Team Leader (MOL)

N.N. (TBA)
Postdoc

Team (MOL)

Dr. Pawel Zmora
Postdoc
Mandy Bachmann
PhD Student

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Milena Wasik
PhD Student

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Sascha Young Kupke
PhD Student

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Nancy Wynserski
Technical Assistant

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Additional Information

Collaborations:

Prof. Dr.-Ing. Achim Kienle, Otto von Guericke University, Magdeburg, Germany

Prof. Dr. Thomas Meyer and Dr. Alexander Karlas, MPI for Infection Biology, Berlin, Germany

Dr. Hansjörg Hauser and Dr. Dagmar Wirth, Helmholtz Centre for Infection Research, Braunschweig, Germany

Prof. Nigel Dimmock and Prof. Andrew Easton, Warwick University, United Kingdom

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 cell culture-based vaccine 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 bottlenecks for virus replication and to develop strategies to increase the cell-specific virus yield. For instance, we genetically modify host cells by overexpression or knockdown of cellular genes that were identified in genome-wide RNA interference studies to affect influenza virus replication. We also address the question how important cellular defense mechanisms are for the yield in cell culture-based vaccine production. In addition, the quality of seed virus stocks can have a significant impact on process yields since so called defective interfering viruses impede the propagation of infectious virus particles. Yet, defective interfering viruses can also be used as a tool to study virus replication.  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 characterize the requirements for highly efficient production processes. In particular, we observed that the majority of individual infected cells is non-productive or releases only 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 vaccine manufacturing by the targeted design of cell lines and vaccine virus strains.

References

  • Heldt F.S., Kupke S.Y., Dorl S., Reichl U., Frensing T. (2015) Single-cell analysis and stochastic modeling unveil large cell-to-cell variability in influenza A virus infection. Nature Communications (accepted)
  • Frensing T. (2015) Defective interfering viruses and their impact on vaccines and viral vectors. Biotechnology Journal DOI: 10.1002/biot.201400429
  • Frensing T.*, Pflugmacher A. * , Bachmann M., Peschel B., Reichl U. (2014) 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):8999-9008 (*contributed equally)
  • Frensing T.*, Heldt F.S.*, Pflugmacher A., Behrend I., Jordan I., Flockerzi D., Genzel Y., Reichl U. (2013) Continuous influenza virus production in cell culture shows a periodic accumulation of defective interfering particles. PLOS ONE. 8(9):e72288 (*contributed equally)
  • Heldt F.S., Frensing T., Pflugmacher A., Gröpler R., Peschel B., Reichl U. (2013) Multiscale modeling of influenza A virus infection supports the development of direct-acting antivirals. PLOS Computational Biology. 9(11):e1003372
  • Heldt F.S., Frensing T., Reichl U. (2012) Modeling the intracellular dynamics of influenza virus replication to understand the control of viral RNA synthesis. Journal of Virology, 86(15):7806-17
  • Seitz C., Isken B., Heynisch B., Rettkowski M., Frensing T., Reichl U. (2012) Trypsin promotes efficient influenza vaccine production in MDCK cells by interfering with the antiviral host response, Applied Microbiology and Biotechnology. 93(2): 601-11
  • Frensing T., Seitz C., Heynisch B., Patzina C., Kochs G., Reichl U. (2011) Efficient influenza B virus propagation due to deficient interferon-induced antiviral activity in MDCK cells. Vaccine, 29(41): 7125-9
  • Seitz C.*, Frensing T.*, Höper D., Kochs G., Reichl U. (2010) High yields of influenza A virus in MDCK cells are promoted by an insufficient IFN-induced antiviral state. Journal of General Virology, 91(Pt 7): 1754-63 (* contributed equally)
  • Heynisch B., Frensing T., Heinze K., Seitz C., Genzel Y., Reichl U. (2010) Differential activation of host cell signalling pathways through infection with two variants of influenza A/PuertoRico/8/34 (H1N1) in MDCK cells, Vaccine, 28(51):8210-8
 
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