BARICITINIB ATTENUATES THE PROINFLAMMATORY PHASE OF COVID-19 DRIVEN BY LUNG-INFILTRATING MONOCYTES

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Abstract: COVID-19 patients are generally asymptomatic during initial SARS-CoV-2 replication, but may suffer severe immunopathology after the virus has receded and blood monocytes have infiltrated the airways. In the bronchoalveolar lavage fluid from patients with severe COVID-19, lung-infiltrating monocytes express high mRNA levels encoding inflammatory mediators, including CXCL8 and IL-1, and contain SARS-CoV-2 transcripts. To study this process in more depth, we leverage a small airway model of infection and inflammation whereby primary human blood monocytes transmigrate across a differentiated human lung epithelium infected by SARS-CoV-2. Infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators including CXCL8 and IL-1, mirroring in vivo data. The JAK1/2 inhibitor baricitinib gained emergency use authorization by the FDA for the treatment of COVID-19 originally in combination with the antiviral remdesivir, and recently as a stand-alone treatment. To explore the mechanisms by which baricitinib alone or in combination with remdesivir may result in more favorable disease outcomes, we leverage this model to characterize viral burden, gene expression and inflammatory mediator secretion by lung epithelial cells and infiltrating monocytes. As expected, remdesivir decreases viral burden in both the epithelium and monocytes, while baricitinib enhances antiviral signaling and decreases specific inflammatory mediators in monocytes. Combined use of baricitinib and remdesivir enhances the rate of virus clearance from SARS-CoV-2-positive monocytes. Taken together, baricitinib enhances the antiviral state of monocytes infiltrating the COVID-19 lung, while decreasing the expression of inflammatory mediators, thus limiting the likelihood of a cytokine storm and ensuing acute respiratory distress syndrome.

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摘要：新型冠状病毒肺炎（COVID-19）患者在新型冠状病毒（SARS-CoV-2）复制初期通常无明显临床症状，但在病毒清除、血液单核细胞浸润气道后，可出现严重免疫病理损伤。对重症COVID-19患者的支气管肺泡灌洗液（bronchoalveolar lavage fluid）分析显示，肺浸润单核细胞高表达编码炎症介质的mRNA，包括CXCL8与白细胞介素1β（IL-1β），且携带SARS-CoV-2转录本。为深入探究该病理过程，本研究构建感染与炎症相关的小气道模型：原代人血液单核细胞跨经被SARS-CoV-2感染的分化人肺上皮细胞迁移。浸润的单核细胞可从上皮细胞获取SARS-CoV-2，并上调包括CXCL8、IL-1β在内的炎症介质的表达与分泌，该现象与体内实验数据相符。JAK1/2抑制剂巴瑞替尼（baricitinib）最初与抗病毒药物瑞德西韦（remdesivir）联合使用时，获美国食品药品监督管理局（FDA）紧急使用授权用于治疗COVID-19，近期也获批作为单一疗法。为探究巴瑞替尼单用或与瑞德西韦联用改善疾病预后的潜在机制，本研究利用该模型对肺上皮细胞与浸润单核细胞的病毒载量、基因表达及炎症介质分泌进行表征。实验结果与预期相符：瑞德西韦可降低上皮细胞与单核细胞内的病毒载量；巴瑞替尼则可增强单核细胞的抗病毒信号通路，并下调特定炎症介质的表达。巴瑞替尼与瑞德西韦联用可加快SARS-CoV-2阳性单核细胞的病毒清除速率。综上，巴瑞替尼可增强浸润重症COVID-19肺部的单核细胞的抗病毒状态，同时下调炎症介质的表达，从而降低细胞因子风暴与后续急性呼吸窘迫综合征发生的风险。