The Role of IFN and other Host Cell Defense Mechanisms in Influenza Vaccine Production


The annual appearance of new influenza virus strains is a challenge in Influenza vaccine production. New virus strains may not only differ in virulence in vivo but also in their replication characteristics in vaccine production processes. In consequence, significant efforts are necessary annually to adapt process conditions to these new virus strains.
A potentially limiting factor known to vary between different Influenza strains and strongly affecting both virulence and replication efficiency is viral interference with the host's immune response. Even on single cell level, as in a vaccine production process, several host cell responses are known which might potentially limit virus replication. Probably the most important player in this innate immune response is the type I interferon (IFN) system (Fig. 1).

Fig.1: Activation of Interferon induced antiviral state by influenza virus replication [1]. In response to viral RNA cells start to produce and secrete type I IFNs. These cytokines activate IFN receptors (IFNAR) of other cells, which results in the induction of the JAK/STAT pathway, initiating the transcriptional activation of ISRE (IFN stimulated response element) controlled genes. These include several genes with antiviral activity. In addition, the IFN-stimulated up-regulation of IRF7 further enhances production of IFNs. As a consequence of this positive feedback loop even small stimuli are sufficient for a strong activation of the IFN-signaling.

When sensing viral RNAs, cells start to produce and release type I interferons, which bind to surface receptors in an auto- and paracrine manner. As a consequence, an antiviral state is induced, characterized by the expression of several IFN stimulated genes having antiviral activity, e.g. Mx proteins (myxovirus resistance proteins). However, Influenza has the potential to counteract the establishment of this antiviral state by its NS1 protein. Furthermore, some virus strains can escape the antiviral state by fast replication.
The effect of the IFN-induced antiviral state on influenza virus replication is known vary for differenct cell lines and influenza virus strains. Examples can be found for strong inhibition or even prevention of influenza virus replication by IFN-signalling. Also, significant increases in virus yield (up to 2 logs) by inhibiting different components of the IFN-system have been reported. But there are also several studies indicating that the replication of some influenza virus strains is not or only slightly affected by the IFN induced antiviral state.

Aim of the project

The aim of this project is to characterize the influence of host cell defence on virus replication dynamics and yield for an MDCK based influenza vaccine production process. Initially, the focus will be on the IFN-system. The interactions of different virus strains with host cell defense will be analyzed on molecular level under process conditions [2]. Depending on these results, options will be evaluated to prevent the establishment of an IFN-induced antiviral state in MDCK cells [3]. We hope that by controlling host cell defense, the yield of influenza vaccine production processes can significantly be increased [4].


[1] Figure 1 was adapted and modified from Haller O., Kochs G., Weber F., 2005. The interferon response circuit: Induction and suppression by pathogenic viruses. Virology 344 (2006) 119 - 130
[2] 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/PR/8/34 (H1N1) in MDCK cells. Vaccine.28, 8210-8218.
[3] Seitz, C., Frensing, T., Hoper, D., Kochs, G. & Reichl, U., 2010. High yields of influenza A virus in Madin-Darby canine kidney cells are promoted by an insufficient interferon-induced antiviral state. J Gen Virol 91, 1754-1763.
[4] Seitz C., Isken B., Heynisch B., Rettkowski M., Frensing T., Reichl U. (2011) Trypsin promotes efficient influenza vaccine production in MDCK cells by interfering with the antiviral host response, Applied Microbiology and Biotechnology in press

Related projects

Analysis of Virus-induced Signaling Pathways in Mammalian Host Cell Systems
Flow Cytometric Analysis of Virus-induced Apoptosis and Virus Replication
Biomolecular Analysis of Dynamic Interactions between Influenza Viruses and Host Cells

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