A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics

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-ai...

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Published inNature biomedical engineering Vol. 5; no. 8; pp. 815 - 829
Main Authors Si, Longlong, Bai, Haiqing, Rodas, Melissa, Cao, Wuji, Oh, Crystal Yuri, Jiang, Amanda, Moller, Rasmus, Hoagland, Daisy, Oishi, Kohei, Horiuchi, Shu, Uhl, Skyler, Blanco-Melo, Daniel, Albrecht, Randy A., Liu, Wen-Chun, Jordan, Tristan, Nilsson-Payant, Benjamin E., Golynker, Ilona, Frere, Justin, Logue, James, Haupt, Robert, McGrath, Marisa, Weston, Stuart, Zhang, Tian, Plebani, Roberto, Soong, Mercy, Nurani, Atiq, Kim, Seong Min, Zhu, Danni Y., Benam, Kambez H., Goyal, Girija, Gilpin, Sarah E., Prantil-Baun, Rachelle, Gygi, Steven P., Powers, Rani K., Carlson, Kenneth E., Frieman, Matthew, tenOever, Benjamin R., Ingber, Donald E.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.08.2021
Nature Publishing Group
Subjects
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Amodiaquine
Animals
Antiviral agents
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Cell Line
Cell lines
Coronaviruses
COVID-19 - diagnosis
COVID-19 - virology
COVID-19 Drug Treatment
COVID-19 Testing - methods
Cricetinae
Cytokines
Drug development
Drug dosages
Drugs
Endothelium
Epithelium
Female
Green Fluorescent Proteins
Hamsters
Humans
Hydroxychloroquine
Immune system
Immunosuppressive agents
Influenza A
Lab-On-A-Chip Devices
Male
Microfluidics
Oseltamivir
Pandemics
Respiratory diseases
Respiratory tract
SARS-CoV-2 - drug effects
Severe acute respiratory syndrome coronavirus 2
Viral diseases
Virulence
Virus Internalization - drug effects
Windows (intervals)
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Summary: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. A microfluidic bronchial-airway-on-a-chip lined by human bronchial-airway epithelium and pulmonary endothelium can be used to rapidly identify antiviral therapeutics and prophylactics with repurposing potential.
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These authors contributed equally.
Current address: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Contributors. L.S., H.B., and D.E.I. conceived this study, and D.E.I. developed the overall collaborative discovery pipeline. L.S. and H.B. performed and analyzed experiments with other authors assisting with experiments and data analysis. M.B. assisted with cytokine detection assay. W.C., C.O., A.J., A.N., and S.K. assisted with RNA extraction and qRT-PCR. D.Z. and G.G. assisted in the characterization of CoV-2pp. S.P.G. assisted in the mass spectrometry experiments. R.K.P. assisted in statistical analysis. R.P. and S.E.G. coordinated experiments and managed the project progress. R.M., D.H., K.O., S.H., T.J., R.A.A., J.F., I.G., and B.R.t. tested the efficacy of drugs against native SARS-CoV-2 in hamster SARS-CoV-2 infection model. K.C. coordinated the hamster PK studies and assisted in the design of dosing and drug formulation in the hamster efficacy studies. J.L., R.H., M.M., S.W., and M.F. tested the activity of amodiaquine and desethylamodiaquine against native SARS-CoV-2 in Vero E6 cells. L.S., H.B. and D.E.I. wrote the manuscript with all authors providing feedback.
ISSN:2157-846X
2157-846X
DOI:10.1038/s41551-021-00718-9