Journal
CELL REPORTS
Volume 39, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.110945
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Funding
- NSF EAGER award [2032273]
- Woodruff Health Science Center COVID-19 CURE award
- NIH [R01MH116695]
- Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children's Healthcare of Atlanta
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [2032273] Funding Source: National Science Foundation
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This study reveals the role of lung-infiltrating monocytes in COVID-19 pathogenesis and highlights their significance as a therapeutic target. The researchers found that monocytes acquire SARS-CoV-2 from lung epithelial cells and upregulate inflammatory mediator expression and secretion. Combination therapy with baricitinib and remdesivir enhances antiviral signaling and viral clearance while reducing the secretion of proneutrophilic mediators associated with acute respiratory distress syndrome.
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 proneutrophilic 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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