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.