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CC BY V4.0, Open Access
Dissertation
Targeting insulin-mediated activation of the PI3K/AKT axis to reduce flavivirus infection in humans and mosquitoes
Washington State University
Doctor of Philosophy (PhD), Washington State University
2022
DOI:
https://doi.org/10.7273/000004999
Abstract
Arthropod-borne viruses (arboviruses) pose a significant health threat that continues to grow due to mosquito habitat expansion and activity during the year. To address this growing concern, more effective vector control protocols and prophylactic treatments are needed. Understanding host immunity to viral infection, whether it be at the mosquito vector or human clinical level, would provide insight and a means to base future protocols or treatments on. This work targets insulin-mediated activation of antiviral immune signaling associated with the PI3K/AKT axis to address mosquito-borne viruses at two approaches: 1) to identify and characterize evolutionarily conserved insulin-mediated antiviral immunity against flaviviruses between the Drosophila melanogaster insect model and humans, and 2) to demonstrate the therapeutic potential that targeting specific proteins in the PI3K/AKT axis in Aedes aegypti mosquitoes has in reducing viral infection and transmission. In the first approach, the work demonstrates that insulin treatment, previously shown to reduce West Nile virus, Kunjin strain (WNV-Kun) replication in Drosophila and Culex quinquefasciatus mosquitoes through induction of canonical antiviral signaling, activates other signaling pathways that are both canonical immune responses and previously unidentified antiviral mechanisms. Specifically, endothelin signaling appears to be involved in the antiviral immune response against WNV-Kun that is conserved between Drosophila and humans and is also protective against the more virulent WNV, New York-99 (WNV-NY99) strain. The work presented in the second approach demonstrates that through small molecule targeting that selectively alters the activation state of the insulin-like receptor (InR) and AKT in Aedes aegypti cells and mosquitoes, canonical immune pathways RNA interference (RNAi) and JAK/STAT can be simultaneously induced and provide more potent protection against Zika virus (ZIKV). Notably, small molecule treatment significantly reduces a mosquito’s ability to become infected and transmit ZIKV which may be a potential avenue in reducing transmission in the field. Taken together, this work compares insulin-mediated immunity among Drosophila, Aedes, and humans against different flaviviruses to evaluate their potential as broad and more efficient vector control protocols and clinical markers for disease and intervention.
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Details
- Title
- Targeting insulin-mediated activation of the PI3K/AKT axis to reduce flavivirus infection in humans and mosquitoes
- Creators
- Chasity Elizabeth Trammell
- Contributors
- Alan G Goodman (Advisor)Jennifer L Watts (Committee Member)Anthony V Nicola (Committee Member)Michael E Konkel (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Molecular Biosciences, School of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 169
- Identifiers
- 99901019840001842
- Language
- English
- Resource Type
- Dissertation