JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.
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DOI：
10.1126/sciadv.abe4724
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发表时间：
2021-01
期刊：
影响因子：
13.6
通讯作者：
Lauschke VM
中科院分区：
文献类型：
--
作者：
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 YJ;Monteil V;Dranitsaris G;Cantini F;Farcomeni A;Dutta S;Burley SK;Zhang H;Pistello M;Li W;Romero MM;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
baricitinib的双重抗细胞因子和抗病毒作用降低了类器官中的SARS-CoV-2感染性和人群的发病率。使用AI，我们确定baricitinib具有抗病毒和抗细胞因子功效。我们现在显示，83例中重度SARS-CoV-2肺炎患者的死亡率获益为71%（95%CI 0.15至0.58），几乎没有药物诱导的不良事件，包括一个大型老年队列（中位年龄81岁）。另有48例轻中度肺炎患者顺利恢复。使用原代人肝细胞的器官型3D培养物，我们证明干扰素-α2使实质细胞中ACE 2表达和SARS-CoV-2感染性增加5倍以上。RNA-seq揭示了与血小板活化相关的基因应答特征，被baricitinib完全抑制。使用病毒载量定量和超分辨率显微镜，我们发现baricitinib通过抑制宿主蛋白质（抗病毒相关激酶）迅速发挥活性，这在抗病毒药物中是独一无二的。这揭示了Janus激酶-1/2抑制剂靶向病毒进入、复制和细胞因子风暴的机制作用，并与包括重症老年患者在内的有益结局相关，这些数据激励了进一步的随机对照试验。
The dual anticytokine and antiviral actions of baricitinib reduce SARS-CoV-2 infectivity in organoids and morbidity in people. 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.
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影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
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影响因子：
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作者：
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