BARICITINIB ATTENUATES THE PROINFLAMMATORY PHASE OF COVID-19 DRIVEN BY LUNG-INFILTRATING MONOCYTES. Dobosh et al.

Supplementary Tables
Abstract: SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication, but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of pro-neutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.

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摘要：感染严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的受试者在病毒复制初期通常呈无症状状态，但在病毒消退、单核细胞浸润气道后，可能出现严重的免疫病理损伤。在重症新型冠状病毒肺炎（COVID-19）患者的支气管肺泡灌洗液中，单核细胞可表达编码炎症介质的信使核糖核酸（mRNA），并携带SARS-CoV-2转录本。本研究利用人小气道感染炎症模型，即外周血原代单核细胞跨膜迁移至被SARS-CoV-2感染的肺上皮细胞层，以此表征上皮细胞与单核细胞的病毒载量、基因表达及炎症介质分泌水平。在该模型中，肺浸润性单核细胞可从上皮细胞获取SARS-CoV-2，并上调炎症介质的表达与分泌，该结果与体内实验数据一致。联合使用巴瑞替尼（Janus kinase inhibitor）与瑞德西韦（nucleoside analog），可增强SARS-CoV-2阳性单核细胞的抗病毒信号通路活性与病毒清除能力，同时减少与急性呼吸窘迫综合征相关的促中性粒细胞介质的分泌。本研究结果揭示了肺浸润性单核细胞在新型冠状病毒肺炎发病机制中的关键作用，以及其作为治疗靶点的重要价值。