MicroRNA reduction of neuronal West Nile virus replication attenuates and affords a protective immune response in mice

Terza Brostoff, Patricia Pesavento, Chris Barker, Joan L. Kenney, Elizabeth A. Dietrich, Nisha K. Duggal, Angela M. Bosco-Lauth, Aaron Brault

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

West Nile virus (WNV) is an important agent of human encephalitis that has quickly become endemic across much of the United States since its identification in North America in 1999. While the majority (∼75%) of infections are subclinical, neurologic disease can occur in a subset of cases, with outcomes including permanent neurologic damage and death. Currently, there are no WNV vaccines approved for use in humans. This study introduces a novel vaccine platform for WNV to reduce viral replication in the central nervous system while maintaining peripheral replication to elicit strong neutralizing antibody titers. Vaccine candidates were engineered to incorporate microRNA (miRNA) target sequences for a cognate miRNA expressed only in neurons, allowing the host miRNAs to target viral transcription through endogenous RNA silencing. To maintain stability, these targets were incorporated in multiple locations within the 3′-untranslated region, flanking sequences essential for viral replication without affecting the viral open reading frame. All candidates replicated comparably to wild type WNV in vitro within cells that did not express the cognate miRNA. Insertional control viruses were also capable of neuroinvasion and neurovirulence in vivo in CD-1 mice. Vaccine viruses were safe at all doses tested and did not demonstrate mutations associated with a reversion to virulence when serially passaged in mice. All vaccine constructs were protective from lethal challenge in mice, producing 93–100% protection at the highest dose tested. Overall, this is a safe and effective attenuation strategy with broad potential application for vaccine development.

Original languageEnglish (US)
Pages (from-to)5366-5375
Number of pages10
JournalVaccine
Volume34
Issue number44
DOIs
StatePublished - Oct 17 2016

Keywords

  • Attenuation
  • Immunogenicity
  • miRNA
  • Neuroinvasive
  • Neurovirulence
  • WNV

ASJC Scopus subject areas

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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