Multiscale modeling of influenza A virus replication in cell cultures predicts infection dynamics for highly different infection conditions

Abstract

Influenza A viruses (IAV) are commonly used to infect animal cell cultures for research purposes and vaccine production. Their replication is influenced strongly by the multiplicity of infection (MOI), which ranges over several orders of magnitude depending on the respective application. So far, mathematical models of IAV replication have paid little attention to the impact of the MOI on infection dynamics and virus yields. To address this issue, we extended an existing model of IAV replication in adherent MDCK cells with kinetics that explicitly consider the time point of cell infection. This modification does not only enable the fitting of high MOI measurements, but also the successful prediction of viral release dynamics of low MOI experiments using the same set of parameters. Furthermore, this model allows the investigation of defective interfering particle (DIP) propagation in different MOI regimes. The key difference between high and low MOI conditions is the percentage of infectious virions among the total virus particle release. Simulation studies show that DIP interference at a high MOI is determined exclusively by the DIP content of the seed virus while, in low MOI conditions, it is predominantly controlled by the de novo generation of DIPs. Overall, the extended model provides an ideal framework for the prediction and optimization of cell culture-derived IAV manufacturing and the production of DIPs for therapeutic use.

The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV

“…Similar effects have been described for the Aureococcus anophagefferens -Brown Tide virus (AaV) where a saturation of infection was observed at a MOI of 8 [75]. Furthermore, a recent study modeling the replication of Influenza A virus in cell culture demonstrated that at high MOIs the number of defective interfering particles (DIPs) present in the inoculum plays a greater role [76]. DIPs have been shown to compete with intact virus particles for cellular resources, and therefore may significantly reduce viral replication [77].…”

Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

“…Nevertheless, a few systematic large-scale experiments aimed at looking at the entire process of viral infection in model organisms have been performed [303], and we predict that they will lead the way to wider uses of the 'alternative system' that may ultimately lead to a deeper understanding of the virus and its pathogenicity and to a better treatment or vaccination. While the traditional models of influenza have their advantages and usefulness, we believe that the alternative models must be used in parallel.…”

Altered Gene Expression in Human Brain Microvascular Endothelial Cells in Response to the Infection of Influenza H1N1 Virus

“…Expression was normalized to the β-actin reference gene levels, while relative expression was calculated using the comparative method of 2-∆∆Ct. The virus replication curve was quanti ed and normalized by using virus copy numbers (Rüdiger et al 2019;Frensing et al 2016). Changes in gene expression were examined by t-test, and p < 0.05 was considered signi cant.…”