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Author Notes:

Address correspondence to Michael S. Diamond, diamond@borcim.wustl.edu.

We thank Kristy Szretter for help in preparing brain samples for cytokine analysis, Tracy Jo Pasieka for assistance with Bio-Plex analysis of serum cytokines, and M. Colonna and T. Egawa for providing MDA5−/− and TCRα−/− mice, respectively.

We also thank the NIH Tetramer Core Facility at Emory University for providing NS4B-specific tetramers.

Subjects:

Research Funding:

NIH grants U54 AI081680 (Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research), U19 AI083019 (M.G. and M.S.D.), PCTAS AI083019-02S1; (H.M.L.), and R01 AI104002 (M.G. and M.S.D.) supported this work.

H.M.L. was supported by an NIH training grant, T32-AI007172.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Virology
  • VIROLOGY
  • RNA HELICASE LGP2
  • ANTIVIRAL INNATE IMMUNITY
  • I INTERFERON RESPONSES
  • TOLL-LIKE RECEPTOR-3
  • INDUCIBLE GENE-I
  • RIG-I
  • CHIKUNGUNYA VIRUS
  • MEDIATED CONTROL
  • INFECTION
  • ENCEPHALITIS

Pattern Recognition Receptor MDA5 Modulates CD8(+) T Cell-Dependent Clearance of West Nile Virus from the Central Nervous System

Tools:

Journal Title:

Journal of Virology

Volume:

Volume 87, Number 21

Publisher:

, Pages 11401-11415

Type of Work:

Article | Final Publisher PDF

Abstract:

Many viruses induce type I interferon responses by activating cytoplasmic RNA sensors, including the RIG-I-like receptors (RLRs). Although two members of the RLR family, RIG-I and MDA5, have been implicated in host control of virus infection, the relative role of each RLR in restricting pathogenesis in vivo remains unclear. Recent studies have demonstrated that MAVS, the adaptor central to RLR signaling, is required to trigger innate immune defenses and program adaptive immune responses, which together restrict West Nile virus (WNV) infection in vivo. In this study, we examined the specific contribution of MDA5 in controlling WNV in animals. MDA5 -/- mice exhibited enhanced susceptibility, as characterized by reduced survival and elevated viral burden in the central nervous system (CNS) at late times after infection, even though small effects on systemic type I interferon response or viral replication were observed in peripheral tissues. Intracranial inoculation studies and infection experiments with primary neurons ex vivo revealed that an absence of MDA5 did not impact viral infection in neurons directly. Rather, subtle defects were observed in CNS-specific CD8 + T cells in MDA5 -/- mice. Adoptive transfer into recipient MDA5 -/- mice established that a non-cell-autonomous deficiency of MDA5 was associated with functional defects in CD8 + T cells, which resulted in a failure to clear WNV efficiently from CNS tissues. Our studies suggest that MDA5 in the immune priming environment shapes optimal CD8 + T cell activation and subsequent clearance of WNV from the CNS.

Copyright information:

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

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