High-throughput human primary cell-based airway model for evaluating influenza, coronavirus, or other respiratory viruses in vitro

Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive p...

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Bibliographic Details
Published in:	Scientific reports Vol. 11; no. 1; p. 14961
Main Authors:	Gard, A. L., Luu, R. J., Miller, C. R., Maloney, R., Cain, B. P., Marr, E. E., Burns, D. M., Gaibler, R., Mulhern, T. J., Wong, C. A., Alladina, J., Coppeta, J. R., Liu, P., Wang, J. P., Azizgolshani, H., Fezzie, R. Fennell, Balestrini, J. L., Isenberg, B. C., Medoff, B. D., Finberg, R. W., Borenstein, J. T.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 22-07-2021 Nature Publishing Group Nature Portfolio
Subjects:	639/166/985 692/699/255/2514 ACE2 Angiotensin-converting enzyme 2 Animal models Antiviral agents Antiviral Agents - pharmacology Bronchi - cytology Bronchi - virology Cell culture Cell Culture Techniques - instrumentation Cell Line Cell lines Coronaviridae Coronavirus - drug effects Coronavirus Infections - drug therapy Coronavirus Infections - virology Coronaviruses COVID-19 COVID-19 - virology COVID-19 Drug Treatment Drug development Epithelial cells Equipment Design Global economy High-Throughput Screening Assays - instrumentation Humanities and Social Sciences Humans Infections Influenza Influenza A Influenza A virus - drug effects Influenza, Human - drug therapy Influenza, Human - virology Microbial Sensitivity Tests - instrumentation Microfluidic Analytical Techniques - instrumentation multidisciplinary Pandemics Public health Respiratory Mucosa - cytology Respiratory Mucosa - virology Respiratory tract Respiratory Tract Infections - drug therapy Respiratory Tract Infections - virology SARS-CoV-2 - drug effects Science Science (multidisciplinary) Severe acute respiratory syndrome coronavirus 2 Spike protein Viral infections Viruses
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Summary:	Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air–liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-021-94095-7