The cellular RNA decay machinery routinely polices the cell and effectively removes unwanted RNAs. We have recently discovered that alphaviruses, including VEE, possess specific RNA stabilizing elements in their 3'UTR that recruit a cellular factor and block the deadenylation/decay of viral transcripts, thereby promoting an efficient and productive infection. Based on these data, we hypothesize that many if not all RNA viruses that encode capped and polyadenylated transcripts have evolved mechanisms to selectively suppress the cellular mRNA decay machinery as a prerequisite for efficient virus gene expression. The goal of Aim I of this proposal is to test this hypothesis by assessing whether we can extend our observations on viral suppression of the cellular RNA deadenylation/decay machinery to additional alphaviruses (WEE and EEE) as well as negative sense RNA viruses (Ebola, Marburg and Nipah). In addition to expanding our knowledge of molecular host-virus interactions, these studies will also test whether these agents employ a similar strategy as the alphaviruses for mediating viral RNA stability. If these RNA viruses use a single (as preliminary data indicate is the case for alphaviruses) or limited number of strategies to suppress the cellular mRNA decay machinery, this represents a novel and attractive target for antiviral therapeutics. To this end, the goal of Aim 2 is to optimize our established in vitro assays for measuring viral mRNA stability to allow for the rapid and effective screening of chemical compound libraries.
The final aim of this proposal is to perform a chemical library screen to identify and validate candidate lead compounds that overcome viral suppression of the cellular RNA decay machinery. These compounds would represent attractive candidates for further development as antiviral therapeutics that may very well have a broad spectrum activity against a variety of viruses of biodefense significance. This research project fits within the RMRCE Integrated Research Focus on Viral Therapeutics, and will interact directly with RPs 3.1, 3.2, 3.5, 3.7 and 3.8, and utilize the resources of Core E. The goals of this project should add significant expertise to and synergize well with the RMRCE Viral Therapeutics Focus Group, particularly due to the innovative basic virology questions being asked and the novel approach to develop antivirals that could target multiple families of RNA viruses of interest to the Group.

Public Health Relevance

We have recently made the novel discovery that several viruses actively suppress the host cell RNA decay machinery to promote virus infection. We propose to test whether other viruses suppress this cellular defense machinery by a similar mechanism and develop novel antiviral drugs that reverse this suppression. These drugs could then be used to treat infections with multiple viruses of biodefense significance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065357-09
Application #
8465808
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$241,839
Indirect Cost
$51,621
Name
Colorado State University-Fort Collins
Department
Type
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Lehman, Stephanie S; Mladinich, Katherine M; Boonyakanog, Angkana et al. (2016) Versatile nourseothricin and streptomycin/spectinomycin resistance gene cassettes and their use in chromosome integration vectors. J Microbiol Methods 129:8-13
Knudson, Susan E; Cummings, Jason E; Bommineni, Gopal R et al. (2016) Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis. Tuberculosis (Edinb) 101:8-14
Charley, Phillida A; Wilusz, Jeffrey (2016) Standing your ground to exoribonucleases: Function of Flavivirus long non-coding RNAs. Virus Res 212:70-7
Phillips, Aaron T; Rico, Amber B; Stauft, Charles B et al. (2016) Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection. J Virol 90:5785-96
Westover, Jonna B; Sefing, Eric J; Bailey, Kevin W et al. (2016) Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses. Antiviral Res 126:62-8
Shankar, Sundaresh; Whitby, Landon R; Casquilho-Gray, Hedi E et al. (2016) Small-Molecule Fusion Inhibitors Bind the pH-Sensing Stable Signal Peptide-GP2 Subunit Interface of the Lassa Virus Envelope Glycoprotein. J Virol 90:6799-807
York, Joanne; Nunberg, Jack H (2016) Myristoylation of the Arenavirus Envelope Glycoprotein Stable Signal Peptide Is Critical for Membrane Fusion but Dispensable for Virion Morphogenesis. J Virol 90:8341-50
Rhodes, Katherine A; Schweizer, Herbert P (2016) Antibiotic resistance in Burkholderia species. Drug Resist Updat 28:82-90
Voge, Natalia V; Perera, Rushika; Mahapatra, Sebabrata et al. (2016) Metabolomics-Based Discovery of Small Molecule Biomarkers in Serum Associated with Dengue Virus Infections and Disease Outcomes. PLoS Negl Trop Dis 10:e0004449
Rico, Amber B; Phillips, Aaron T; Schountz, Tony et al. (2016) Venezuelan and western equine encephalitis virus E1 liposome antigen nucleic acid complexes protect mice from lethal challenge with multiple alphaviruses. Virology 499:30-39

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