Senior Scholar Award in Global Infectious Disease
Lee Gehrke, Ph.D.
Massachusetts Institute of Technology

Exploiting an Evolutionary Omission in Pathogenic RNA Viruses: Understanding the Advantages of BeingNon-polyadenylated

The identification of features that are pathogen-specific and sensitive to therapeutic agents is fundamental to treating infectious human diseases. This proposal focuses on a feature common to a wide range of pathogenic RNA viruses: the absence of poly(A) tails on the viral messenger RNAs. Viruses included in this group include dengue hemorrhagic fever, West Nile, Japanese and St. Louis encephalitis, and rotaviruses. We propose to define the molecular mechanisms enabling the viral mRNAs to circumvent the functional requirement for poly(A) tails that is shared among cellular mRNAs. The ultimate goal is to develop a unified approach for drug therapy.

Brief Description of Proposed Research: With exceedingly few exceptions, cellular messenger RNAs (mRNAs) terminate in poly(A) tails, which are now known to regulate the efficiency of cellular mRNA translation. RNA-protein and protein-protein interactions between the 5’ cap structure and the 3’ poly(A) facilitate ribosome binding during the initiation stage of protein biosynthesis. In contrast, the mRNAs of a number of pathogenic RNA viruses share a common feature that distinguishes them from cellular mRNAs: they lack 3’ poly(A) tails, yet are in fact stable and fully capable of supporting protein synthesis. Our goal is to define the common mechanism(s) that allow these viral mRNAs to circumvent the poly(A) requirement during mRNA translation. Our approach is two-fold. First, we propose to identify nucleotide sequences or structures in the 5' and/or 3' untranslated regions of the viral RNAs that both distinguish them from cellular mRNAs and release them from dependence on the poly(A) tail. Second, we propose to define RNA binding proteins that interact with these untranslated regions, thereby allowing them to translate efficiently without the poly(A) tail. This experimental strategy will provide important new insights into mechanisms of viral gene statement and will identify new targets for therapeutics to treat viruses that cause significant morbidity and mortality worldwide.

This proposal has three Specific Aims. The experiments will focus on the 5’ and 3’ untranslated regions of the viral mRNAs, which very likely contribute to the translation-level regulation. The first Specific Aim will be to use bioinformatics approaches to compare the 5’ and 3’ untranslated regions of the viral RNAs in an effort to identify nucleotide sequences or structures that may be related among this diverse group of viruses. The second Specific Aim will use genetic approaches to identify nucleotides that are required for efficient viral mRNA translation. The third Specific Aim will be to apply biochemical methods toward the identification of host factors and/or viral proteins that bind to the viral RNAs and influence translation.

Contact Dr. Gehrke.