BARICITINIB ATTENUATES THE PROINFLAMMATORY PHASE OF COVID-19 DRIVEN BY LUNG-INFILTRATING MONOCYTES
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Supplementary Tables 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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Lead Contact: Requests for further information should be directed to and will be fulfilled by the lead contact, Rabindra Tirouvanziam (tirouvanziam@emory.edu) Data and Code availability: RNA-seq data has been deposited at GEO and are available as of the date of publication. It can be accessed under accession: GSE186460 Please refer to the same-named publication from Cell Reports