Dissertation
Membrane fusion prevention by broad-spectrum antivirals LJ001 and JL122 in aquaculture
Doctor of Philosophy (PhD), Washington State University
01/2018
Handle:
https://hdl.handle.net/2376/112462
Abstract
The goal of this work was to test the hypothesis that the broad-spectrum antiviral LJ001 can inhibit aquatic enveloped viral infections and transmission. LJ001 is a small molecule that inserts into viral envelopes, produces singlet oxygen radicals, modifies lipids, and ultimately prevents fusion of host and viral membranes to inhibit viral entry. We first tested LJ001 against infectious hematopoietic necrosis virus (IHNV), our model fish virus in vitro. Our results displayed a dose-dependent inhibition of IHNV infection in Epithelioma papulosum cyprini (EPC) cells. This work was expanded to demonstrate inhibition of IHNV in highly susceptible rainbow trout fry by pre-incubation of virus with varying concentrations of LJ001. Similarly, there was a dose-dependent inhibition of infection in vivo, where significant inhibition occurred at non-toxic LJ001 concentrations. We then tested the ability of LJ001 to prevent IHNV transmission from infected rainbow trout to previously unexposed fish. We demonstrated that treatment with LJ001 led to a significant decrease in viral loads in the naïve fish compared to positive controls. However, LJ001 did not completely block transmission of IHNV in this cohabitation experiment.
A newly developed structural homolog JL122 had improved pharmacokinetics in previously explored ex vivo mammalian studies as compared to LJ001. This led us to further hypothesize that JL122 is a more efficacious aquatic enveloped viral inhibitor than LJ001. We tested this hypothesis by comparing in vitro inhibition of LJ001 and JL122 against fish rhabdoviruses, including IHNV, viral hemorrhagic septicemia virus (VHSV) and spring viremia of carp virus (SVCV). JL122 was consistently a better inhibitor for each of these viruses. We tested JL122 in vivo, and our results showed complete inhibition of IHNV infection at relatively lower concentrations of JL122. Finally, we explored the efficacy of JL122 to inhibit horizontal transmission of IHNV in rainbow trout. Our results showed complete prevention of transmission of IHNV in 8/36 (22%) naïve trout during 72 hours of cohabitation using non-toxic antiviral doses of JL122. Based on these results, we propose that JL122 may have utility as a water immersion treatment to inhibit the spread of aquatic enveloped viruses during outbreaks.
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Details
- Title
- Membrane fusion prevention by broad-spectrum antivirals LJ001 and JL122 in aquaculture
- Creators
- Bethany Frances Balmer
- Contributors
- Kevin R Snekvik (Advisor)Hector Aguilar-Carreno (Committee Member)Anthony V Nicola (Committee Member)Maureen K Purcell (Committee Member)Santanu Bose (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 53
- Identifiers
- 99900581424101842
- Language
- English
- Resource Type
- Dissertation