Show simple item record

dc.contributor.authorLaske, Tanja
dc.contributor.authorBachmann, Mandy
dc.contributor.authorDostert, Melanie
dc.contributor.authorKarlas, Alexander
dc.contributor.authorWirth, Dagmar
dc.contributor.authorFrensing, Timo
dc.contributor.authorMeyer, Thomas F
dc.contributor.authorHauser, Hansjörg
dc.contributor.authorReichl, Udo
dc.date.accessioned2019-06-12T08:45:32Z
dc.date.available2019-06-12T08:45:32Z
dc.date.issued2019-01-01
dc.identifier.citationPLoS Comput Biol. 2019 Apr 11;15(4):e1006944. doi: 10.1371/journal.pcbi.1006944 eCollection 2019 Apr.en_US
dc.identifier.issn1553-7358
dc.identifier.pmid30973879
dc.identifier.doi10.1371/journal.pcbi.1006944
dc.identifier.urihttp://hdl.handle.net/10033/621813
dc.description.abstractThe 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.en_US
dc.language.isoenen_US
dc.publisherPLOSen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleModel-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.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalPLOS computational biologyen_US
refterms.dateFOA2019-06-12T08:45:33Z
dc.source.journaltitlePLoS computational biology


Files in this item

Thumbnail
Name:
Laske et al.pdf
Size:
3.367Mb
Format:
PDF
Description:
Open Access publication

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-ShareAlike 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International