Baricitinib Attenuates the Proinflammatory Phase of COVID-19 Driven by Lung-Infiltrating Monocytes

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 expressed high mRNA levels encoding inflammatory mediators, including CXCL8 and IL-1s, and contained SARS-CoV-2 transcripts. To study this process in more depth, we developed a novel organotypic model whereby primary human blood monocytes are transmigrated across a differentiated human lung epithelium infected by SARSCoV-2. Infiltrating monocytes acquired SARS-CoV-2 from the epithelium and upregulated expression and secretion of inflammatory mediators including CXCL8 and IL-1s, 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 leveraged this model to characterize viral burden, gene expression and inflammatory mediator secretion by lung epithelial cells and infiltrating monocytes. As expected, remdesivir decreased viral burden in both the epithelium and monocytes, while baricitinib enhanced antiviral signaling and decreased specific inflammatory mediators in monocytes. Combined use of baricitinib and remdesivir enhanced 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 (ARDS). Funding: This study was supported by NSF EAGER award 2032273 (to RT, RFS and KZ) and Woodruff Health Science Center COVID-19 CURE award (to RT, RFS, KZ, MB and VS). RFS is also funded in part by NIH grant R01MH116695. We thank Dr. Matt Frieman (University of Maryland) for sharing primer sequences targeting the N-subgenome of SARS-CoV-2. We thank Dalia Gulick and Gregory Gibson (Georgia Tech) for running the monocyte cDNA samples for multiplexed qRT-PCR. SARS-CoV-2, Isolate USA-WA1/2020 was obtained from BEI Resources, Manassas, VA. Declaration of Interests: RFS is the inventor of the use of baricitinib for coronavirus infections and receives royalties from Eli Lilly and Company. His conflict of interest has been reviewed and approved by Emory University. All other authors have declared that no conflict of interest exists.