Date of Award:
8-2023
Document Type:
Thesis
Degree Name:
Master of Science (MS)
Department:
Animal, Dairy, and Veterinary Sciences
Committee Chair(s)
Justin G. Julander
Committee
Justin G. Julander
Committee
Mirella L. Meyer-Ficca
Committee
Brett L. Hurst
Committee
Thayne L. Sweeten
Abstract
Yellow fever (YF) is an acute and often severe disease cause by yellow fever virus (YFV). Although there is an effective vaccine available to prevent YF, there are no antiviral drugs approved to treat the disease, which has a considerable disease burden in endemic areas of South America and Africa. BDAA is an experimental antiviral treatment which has shown efficacy against YFV both in cell culture and when administered before infection in an animal model of disease. BDAA targets the YFV protein NS4B and has two reported mechanisms of action: the primary mechanism of action is the direct inhibition of YFV replication and the second mechanism increases activation of dsRNA-sensing innate immune pathways in YFV-infected cells. We evaluated whether this secondary immunological mechanism of BDAA is evident in animal models of YFV. We first used a hamster model to demonstrate that BDAA is effective against YFV when administration began four hours before or two days post infection. BDAA treatment significantly improved several disease parameters in YFV-infected hamsters, including survival, weight change, serum virus titer, and parameters of liver damage. We also demonstrated that BDAA treatment of YFV-infected mice increases concentrations of particular cytokines shortly after treatment of an established YFV infection, with proinflammatory cytokine concentrations broadly reduced two and four days after treatment begins in a separate study. This indicates that the increased immune response to BDAA detected in YFV-infected cells is a transient effect which is evident shortly after administration begins. BDAA treatment also transiently increased biomarkers of immune-related cell death (apoptosis) shortly after treatment initiation. BDAA is a potently effective anti-YFV compound with a unique mechanism which warrants further evaluation as an antiviral treatment for YFV.
Checksum
fb60cdadcf30e7ebcc83efb8df0a3b6f
Recommended Citation
Weight, Abbie E., "Treatment of Yellow Fever Virus With the NS4B Inhibitor BDAA and Effects on RNA‐Sensing Innate Immune Pathways in Hamster and Mouse Models" (2023). All Graduate Theses and Dissertations, Spring 1920 to Summer 2023. 8914.
https://digitalcommons.usu.edu/etd/8914
Included in
Copyright for this work is retained by the student. If you have any questions regarding the inclusion of this work in the Digital Commons, please email us at .