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Cell Host Microbe. 2018 Apr 11;23(4):549-556.e3. doi: 10.1016/j.chom.2018.03.001. Epub 2018 Mar 29.

Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus.

Author information

1
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul 133-791, Korea.
3
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA.
4
Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul 133-791, Korea. Electronic address: sangkyunglee@hanyang.ac.kr.
5
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: priti.kumar@yale.edu.

Abstract

No vaccines or therapeutics are licensed for West Nile virus (WNV), a mosquito-transmitted neuroencephalitic flavivirus. The small interfering RNA siFvEJW targets a conserved sequence within the WNV E protein and limits virus infection. Using a rabies virus-derived neuron-targeting peptide (RVG9R) and an intranasal route for delivering siFvEJW 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.

KEYWORDS:

CNS delivery; West Nile virus; flavivirus; intranasal treatment; natural immunity; rabies virus glycoprotein; siRNA; therapeutics

PMID:
29606496
PMCID:
PMC6074029
DOI:
10.1016/j.chom.2018.03.001
[Indexed for MEDLINE]
Free PMC Article

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