Model-based analysis of influenza A virus replication in genetically engineered cell lines elucidates the impact of host cell factors on key kinetic parameters of virus growth.
A549 Cells
Active Transport, Cell Nucleus
Animals
Computational Biology
Computer Simulation
Dogs
Genetic Engineering
Genome, Viral
Host Microbial Interactions
/ genetics
Humans
Influenza A virus
/ genetics
Influenza Vaccines
/ biosynthesis
Kinetics
Madin Darby Canine Kidney Cells
Models, Biological
Virus Replication
/ genetics
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
14
09
2018
accepted:
11
03
2019
revised:
23
04
2019
pubmed:
12
4
2019
medline:
29
5
2019
entrez:
12
4
2019
Statut:
epublish
Résumé
The best measure to limit spread of contagious diseases caused by influenza A viruses (IAVs) is annual vaccination. The growing global demand for low-cost vaccines requires the establishment of high-yield production processes. One possible option to address this challenge is the engineering of novel vaccine producer cell lines by manipulating gene expression of host cell factors relevant for virus replication. To support detailed characterization of engineered cell lines, we fitted an ordinary differential equation (ODE)-based model of intracellular IAV replication previously established by our group to experimental data obtained from infection studies in human A549 cells. Model predictions indicate that steps of viral RNA synthesis, their regulation and particle assembly and virus budding are promising targets for cell line engineering. The importance of these steps was confirmed in four of five single gene overexpression cell lines (SGOs) that showed small, but reproducible changes in early dynamics of RNA synthesis and virus release. Model-based analysis suggests, however, that overexpression of the selected host cell factors negatively influences specific RNA synthesis rates. Still, virus yield was rescued by an increase in the virus release rate. Based on parameter estimations obtained for SGOs, we predicted that there is a potential benefit associated with overexpressing multiple host cell genes in one cell line, which was validated experimentally. Overall, this model-based study on IAV replication in engineered cell lines provides a step forward in the dynamic and quantitative characterization of IAV-host cell interactions. Furthermore, it suggests targets for gene editing and indicates that overexpression of multiple host cell factors may be beneficial for the design of novel producer cell lines.
Identifiants
pubmed: 30973879
doi: 10.1371/journal.pcbi.1006944
pii: PCOMPBIOL-D-18-01595
pmc: PMC6478349
doi:
Substances chimiques
Influenza Vaccines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1006944Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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