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

Supplementary TablesAbstract: 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.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

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

Supplementary TablesAbstract: 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.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV