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Theo Dreher
Professor and Chair, Microbiology
Affiliate Faculty, Biochemistry and Biophysics
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RESEARCH:
G Functions of the 5´ and 3´ untranslated regions of Positive Strand RNA Viruses
Positive strand RNA viruses form a large group of viruses that infect humans (e.g., poliovirus, West Nile virus, hepatitis C virus), animals (e.g., foot and mouth disease virus) and plants (e.g., tobacco mosaic virus). The replication strategies of all members of this group share characteristic similarities, whose understanding may lead to new antiviral strategies. Our studies with these viruses encompass the plant virus, turnip yellow mosaic virus (TYMV), and the human pathogen flaviviruses, dengue virus and West Nile virus. Our common interest with these viruses is in understanding the roles of the 5' and 3' untranslated regions (UTRs) of the genome in directing viral protein synthesis (gene expression) and genome replication.
For the typical eukaryotic mRNA, efficient translation is controlled by the 5'm7GpppX cap and poly(A) tail. While the genomic RNAs of the above viruses possess a 5'-cap, they lack a poly(A) tail. We are determining how the TYMV and flaviviral 3'-UTRs provide the translational enhancement typical of a poly(A) tail. In the case of TYMV, the 3'-UTR contains a transfer RNA-like structure (TLS) that functionally resembles tRNA Val. We have obtained evidence that the binding of eEF1A translation elongation factor to the TLS serves to negatively regulate the initiation of genome replication while at the same time enhancing genome translation. The TLS thus seems to be involved in regulating the transition from the translation of the viral genome to its replication as the viral infection progresses. To investigate whether the TLS might be involved in RNA encapsidation, we are studying this process in planta using agro-infiltration.
With the flaviviruses dengue and West Nile we are identifying the previously uncharacterized roles of the 5' and 3' UTRs in directing translation, and investigating their role in the translation/replication transition. Some of the conserved sequence and structural elements present in the UTRs of these mosquito-borne viruses are involved in these processes. Understanding UTR function is important in deriving stable attenuated strains of dengue virus that are suitable as live vaccine viruses. Worldwide dengue research is currently focused on the development of a vaccine that can bring to an end the widespread misery caused by this virus.