Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes

Sci Adv. 2020 Feb 5;6(6):eaax7989. doi: 10.1126/sciadv.aax7989. eCollection 2020 Feb.

Abstract

Mosquito-borne flaviviruses infect both mammals and mosquitoes. RNA interference (RNAi) has been demonstrated as an anti-flavivirus mechanism in mosquitoes; however, whether and how flaviviruses induce and antagonize RNAi-mediated antiviral immunity in mammals remains unknown. We show that the nonstructural protein NS2A of dengue virus-2 (DENV2) act as a viral suppressor of RNAi (VSR). When NS2A-mediated RNAi suppression was disabled, the resulting mutant DENV2 induced Dicer-dependent production of abundant DENV2-derived siRNAs in differentiated mammalian cells. VSR-disabled DENV2 showed severe replication defects in mosquito and mammalian cells and in mice that were rescued by RNAi deficiency. Moreover, NS2As of multiple flaviviruses act as VSRs in vitro and during viral infection in both organisms. Overall, our findings demonstrate that antiviral RNAi can be induced by flavivirus, while flavivirus uses NS2A as a bona fide VSR to evade RNAi in mammals and mosquitoes, highlighting the importance of RNAi in flaviviral vector-host life cycles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Culicidae / virology*
  • Flavivirus / physiology*
  • Flavivirus Infections / genetics*
  • Flavivirus Infections / transmission
  • Flavivirus Infections / virology*
  • Gene Expression Regulation
  • Host-Pathogen Interactions / genetics*
  • Mosquito Vectors / virology
  • RNA Interference*
  • Ribonuclease III / metabolism
  • Viral Nonstructural Proteins / metabolism

Substances

  • NS2A protein, Dengue virus type 2
  • Viral Nonstructural Proteins
  • Ribonuclease III