The long-term objective of this project is to discover treatments for West Nile virus (WNV) when administered after the virus has infected the central nervous system (CMS) and after the development of neurological sequelae, since no known therapy is currently available. Rationale: We have identified two antiviral agents, in the prior 3 years, with the potential for treating WNV disease. To facilitate pre-clinical development of the drugs, we have employed electrophysiological measurements to identify rodents with persistent neuropathology after the acute phase of infection. We are now poised in this proposal to answer important basic questions about pathogenic mechanisms causing or reversing viral encephalitis and persistent neuropathology, and to discover effective therapies that are important for the objectives of the RMRCE.
Specific Aims : 1. Improve the efficacy of E16 and T-705. A therapeutic antibody, E16, will be mutated to remove the interaction with a receptor that mediates IgG efflux out of the brain back into the blood. Additionally, a 20-mer rabies virus glycoprotein will be used to influx E16 across the blood brain barrier (BBB) into the CNS. The efficacy and ribophosphorylation of an active pyrazine analog, T-705, will be verified directly in neurons, after which it will be administered directly into the brain or by intrathecal administration of hamsters to directly test its efficacy in the CNS. 2. Identify in rodents the pathogenesis for the transition from acute viral encephalitis to persisting neuropathology. Clinicoelectrophysiological assays that measure the function of three anatomical areas of the CNS will be used to identify rodents with persistent neuropathology. Immunohistochemistry, body temperature, animal motion/activity, and functional motor tests will also be employed to make comparisons between the acute infection and persisting neuropathology. 3. Verify the pre-clinical efficacy of anti-WNV drugs in rodent models. Improved antiviral drugs will be investigated for efficacy against acute WNV encephalitis and persisting neuropathology. We expect that improved therapeutics will still be efficacious after delaying the initiation of treatment, and that treatments may be effective during persisting neuropathology. Neuroprotective agents, based on published mechanisms, will be evaluated in the persistent neuropathology model. Two companies will collaborate for clinical development of these therapies. This research project fits within the RMRCE Integrated Research Focus on Viral Therapeutics, and will interact directly with RP 3.2.

Public Health Relevance

Many patients first visit physicians after West Nile virus has infected the brain or spinal cord. Antiviral or neuroprotective treatments, developed in this proposal, that are effective when administered during acute viral infection of neurons or during subsequent neurological sequelae will be important for solving this public health problem.

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 #
8465804
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
$288,231
Indirect Cost
$51,622
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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