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A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics.
Nat Biomed Eng. 2021 May 03 [Online ahead of print]NB

Abstract

The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.

Authors+Show Affiliations

Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.Department of Cell Biology, Harvard Medical School, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. Center on Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Department of Cell Biology, Harvard Medical School, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. don.ingber@wyss.harvard.edu. Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. don.ingber@wyss.harvard.edu. Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA, USA. don.ingber@wyss.harvard.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33941899

Citation

Si, Longlong, et al. "A Human-airway-on-a-chip for the Rapid Identification of Candidate Antiviral Therapeutics and Prophylactics." Nature Biomedical Engineering, 2021.
Si L, Bai H, Rodas M, et al. A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. Nat Biomed Eng. 2021.
Si, L., Bai, H., Rodas, M., Cao, W., Oh, C. Y., Jiang, A., Moller, R., Hoagland, D., Oishi, K., Horiuchi, S., Uhl, S., Blanco-Melo, D., Albrecht, R. A., Liu, W. C., Jordan, T., Nilsson-Payant, B. E., Golynker, I., Frere, J., Logue, J., ... Ingber, D. E. (2021). A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-021-00718-9
Si L, et al. A Human-airway-on-a-chip for the Rapid Identification of Candidate Antiviral Therapeutics and Prophylactics. Nat Biomed Eng. 2021 May 3; PubMed PMID: 33941899.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. AU - Si,Longlong, AU - Bai,Haiqing, AU - Rodas,Melissa, AU - Cao,Wuji, AU - Oh,Crystal Yuri, AU - Jiang,Amanda, AU - Moller,Rasmus, AU - Hoagland,Daisy, AU - Oishi,Kohei, AU - Horiuchi,Shu, AU - Uhl,Skyler, AU - Blanco-Melo,Daniel, AU - Albrecht,Randy A, AU - Liu,Wen-Chun, AU - Jordan,Tristan, AU - Nilsson-Payant,Benjamin E, AU - Golynker,Ilona, AU - Frere,Justin, AU - Logue,James, AU - Haupt,Robert, AU - McGrath,Marisa, AU - Weston,Stuart, AU - Zhang,Tian, AU - Plebani,Roberto, AU - Soong,Mercy, AU - Nurani,Atiq, AU - Kim,Seong Min, AU - Zhu,Danni Y, AU - Benam,Kambez H, AU - Goyal,Girija, AU - Gilpin,Sarah E, AU - Prantil-Baun,Rachelle, AU - Gygi,Steven P, AU - Powers,Rani K, AU - Carlson,Kenneth E, AU - Frieman,Matthew, AU - tenOever,Benjamin R, AU - Ingber,Donald E, Y1 - 2021/05/03/ PY - 2020/12/31/received PY - 2021/03/19/accepted PY - 2021/5/4/entrez PY - 2021/5/5/pubmed PY - 2021/5/5/medline JF - Nature biomedical engineering JO - Nat Biomed Eng N2 - The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential. SN - 2157-846X UR - https://www.unboundmedicine.com/medline/citation/33941899/A_human-airway-on-a-chip_for_the_rapid_identification_of_candidate_antiviral_therapeutics_and_prophylactics. L2 - https://doi.org/10.1038/s41551-021-00718-9 DB - PRIME DP - Unbound Medicine ER -
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