RT Journal Article SR Electronic T1 JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eabe4724 DO 10.1126/sciadv.abe4724 VO 7 IS 1 A1 Stebbing, Justin A1 Sánchez Nievas, Ginés A1 Falcone, Marco A1 Youhanna, Sonia A1 Richardson, Peter A1 Ottaviani, Silvia A1 Shen, Joanne X. A1 Sommerauer, Christian A1 Tiseo, Giusy A1 Ghiadoni, Lorenzo A1 Virdis, Agostino A1 Monzani, Fabio A1 Rizos, Luis Romero A1 Forfori, Francesco A1 Avendaño Céspedes, Almudena A1 De Marco, Salvatore A1 Carrozzi, Laura A1 Lena, Fabio A1 Sánchez-Jurado, Pedro Manuel A1 Lacerenza, Leonardo Gianluca A1 Cesira, Nencioni A1 Caldevilla Bernardo, David A1 Perrella, Antonio A1 Niccoli, Laura A1 Méndez, Lourdes Sáez A1 Matarrese, Daniela A1 Goletti, Delia A1 Tan, Yee-Joo A1 Monteil, Vanessa A1 Dranitsaris, George A1 Cantini, Fabrizio A1 Farcomeni, Alessio A1 Dutta, Shuchismita A1 Burley, Stephen K. A1 Zhang, Haibo A1 Pistello, Mauro A1 Li, William A1 Romero, Marta Mas A1 Andrés Pretel, Fernando A1 Simón-Talero, Rafaela Sánchez A1 García-Molina, Rafael A1 Kutter, Claudia A1 Felce, James H. A1 Nizami, Zehra F. A1 Miklosi, Andras G. A1 Penninger, Josef M. A1 Menichetti, Francesco A1 Mirazimi, Ali A1 Abizanda, Pedro A1 Lauschke, Volker M. YR 2021 UL http://advances.sciencemag.org/content/7/1/eabe4724.abstract 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.