Molecular Biology

Molecular Biology

Understanding virus-host cell interactions is not only crucial for the development of new antiviral drugs but can also lead to novel biotechnological strategies for the optimization of vaccine and viral vector production. Thus, the research team “Molecular Biology” of the Bioprocess Engineering department is analyzing the interactions of viruses and their host cells on the molecular level. It is our aim to identify host cell factors essential for the virus life cycle, bottlenecks for virus replication, or viral determinants of efficient spread and pathogenesis. Furthermore, we aiming for the development of strategies to increase cell-specific virus yields. For instance, we genetically modify host cells to overexpress or to silence (with siRNA, shRNA or miRNAs) cellular genes that were identified in genome-wide RNA interference studies to affect influenza A virus (IAV) replication. In addition, we investigate the impact of so-called defective interfering particles on the quality of seed virus and process yields, and explore options to use their induction of antiviral responses for new therapeutic and preventive approaches.

For the analysis of the complex interplay between influenza viruses and their host cells sophisticated analytical methods such as quantitative real-time PCR and imaging cytometry in combination with mathematical modeling are essential. Moreover, single-cell analysis is an important novel tool to study details regarding the design of highly efficient production processes. In particular, we observed that the majority of individual infected cells is non-productive or releases relatively few progeny virions. However, some cells produce very high virus titers. We were able to demonstrate that this high cell-to-cell heterogeneity in influenza virus infection is caused by stochastic fluctuations that are intrinsic to viral replication and by extrinsic noise, which can originate from cellular factors. In conclusion, the detailed investigation of virus replication in production cell lines using state-of-the-art analytical tools and mathematical modeling paves the way to optimize virus production by the targeted design of cell lines and virus strains.

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Heldt, F. S.; Kupke, S. Y.; Dorl, S.; Frensing, T.; Reichl, U.: Single-cell analysis and stochastic modelling unveil large cell-to-cell variability in influenza A virus infection. Nature Communications 6, 8938 (2015)
Frensing, T.: Defective interfering viruses and their impact on vaccines and viral vectors. Biotechnology Journal 10 (5), pp. 681 - 689 (2015)
Frensing, T.; Pflugmacher, A.; Bachmann, M.; Peschel, B.; Reichl, U.: Impact of defective interfering particles on virus replication and antiviral host response in cell culture-based influenza vaccine production. Applied Microbiology and Biotechnology 98 (21), pp. 8999 - 9008 (2014)
Frensing, T.; Heldt, S.; Pflugmacher, A.; Behrendt, I.; Jordan, I.; Flockerzi, D.; Genzel, Y.; Reichl, U.: Continuous Influenza Virus Production in Cell Culture Shows a Periodic Accumulation of Defective Interfering Particles. PLoS One 8 (9), p. e72288 (2013)
Heldt, S.; Frensing, T.; Pflugmacher, A.; Gröpler, R.; Peschel, B.; Reichl, U.: Multiscale Modeling of Influenza A Virus Infection Supports the Development of Direct-Acting Antivirals. PLoS Computational Biology 9 (11), p. e1003372 (2013)
Heldt, F. S.; Frensing, T.; Reichl, U.: Modeling the intracellular dynamics of influenza virus replication to understand the control of viral RNA synthesis. Journal of Virology 86 (15), pp. 7806 - 7817 (2012)
Seitz, C.; Isken, B.; Heynisch, B.; Rettkowski, M.; Frensing, T.; Reichl, U.: Trypsin promotes efficient influenza vaccine production in MDCK cells by interfering with the antiviral host response. Applied Microbiology and Biotechnology 93 (2), pp. 601 - 611 (2012)
Frensing, T.; Seitz, C.; Heynisch, B.; Patzina, C.; Kochs, G.; Reichl, U.: Efficient influenza B virus propagation due to deficient interferon-induced antiviral activity in MDCK cells. Vaccine 29 (41), pp. 7125 - 7129 (2011)
Seitz, C.; Frensing, T.; Höper, D.; Kochs, G.; Reichl, U.: High yields of Influenza A virus in MDCK cells are promoted by an insufficient IFN-induced antiviral state. Journal of General Virology 91 (7), pp. 1754 - 1763 (2010)
Heynisch, B.; Frensing, T.; Heinze, K.; Seitz, C.; Genzel, Y.; Reichl, U.: Differential activation of host cell signaling pathways through infection with two variants of influenza A /Puerto Rico /8/34 (H1N1) in MDCK cells. Vaccine 28 (51), pp. 8210 - 8218 (2010)

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