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Author Notes:

Address correspondence to Michael Gale, Jr., mgale@u.washington.edu.

We also thank Maggie Brassil and Gabrielle Blahnik for technical assistance.

Subjects:

Research Funding:

This work was supported by National Institutes of Health grants U19 AI083019; and RO1 AI104002.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Virology
  • VIROLOGY
  • INTERFERON REGULATORY FACTOR-3
  • DOUBLE-STRANDED-RNA
  • HEPATITIS-C VIRUS
  • INNATE IMMUNITY
  • ALPHA/BETA-INTERFERON
  • VIRAL SPREAD
  • RECOGNITION
  • PATHWAY
  • REPLICATION
  • ACTIVATION

The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Tools:

Journal Title:

Journal of Virology

Volume:

Volume 87, Number 21

Publisher:

, Pages 11416-11425

Type of Work:

Article | Final Publisher PDF

Abstract:

Virus recognition and response by the innate immune system are critical components of host defense against infection. Activation of cell-intrinsic immunity and optimal priming of adaptive immunity against West Nile virus (WNV), an emerging vector-borne virus, depend on recognition by RIG-I and MDA5, two cytosolic pattern recognition receptors (PRRs) of the RIG-I-like receptor (RLR) protein family that recognize viral RNA and activate defense programs that suppress infection. We evaluated the individual functions of RIG-I and MDA5 both in vitro and in vivo in pathogen recognition and control of WNV. Lack of RIG-I or MDA5 alone results in decreased innate immune signaling and virus control in primary cells in vitro and increased mortality in mice. We also generated RIG-I−/− × MDA5−/− double-knockout mice and found that a lack of both RLRs results in a complete absence of innate immune gene induction in target cells of WNV infection and a severe pathogenesis during infection in vivo, similar to findings for animals lacking MAVS, the central adaptor molecule for RLR signaling. We also found that RNA products from WNV-infected cells but not incoming virion RNA display at least two distinct pathogen-associated molecular patterns (PAMPs) containing 5′ triphosphate and double-stranded RNA that are temporally distributed and sensed by RIG-I and MDA5 during infection. Thus, RIG-I and MDA5 are essential PRRs that recognize distinct PAMPs that accumulate during WNV replication. Collectively, these experiments highlight the necessity and function of multiple related, cytoplasmic host sensors in orchestrating an effective immune response against an acute viral infection.

Copyright information:

© 2013, American Society for Microbiology. All Rights Reserved.

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