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Invasion and Replication Strategies of Pathogenes
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SP B12

Relevance of Virus Induced Host Functions
for the Replication of Influenza Viruses



Dr. Stephan Pleschka
Institut für Med. Virologie (FB 11), Justus-Liebig-Universität, Gießen



Summary

Influenza viruses are a continuous and severe global threat to mankind and many animal species. The re-emerging disease gives rise to thousands of deaths and enormous economic losses each year. The devastating results of the recent outbreaks of avian influenza (Bird-Flu) in Europe and south East Asia demonstrate this immanent danger. Not only fowl is highly endangered, also humans can be infected by this pathogen, which can lead to a high mortality rate. The threat of a man-to-man transmission of these highly pathogenic strains has steadily risen, which makes the scenario of a new pandemic more likely. The currently incompletely studied dependence of influenza viruses from cellular “services” for their propagation provides an approach to new targets against the viral replication.
In contrast to most RNA-viruses influenza viruses replicate their genome in the nucleus of the infected cell. Within this cellular compartment new copies of the viral genome as well as viral mRNA are made. Viral envelope proteins are post-translationally modified and processed and finally embedded in the cell membrane. RNA-associated viral proteins return to the nucleus to support viral replication and transcription. Replication-active ribonucleoprotein-complexes (RNPs) have to be exported from the nucleus in the late phase of the replication cycle to ensure that sufficient genetic material is provided for the generation of new viral particles at the cell membrane. This nuclear RNP-export has therefore to be specifically regulated to provide enough RNPs for viral genome replication and transcription on one hand, and - on the other hand - enough RNPs in the cytoplasm at the correct time point to be packaged into new virions. We could show that the virus induced activation of the Raf/MEK/ERK (MAPK)-signal cascade is essential for effective nuclear RNP-export and that influenza viruses can not adapt to an inhibition of the cellular service. This demonstrates, that RNP-export of influenza viruses is indeed a signal regulated process and that the viruses are dependent on this mechanism for efficient nuclear export of their genome. At the moment it is unknown by which viral factors or mechanisms the signal cascade is being activated and which processes, like phosphorylation of viral or cellular components, regulate the nuclear export.
Results from last grant period about the definition of viral and cellular factors/mechanisms of virus induced MAPK-activation have shown, that in this context membrane accumulation of the haemagglutinin (HA) and its interaction with “Lipid-Rafts” is important. As it can not be excluded, that further membrane resident viral proteins, the dsRNA and the RNPs are also involved in this induction, we want to investigate a possible role of these components in MAPK-activation. Furthermore hints, that calcium dependent PKCs might play a role in signal transmission from the membrane to the MAPK-cascade will be investigated.
The final substrate of the virus induced MAPK-cascade is still unknown. As the MAPK-activity influences the intra-cellular localization of the viral RNPs, NP, which is known to be a phosphorylated protein, could be a target. Analysis so far point at a functional role of the MAPK-cascade for NP-phosphorylation and RNP-localization.


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