JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
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Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, Ottaviani S, Shen JX, Sommerauer C, Tiseo G, Ghiadoni L, Virdis A, Monzani F, Rizos LR, Forfori F, Avendaño-Céspedes A, De Marco S, Carrozzi L, Lena F, Sánchez-Jurado PM, Lacerenza LG, Cesira N, Caldevilla-Bernardo D, Perrella A, Niccoli L, Méndez LS, Matarrese D, Goletti D, Tan Y, Monteil V, Dranitsaris G, Cantini F, Farcomeni A, Dutta S, Burley SK, Zhang H, Pistello M, Li W, Mas Romero M, Andrés Pretel F, Simón-Talero RS, García-Molina R, Kutter C, Felce JH, Nizami ZF, Miklosi AG, Penninger JM, Menichetti F, Mirazimi A, Abizanda P, Lauschke VM
Sci Adv 7 (1) -
[2020-11-13; online 2020-11-13]
Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) 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). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. 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 incentivizes further randomized controlled trials.
Research Area: Host cell systems biology and targets
PubMed 33187978
DOI 10.1126/sciadv.abe4724
Crossref 10.1126/sciadv.abe4724
Array Express E-MTAB-9711: RNA-seq of SARS-CoV-2-infected human primary hepatocyte-derived spheroids upon interferon a2 and baricitinib treatment
Supplementary information