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Title: JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
Authors: Stebbing, Justin
Nievas, Gines Sanchez
Falcone, Marco
Youhanna, Sonia
Richardson, Peter
Ottaviani, Silvia
Shen, Joanne X
Sommerauer, Christian
Tiseo, Giusy
Ghiadoni, Lorenzo
Virdis, Agostino
Monzani, Fabio
Rizos, Luis Romero
Forfori, Francesco
Avendano-Cespedes, Almudena
De Marco, Salvatore
Carrozzi, Laura
Lena, Fabio
Sanchez-Jurado, Pedro Manuel
Lacerenza, Leonardo Gianluca
Cesira, Nencioni
Caldevilla-Bernardo, David
Perrella, Antonio
Niccoli, Laura
Mendez, Lourdes Saez
Matarrese, Daniela
Goletti, Delia
Tan, Yee-Joo 
Monteil, Vanessa
Dranitsaris, George
Cantini, Fabrizio
Farcomeni, Alessio
Dutta, Shuchismita
Burley, Stephen K
Zhang, Haibo
Pistello, Mauro
Li, William
Romero, Marta Mas
Pretel, Fernando Andres
Simon-Talero, Rafaela Sanchez
Garcia-Molina, Rafael
Kutter, Claudia
Felce, James H
Nizami, Zehra F
Miklosi, Andras G
Penninger, Josef M
Menichetti, Francesco
Mirazimi, Ali
Abizanda, Pedro
Lauschke, Volker M
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Issue Date: 1-Jan-2021
Citation: Stebbing, Justin, Nievas, Gines Sanchez, Falcone, Marco, Youhanna, Sonia, Richardson, Peter, Ottaviani, Silvia, Shen, Joanne X, Sommerauer, Christian, Tiseo, Giusy, Ghiadoni, Lorenzo, Virdis, Agostino, Monzani, Fabio, Rizos, Luis Romero, Forfori, Francesco, Avendano-Cespedes, Almudena, De Marco, Salvatore, Carrozzi, Laura, Lena, Fabio, Sanchez-Jurado, Pedro Manuel, Lacerenza, Leonardo Gianluca, Cesira, Nencioni, Caldevilla-Bernardo, David, Perrella, Antonio, Niccoli, Laura, Mendez, Lourdes Saez, Matarrese, Daniela, Goletti, Delia, Tan, Yee-Joo, Monteil, Vanessa, Dranitsaris, George, Cantini, Fabrizio, Farcomeni, Alessio, Dutta, Shuchismita, Burley, Stephen K, Zhang, Haibo, Pistello, Mauro, Li, William, Romero, Marta Mas, Pretel, Fernando Andres, Simon-Talero, Rafaela Sanchez, Garcia-Molina, Rafael, Kutter, Claudia, Felce, James H, Nizami, Zehra F, Miklosi, Andras G, Penninger, Josef M, Menichetti, Francesco, Mirazimi, Ali, Abizanda, Pedro, Lauschke, Volker M (2021-01-01). JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. SCIENCE ADVANCES 7 (1). ScholarBank@NUS Repository.
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.
ISSN: 23752548
DOI: 10.1126/sciadv.abe4724
Appears in Collections:Staff Publications

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