PT  - JOURNAL ARTICLE
AU  - Stebbing, Justin
AU  - Sánchez Nievas, Ginés
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  - Avendaño Céspedes, Almudena
AU  - De Marco, Salvatore
AU  - Carrozzi, Laura
AU  - Lena, Fabio
AU  - Sánchez-Jurado, Pedro Manuel
AU  - Lacerenza, Leonardo Gianluca
AU  - Cesira, Nencioni
AU  - Caldevilla Bernardo, David
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  - Andrés Pretel, Fernando
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.
TI  - JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
AID  - 10.1126/sciadv.abe4724
DP  - 2021 Jan 01
TA  - Science Advances
PG  - eabe4724
VI  - 7
IP  - 1
4099  - http://advances.sciencemag.org/content/7/1/eabe4724.short
4100  - http://advances.sciencemag.org/content/7/1/eabe4724.full
SO  - Sci Adv2021 Jan 01; 7
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.