OpenLB
Open Library of Bioscience
Advanced Search
Cell reports
06 14, 2022;39 (11): 110945.

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

Brian Dobosh, Keivan Zandi, Diego Moncada Giraldo, Shu Ling Goh, Kathryn Musall, Milagros Aldeco, Julia LeCher, Vincent D Giacalone, Junkai Yang, Devon J Eddins, Manoj Bhasin, Eliver Ghosn, Vikas Sukhatme, Raymond F Schinazi, Rabindra Tirouvanziam
Author Information
  1. Brian Dobosh: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Center for CF and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA, USA.
  2. Keivan Zandi: Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
  3. Diego Moncada Giraldo: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Center for CF and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA, USA.
  4. Shu Ling Goh: Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
  5. Kathryn Musall: Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
  6. Milagros Aldeco: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Center for CF and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA, USA.
  7. Julia LeCher: Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
  8. Vincent D Giacalone: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Center for CF and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA, USA.
  9. Junkai Yang: Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  10. Devon J Eddins: Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  11. Manoj Bhasin: Department of Pediatrics and Department of Biomedical Bioinformatics, Emory University School of Medicine, Atlanta, GA, USA.
  12. Eliver Ghosn: Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  13. Vikas Sukhatme: Department of Medicine and the Morningside Center for Innovative and Affordable Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  14. Raymond F Schinazi: Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
  15. Rabindra Tirouvanziam: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Center for CF and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA, USA. Electronic address: tirouvanziam@emory.edu.
PMID: 35688145 DOI: 10.1016/j.celrep.2022.110945

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.

Keywords

CP: Immunology CP: Microbiology Janus kinase RNA-seq cytokine release syndrome inflammation interferon therapy

References

STAR Protoc. 2021 Oct 21;2(4):100892 [PMID: 34746861]
Arthritis Rheumatol. 2020 Jul;72(7):1059-1063 [PMID: 32293098]
Cell. 2021 Jan 21;184(2):460-475.e21 [PMID: 33278358]
mSphere. 2020 Mar 18;5(2): [PMID: 32188753]
Lancet. 1993 Mar 13;341(8846):643-7 [PMID: 8095568]
Eur Respir J. 2020 Apr 16;55(4): [PMID: 32269085]
Nat Rev Immunol. 2020 Jun;20(6):355-362 [PMID: 32376901]
J Leukoc Biol. 2018 Oct;104(4):665-675 [PMID: 29741792]
PLoS Biol. 2021 Mar 17;19(3):e3001143 [PMID: 33730024]
Nat Biotechnol. 2020 Jul;38(7):789-791 [PMID: 32504046]
Immunol Cell Biol. 2022 May;100(5):352-370 [PMID: 35318736]
IEEE/ACM Trans Comput Biol Bioinform. 2014 Mar-Apr;11(2):375-88 [PMID: 26355784]
Front Immunol. 2020 Jun 05;11:1312 [PMID: 32582222]
Bioinformatics. 2014 Apr 1;30(7):923-30 [PMID: 24227677]
Cell Res. 2021 Jan;31(1):17-24 [PMID: 33262453]
Nat Med. 2020 Jun;26(6):842-844 [PMID: 32398875]
Nat Rev Immunol. 2020 Jul;20(7):397-398 [PMID: 32457522]
Am J Physiol Cell Physiol. 2021 Mar 1;320(3):C279-C281 [PMID: 33502950]
Nat Commun. 2021 Mar 5;12(1):1428 [PMID: 33674591]
J Biol Chem. 2021 Jan-Jun;296:100306 [PMID: 33476648]
Genome Biol. 2014;15(12):550 [PMID: 25516281]
Clin Infect Dis. 2020 Jul 28;71(15):762-768 [PMID: 32161940]
Front Mol Biosci. 2020 Jul 03;7:157 [PMID: 32719810]
Immunol Rev. 2018 Jan;281(1):8-27 [PMID: 29247995]
Front Immunol. 2022 Jan 10;12:746021 [PMID: 35082777]
J Virol. 2020 Sep 15;94(19): [PMID: 32699094]
Nature. 2022 Jun;606(7914):585-593 [PMID: 35483404]
Gigascience. 2021 Feb 16;10(2): [PMID: 33590861]
Lancet Respir Med. 2022 Apr;10(4):327-336 [PMID: 35123660]
Sci Rep. 2019 Feb 27;9(1):2874 [PMID: 30814584]
Med Hypotheses. 2020 Nov;144:109861 [PMID: 32505066]
N Engl J Med. 2021 Mar 4;384(9):795-807 [PMID: 33306283]
Immunology. 2020 Jul;160(3):261-268 [PMID: 32460357]
Bioinformatics. 2013 Jan 1;29(1):15-21 [PMID: 23104886]
Cell Host Microbe. 2020 Jun 10;27(6):883-890.e2 [PMID: 32407669]
J Microbiol Immunol Infect. 2021 Oct;54(5):787-793 [PMID: 34294593]
Int J Mol Sci. 2021 Mar 03;22(5): [PMID: 33802410]
Cell. 2019 Jun 13;177(7):1888-1902.e21 [PMID: 31178118]
Cell. 2020 Sep 17;182(6):1419-1440.e23 [PMID: 32810438]
J Infect Dis. 2020 Nov 9;222(11):1807-1815 [PMID: 32914853]
Cell. 2020 May 28;181(5):1036-1045.e9 [PMID: 32416070]
Cytokine Growth Factor Rev. 2020 Jun;53:25-32 [PMID: 32446778]
Clin Infect Dis. 2020 Sep 12;71(6):1400-1409 [PMID: 32270184]
Annu Rev Virol. 2015 Nov;2(1):573-97 [PMID: 26958929]
Bioinformatics. 2009 Aug 15;25(16):2078-9 [PMID: 19505943]
J Infect Dis. 2021 Aug 2;224(3):395-406 [PMID: 33493287]
N Engl J Med. 2020 Nov 5;383(19):1813-1826 [PMID: 32445440]
Nat Rev Immunol. 2020 Jun;20(6):363-374 [PMID: 32346093]
PLoS Pathog. 2020 May 22;16(5):e1008536 [PMID: 32442210]
EMBO Mol Med. 2020 Aug 7;12(8):e12697 [PMID: 32473600]
Cell. 2020 May 14;181(4):905-913.e7 [PMID: 32333836]
Nature. 2020 Jul;583(7816):459-468 [PMID: 32353859]
Pathogens. 2021 Aug 30;10(9): [PMID: 34578138]

Grants

  1. R01 AI123126/NIAID NIH HHS
  2. R01 MH116695/NIMH NIH HHS

MeSH Term

Azetidines
Humans
Inflammation Mediators
Lung
Monocytes
Purines
Pyrazoles
SARS-CoV-2
Sulfonamides
COVID-19 Drug Treatment

Chemicals

Azetidines
Inflammation Mediators
Purines
Pyrazoles
Sulfonamides
baricitinib
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Word Cloud

Similar Articles

Cited By