Copyright © 2021 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).)
- Subjects :
- Adult
Aged
Aged, 80 and over
COVID-19 metabolism
COVID-19 virology
Cytokine Release Syndrome
Cytokines metabolism
Drug Evaluation, Preclinical
Female
Gene Expression Profiling
Humans
Interferon alpha-2 metabolism
Italy
Janus Kinases metabolism
Liver drug effects
Male
Middle Aged
Patient Safety
Platelet Activation
Proportional Hazards Models
RNA-Seq
Spain
Virus Internalization drug effects
COVID-19 Drug Treatment
Antiviral Agents pharmacology
Azetidines pharmacology
COVID-19 mortality
Enzyme Inhibitors pharmacology
Janus Kinases antagonists & inhibitors
Liver virology
Purines pharmacology
Pyrazoles pharmacology
SARS-CoV-2 pathogenicity
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 33187978
- Full Text :
- https://doi.org/10.1126/sciadv.abe4724