JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality
Justin Stebbing, Ginés Sánchez Nievas, Marco Falcone, Sonia Youhanna, Peter J. Richardson, Silvia Ottaviani, Joanne X. Shen, Christian Sommerauer, Giusy Tiseo, Lorenzo Ghiadoni, Agostino Virdis, Fabio Monzani, Luis Romero Rizos, Francesco Forfori, Almudena Avendaño Céspedes, Salvatore De Marco, Laura Carrozzi, Fabio Lena, Pedro Manuel Sánchez‐Jurado, Leonardo Gianluca Lacerenza, Cesira Nencioni, David Caldevilla Bernardo, Antonio Perrella, Laura Niccoli, L. Sáez Méndez, Daniela Matarrese, Delia Goletti, Yee‐Joo Tan, Vanessa Monteil, George Dranitsaris, Fabrizio Cantini, Alessio Farcomeni, Shuchismita Dutta, S.K. Burley, Haibo Zhang, Mauro Pistello, William Li, Marta Mas Romero, Fernando Andrés‐Pretel, Rafaela Sánchez Simón-Talero, Rafael García Molina, Claudia Kutter, James H. Felce, Zehra F. Nizami, Andras G. Miklosi, Josef Penninger, Francesco Menichetti, Alì Mirazimi, Pedro Abizanda, Volker M. Lauschke
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.