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https://doi.org/10.1126/sciadv.abe4724
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 RHEUMATOID-ARTHRITIS FUNCTIONAL RECEPTOR BARICITINIB PLACEBO PROTEIN INJURY |
Issue Date: | 1-Jan-2021 | Publisher: | AMER ASSOC ADVANCEMENT SCIENCE | 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. https://doi.org/10.1126/sciadv.abe4724 | 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. | Source Title: | SCIENCE ADVANCES | URI: | https://scholarbank.nus.edu.sg/handle/10635/219373 | ISSN: | 23752548 | DOI: | 10.1126/sciadv.abe4724 |
Appears in Collections: | Staff Publications Elements |
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