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Author Notes:

B.D., K.Z., D.M.G., S.L.G., K.M., M.A., J.L., V.D.G., J.K., D.E., and J.Y. performed and analyzed experiments. M.B., V.S., and E.G. provided conceptualization and input for the work. B.D., K.Z., D.M.G., R.T., and R.F.S. wrote the original manuscript. R.F.S. and R.T. conceptualized the experiments. All authors reviewed and edited the manuscript.

R.F.S. is the inventor of the use of baricitinib for coronavirus infections and receives royalties from Eli Lilly. His conflict of interest has been reviewed and approved by Emory University. All other authors have declared that no conflict of interest exists. Contents within this manuscript are included in patent USPTO 10670594.

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Research Funding:

This study was supported by NSF EAGER award 2032273 (to R.T., R.F.S., and K.Z.) and a Woodruff Health Science Center COVID-19 CURE award (to R.T., R.F.S., K.Z., M.B., and V.S.). R.F.S. 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, Naima Djeddar, and Gregory Gibson (Georgia Tech) for assisting with multiplexed qRT-PCR. Research reported in this publication was supported in part by the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children's Healthcare of Atlanta. The graphical abstract was generated in Biorender. SARS-CoV-2 isolate USA-WA1/2020 was obtained from BEI Resources, Manassas, VA.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • INFLAMMATION
  • INNATE

Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes

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Journal Title:

CELL REPORTS

Volume:

Volume 39, Number 11

Publisher:

, Pages 110945-110945

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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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© 2022 The Author(s)

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