1. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
- Author
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Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, Ottaviani S, Shen JX, Sommerauer C, Tiseo G, Ghiadoni L, Virdis A, Monzani F, Rizos LR, Forfori F, Avendaño Céspedes A, De Marco S, Carrozzi L, Lena F, Sánchez-Jurado PM, Lacerenza LG, Cesira N, Caldevilla Bernardo D, Perrella A, Niccoli L, Méndez LS, Matarrese D, Goletti D, Tan YJ, Monteil V, Dranitsaris G, Cantini F, Farcomeni A, Dutta S, Burley SK, Zhang H, Pistello M, Li W, Romero MM, Andrés Pretel F, Simón-Talero RS, García-Molina R, Kutter C, Felce JH, Nizami ZF, Miklosi AG, Penninger JM, Menichetti F, Mirazimi A, Abizanda P, and Lauschke VM
- 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
- 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., (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).)
- Published
- 2021
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