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Invasion and Replication Strategies of Pathogenes
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SP B4

Replication and cytopathogenicity of pestiviruses



Institut für Virologie (FB 10), Justus-Liebig-Universität, Gießen
Tautz Research Group

Summary

For the pestivirus bovine viral diarrhea virus (BVDV) cytopathogenic (cp) and noncytopathogenic (noncp) strains can be distinguished in cell culture. Only the noncp strains have the capability to establish in cattle lifelong persistent infections. Enhanced viral RNA synthesis and permanent expression of viral non-structural protein 3 (NS3) are correlated with the cytopathogenicity of BVDV. NS3 is an essential component of the viral replicase which can not be functionally replaced by uncleaved NS2-3. In general, the release of NS3 by cleavage of NS2-3 is catalyzed by an autoprotease residing in NS2. Surprisingly, in noncp BVDV infected cells efficient cleavage of NS2-3 is restricted to the first hours after infection; thereby viral RNA replication is downregulated at later time points. According to our data the cellular J-domain protein Jiv (J-domain protein interacting with viral protein) represents an essential cofactor of the viral NS2 protease. In noncp BVDV infected cells the intracellular amount of Jiv limits the number of released NS3 molecules and thereby the number of active replication complexes. When this limitation is abrogated, e.g. by an increase of the intracellular Jiv level, also noncp BVDV strains become cytopathogenic. cp BVDV strains generate NS3 independent of cellular Jiv by a variety of different mechanisms depending in each case on the specific genomic alterations present in the respective genome.
In conclusion, our data demonstrate that the regulation of the viral NS2 autoprotease by a cellular cofactor is crucial for the capability of BVDV to establish lifelong persistent infection.

Current topics:

(i) Jiv and its fragment Jiv90 can induce NS2-3 cleavage in the context of NS2-3, as well as in trans. Analysis of Jiv / NS2 interaction revealed two Jiv binding sites in NS2. The consequences of Jiv binding to NS2 shall be clarified on structural level.
(ii) The NS2 autoprotease can be divided into a protease domain and a substrate domain. When both domains are coexpressed together with Jiv90 an active NS2 protease assembles. This process shall be studied with purified components. Provided that further cellular factors are essential these are to be identified and characterized.
(iii) Role of the viral NS proteins in cytopathogenicity: Surprisingly, expression of NS2-3-4A of cp BVDV (NS3 release) as well as of noncp BVDV (no NS3 release) in eukaryotic cells induces cell death by apoptosis. It shall be determined which NS proteins determine the viral biotype.

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