Characterisation of RIG-I-like receptor agonists for dengue virus therapy or vaccination
Dengue is a growing problem globally owing to failure in preventing the spread of the virus. Dengue virus (DENV) replication can be blocked through the activation of innate immune responses using RIG‐I‐like receptor agonists comprising naturally of double-stranded RNA containing a triphosphate group...
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| Format: | Theses and Dissertations |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/105486 http://hdl.handle.net/10220/47846 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | Dengue is a growing problem globally owing to failure in preventing the spread of the virus. Dengue virus (DENV) replication can be blocked through the activation of innate immune responses using RIG‐I‐like receptor agonists comprising naturally of double-stranded RNA containing a triphosphate group at the 5’ end. Using the smallest dsRNA ligand that can activate RIG‐I signalling, a short hairpin with a 10 base pair stem (3p10L), we demonstrated that this minimal size immune-modulating RNA molecule (minimal immRNA) is capable of inducing an anti-viral state in human epithelial A549 cells and human monocytic U937 cells. The addition of a guanine nucleotide in position 9 of 3p10L generated a kink near the hairpin loop. This modified molecule called 3p10LG9 was more potent than 3p10L in activating RIG-I dependent type I interferon signalling in human cell lines. Both 3p10LG9 and 3p10L potently inhibited DENV replication in primary human dendritic cells isolated from human skin samples (primary human skin DCs) obtained from healthy donors. When injected with a cationic polymer, 3p10LG9 induced type I interferon production in CD11c-cre IFNARf/f mice and LysM-cre IFNARf/f mice. However, no protective effect was observed when mice were challenged with DENV-2. Overall, these results suggest that 3p10L and 3p10LG9 can activate anti-viral responses and confer short-term protection against DENV. We also found that 3p10LG9 increased the expression of CD80 on human skin APCs and enhanced protection against DENV-2 challenge in CD11c-cre IFNARflox/flox mice vaccinated with DENV-2 VLPs. Based on these preliminary findings, the ongoing work involves investigating the potential of 3p10LG9 to be used as a vaccine adjuvant and its ability to enhance long-term protection through the adaptive immune response. |
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