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Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease

Minato Hirano, Memi Muto, Mizuki Sakai, Hirofumi Kondo, Shintaro Kobayashi, Hiroaki Kariwa, and Kentaro Yoshii
PNAS published ahead of print August 28, 2017 https://doi.org/10.1073/pnas.1704454114
Minato Hirano
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Memi Muto
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Mizuki Sakai
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Hirofumi Kondo
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Shintaro Kobayashi
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Hiroaki Kariwa
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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Kentaro Yoshii
aLaboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan
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  • For correspondence: kyoshii@vetmed.hokudai.ac.jp
  1. Edited by Eckard Wimmer, Stony Brook University, Stony Brook, NY, and approved July 27, 2017 (received for review March 20, 2017)

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Significance

Flaviviruses represent a significant threat to public health worldwide, and several cause severe neurological disease in humans and animals. However, no specific treatment has been developed, due to the lack of information about their detailed pathogenic mechanisms. In the current study, we reveal that the transport of viral RNA of tick-borne flavivirus in neuronal dendrites is involved in the development of neurological disease. The virus hijacked the transport system of host mRNA in dendrites, which is important for neuronal functions such as neurogenesis and the plasticity of the synaptic communication. Our finding of this unique virus–host interaction will promote the study of neurodegenerative diseases caused by disruption of dendritic mRNA transport and the development of their treatment.

Abstract

Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5′ untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.

  • tick-borne encephalitis virus
  • flavivirus
  • neuropathogenicity
  • neuronal granule
  • dendritic mRNA

Footnotes

  • ↵1To whom correspondence should be addressed. Email: kyoshii{at}vetmed.hokudai.ac.jp.
  • Author contributions: M.H. and K.Y. designed research; M.H., M.M., M.S., H. Kondo, S.K., and K.Y. performed research; M.H., M.M., and S.K. analyzed data; and M.H., S.K., H. Kariwa, and K.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1704454114/-/DCSupplemental.

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Hijacking of mRNA transport in dendrites by TBEV
Minato Hirano, Memi Muto, Mizuki Sakai, Hirofumi Kondo, Shintaro Kobayashi, Hiroaki Kariwa, Kentaro Yoshii
Proceedings of the National Academy of Sciences Aug 2017, 201704454; DOI: 10.1073/pnas.1704454114

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Hijacking of mRNA transport in dendrites by TBEV
Minato Hirano, Memi Muto, Mizuki Sakai, Hirofumi Kondo, Shintaro Kobayashi, Hiroaki Kariwa, Kentaro Yoshii
Proceedings of the National Academy of Sciences Aug 2017, 201704454; DOI: 10.1073/pnas.1704454114
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