Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virusopen access
- Authors
- Beloor, Jagadish; Maes, Nyree; Ullah, Irfan; Uchil, Pradeep; Jackson, Andrew; Fikrig, Erol; Lee, Sang Kyung; Kumar, Priti
- Issue Date
- Apr-2018
- Publisher
- CELL PRESS
- Keywords
- CNS delivery; flavivirus; intranasal treatment; natural immunity; rabies virus glycoprotein; siRNA; therapeutics; West Nile virus
- Citation
- CELL HOST & MICROBE, v.23, no.4, pp.549 - 561
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELL HOST & MICROBE
- Volume
- 23
- Number
- 4
- Start Page
- 549
- End Page
- 561
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/4717
- DOI
- 10.1016/j.chom.2018.03.001
- ISSN
- 1931-3128
- Abstract
- No vaccines or therapeutics are licensed for West Nile virus (WNV), a mosquito-transmitted neuroencephalitic flavivirus. The small interfering RNA siFvE(JW) targets a conserved sequence within the WNV E protein and limits virus infection. Using a rabies virusderived neuron-targeting peptide (RVG9R) and an intranasal route for delivering siFvE(JW) to the CNS, we demonstrate that treatment of WNV-infected mice at late stages of neuroinvasive disease results in recovery. Selectively targeting virus in the CNS lowers viral burdens in the brain, reduces neuropathology, and results in a 90% survival rate at 5-6 days post-infection (when viral titers peak in the CNS), while placebo-treated mice succumb by days 9-10. Importantly, CNS virus clearance is achieved by humoral and cell-mediated immune responses to WNV infection in peripheral tissues, which also engender sterilizing immunity against subsequent WNV infection. These results indicate that intranasal RVG9R-siRNA treatment offers efficient late-stage therapy and facilitates natural long-term immunity against neuroinvasive flaviviruses.
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