TY - JOUR
T1 - JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
AU - Stebbing, Justin
AU - Nievas, Ginés Sánchez
AU - Falcone, Marco
AU - Youhanna, Sonia
AU - Richardson, Peter
AU - Ottaviani, Silvia
AU - Shen, Joanne X.
AU - Sommerauer, Christian
AU - Tiseo, Giusy
AU - Ghiadoni, Lorenzo
AU - Virdis, Agostino
AU - Monzani, Fabio
AU - Rizos, Luis Romero
AU - Forfori, Francesco
AU - Céspedes, Almudena Avendaño
AU - de Marco, Salvatore
AU - Carrozzi, Laura
AU - Lena, Fabio
AU - Sánchez-Jurado, Pedro Manuel
AU - Lacerenza, Leonardo Gianluca
AU - Cesira, Nencioni
AU - Bernardo, David Caldevilla
AU - Perrella, Antonio
AU - Niccoli, Laura
AU - Méndez, Lourdes Sáez
AU - Matarrese, Daniela
AU - Goletti, Delia
AU - Tan, Yee Joo
AU - Monteil, Vanessa
AU - Dranitsaris, George
AU - Cantini, Fabrizio
AU - Farcomeni, Alessio
AU - Dutta, Shuchismita
AU - Burley, Stephen K.
AU - Zhang, Haibo
AU - Pistello, Mauro
AU - Li, William
AU - Romero, Marta Mas
AU - Pretel, Fernando Andrés
AU - Simón-Talero, Rafaela Sánchez
AU - García-Molina, Rafael
AU - Kutter, Claudia
AU - Felce, James H.
AU - Nizami, Zehra F.
AU - Miklosi, Andras G.
AU - Penninger, Josef M.
AU - Menichetti, Francesco
AU - Mirazimi, Ali
AU - Abizanda, Pedro
AU - Lauschke, Volker M.
N1 - Funding Information:
V.M.L. acknowledges support by the Swedish Research Council (grant agreement numbers 2016-01153, 2016-01154, and 2019-01837), the Strategic Research Programmes in Diabetes (SFO Diabetes) and Stem Cells and Regenerative Medicine (SFO StratRegen), and the EU/ EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant 875510). D.G. is partially funded by Ricerca Corrente Linea 1 and 3. J.S. and S.O. wish to thank the Imperial BRC, ECMC, the NIHR, BSAC, and AAC. The RCSB Protein Data Bank is supported by grants to S.K.B. from the NSF (DBI-1832184), the NIH (R01GM133198), and the Department of Energy (DE-SC0019749). P.A. acknowledges support by CIBERFES, Instituto de Salud Carlos III, Ministerio de Econom?a y Competitividad, Espa?a, and Ayuda cofinanciada por el Fondo Europeo de Desarrollo Regional (FEDER) Una Manera de hacer Europa (grant number CB16/10/00408). This study was supported by the Imperial BRC and ECMC, the NIHR, and AAC. Role of the funding sources: none declared.
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/13
Y1 - 2020/11/13
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abe4724
DO - 10.1126/sciadv.abe4724
M3 - Article
AN - SCOPUS:85098648758
VL - 7
SP - 1
EP - 23
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 1
M1 - eabe4724
ER -