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High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Viruses in vitro

A.L. Gard, R. Maloney, B.P. Cain, C.R. Miller, R.J. Luu, J.R. Coppeta, P. Liu, J.P. Wang, H. Azizgolshani, R.F. Fezzie, J.L. Balestrini, B.C. Isenberg, R.W. Finberg, View ORCID ProfileJ.T. Borenstein
doi: https://doi.org/10.1101/2020.05.23.112797
A.L. Gard
1Bioengineering Division, Draper, Cambridge MA 02139
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R. Maloney
1Bioengineering Division, Draper, Cambridge MA 02139
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B.P. Cain
1Bioengineering Division, Draper, Cambridge MA 02139
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C.R. Miller
1Bioengineering Division, Draper, Cambridge MA 02139
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R.J. Luu
1Bioengineering Division, Draper, Cambridge MA 02139
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J.R. Coppeta
1Bioengineering Division, Draper, Cambridge MA 02139
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P. Liu
2Department of Medicine, University of Massachusetts Medical School, Worcester MA
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J.P. Wang
2Department of Medicine, University of Massachusetts Medical School, Worcester MA
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H. Azizgolshani
1Bioengineering Division, Draper, Cambridge MA 02139
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R.F. Fezzie
1Bioengineering Division, Draper, Cambridge MA 02139
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J.L. Balestrini
1Bioengineering Division, Draper, Cambridge MA 02139
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B.C. Isenberg
1Bioengineering Division, Draper, Cambridge MA 02139
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R.W. Finberg
2Department of Medicine, University of Massachusetts Medical School, Worcester MA
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J.T. Borenstein
1Bioengineering Division, Draper, Cambridge MA 02139
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  • ORCID record for J.T. Borenstein
  • For correspondence: jborenstein@draper.com
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Abstract

Influenza and other respiratory viruses represent a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as the current COVID-19 crisis. One of the greatest barriers to the development of effective therapeutic agents to treat influenza, coronaviruses, and many other infections of the respiratory tract is the absence of a robust preclinical model. Preclinical studies currently rely on high-throughput, low-fidelity in vitro screening with cell lines and/or low-throughput animal models that often provide a poor correlation to human clinical responses. Here, we introduce a human primary airway epithelial cell-based model integrated into a high-throughput platform where tissues are cultured at an air-liquid interface (PREDICT96-ALI). We present results on the application of this platform to influenza and coronavirus infections, providing multiple readouts capable of evaluating viral infection kinetics and potentially the efficacy of therapeutic agents in an in vitro system. Several strains of influenza A virus are shown to successfully infect the human primary cell-based airway tissue cultured at an air-liquid interface (ALI), and as a proof-of-concept, the effect of the antiviral oseltamivir on one strain of Influenza A is evaluated. Human coronaviruses NL63 (HCoV-NL63) and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for protein priming, and we confirm expression of both in our ALI model. We also demonstrate coronavirus infection in this system with HCoV-NL63, observing sufficient viral propagation over 96 hours post-infection to indicate successful infection of the primary cell-based model. This new capability has the potential to address a gap in the rapid assessment of therapeutic efficacy of various small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 23, 2020.
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High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Viruses in vitro
A.L. Gard, R. Maloney, B.P. Cain, C.R. Miller, R.J. Luu, J.R. Coppeta, P. Liu, J.P. Wang, H. Azizgolshani, R.F. Fezzie, J.L. Balestrini, B.C. Isenberg, R.W. Finberg, J.T. Borenstein
bioRxiv 2020.05.23.112797; doi: https://doi.org/10.1101/2020.05.23.112797
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High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Viruses in vitro
A.L. Gard, R. Maloney, B.P. Cain, C.R. Miller, R.J. Luu, J.R. Coppeta, P. Liu, J.P. Wang, H. Azizgolshani, R.F. Fezzie, J.L. Balestrini, B.C. Isenberg, R.W. Finberg, J.T. Borenstein
bioRxiv 2020.05.23.112797; doi: https://doi.org/10.1101/2020.05.23.112797

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