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

摘要

Author summary Influenza viruses depend on cellular functions at every step of their life cycle and a comprehensive picture of virus-host cell interactions is the key to understand influenza disease and establish antiviral therapies. Over the past decade, this was supported by numerous screening approaches, which identified cellular factors relevant for intracellular virus replication. Ideally, the identification of pro-viral targets should also support the generation of cell lines to optimize influenza virus replication in cell cultures. As a first approach towards this goal, we used a mathematical model to identify mechanisms of viral growth that would be most promising targets for host cell factor manipulation. Based on predictions, we expected a significant increase in virus production if RNA synthesis and virus assembly and virus budding were perturbed, which was partially confirmed by cell lines overexpressing single and multiple selected host cell factors. However, the cell-specific productivity of engineered cell lines was not improved significantly and, according to model-based analysis, this can be explained by adverse changes in kinetic parameters of intracellular replication steps. Finally, results indicate that screening approaches should focus on late time points post infection to identify targets for engineering of cell lines that support high-yield vaccine production processes.