High-throughput human primary cell-based airway model for evaluating influenza, coronavirus, or other respiratory viruses in vitro
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 22, 2021
- Source ID
- 10.1038/s41598-021-94095-7
Entities
People
- A. L. Gard
- B. D. Medoff
- B. P. Cain
- Brett C. Isenberg
- C. A. Wong
- C. R. Miller
- D. M. Burns
- E. E. Marr
- H. Azizgolshani
- J. Alladina
- J. L. Balestrini
- J. P. Wang
- J. R. Coppeta
- J. T. Borenstein
- Ping Liu
- R. Fennell Fezzie
- R. Gaibler
- R. J. Luu
- R. Maloney
- Robert W. Finberg
- T. J. Mulhern
Organizations
- Defense Advanced Research Projects Agency