The Effect of Autophagy Inhibitors on RVFV Production
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Authors
Boghdeh, Niloufar
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Abstract
Rift Valley Fever Virus (RVFV) is an arbovirus that can infect ruminants and humans. It can cause many diseases including encephalitis, hemorrhagic fever, and ocular disease. A severe version of the disease is observed predominantly in pregnant and young livestock. While it is primarily transmitted by mosquitoes, most human cases are acquired through contact with blood or organs of an infected animal. Autophagy is an intracellular pathway that allows for the degradation of cytoplasmic organelles during cellular stress. The role of autophagy during viral infections is unclear. In some cases, it slows the progression of the infection, whereas, in many other cases the virus uses the autophagy system to enhance its replication. We hypothesized that inhibition of autophagy will cause RVFV titer reduction and provide evidence that the process of autophagy can be pro-viral to RVFV. To explore the impact of autophagy on RVFV replication, small molecule modulators of autophagy were utilized. CA-5F, DBBC661, and ML240, which are all known autophagy inhibitors, were shown to be capable of reducing RVFV infectious titers. CA-5F was selected for further studies due to it being one of the most potent and least toxic inhibitors. CA-5F is a late-stage autophagy inhibitor that functions by inhibiting the autophagosome-lysosome fusion. Previous studies have shown CA-5F to have anti-tumor effects against lung cancer cells. HSEACs (Human Small Airway Epithelial Cells) were treated with non-toxic concentrations of CA-5F and a significant decrease in viral production was observed. Furthermore, the greatest decrease in RVFV titers was observed at 16 and 24 hours post-infection as compared to 8 hours post-infection. Additionally, intracellular RNA analysis showed that although CA-5F decreases RVFV infectious titers in a dose-dependent manner, it does not impact viral RNA production. This study provides evidence that the autophagy inhibitor, CA-5F, is capable of reducing RVFV production. Future studies will assess the importance of the viral protein NSs in CA-5F inhibition.
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This thesis has been embargoed for 2 years. It will not be available until April 2023 at the earliest.
Keywords
Rift Valley River Virus, Autophagy inhibitors, Autophagy, RVFV, CA-5F