Send to

Choose Destination
PLoS Comput Biol. 2019 Apr 11;15(4):e1006944. doi: 10.1371/journal.pcbi.1006944. eCollection 2019 Apr.

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.

Author information

Department of Bioprocess Engineering, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Research Group Model Systems for Infection and Immunity, Helmholtz Center for Infection Research, Braunschweig, Germany.
Division of Experimental Hematology, Medical University Hannover, Hannover, Germany.
Department of Gene Regulation and Differentiation, Helmholtz Center for Infection Research, Braunschweig, Germany.
Chair of Bioprocess Engineering, Faculty of Process and Systems Engineering, Otto von Guericke University, Magdeburg, Germany.


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.

Free full text

Conflict of interest statement

The authors have declared that no competing interests exist.

Supplemental Content

Full text links

Icon for Public Library of Science
Loading ...
Support Center