Combating herpesvirus encephalitis by potentiating a TLR3–mTORC2 axis

Ryota Sato, Akihisa Kato, Takahiko Chimura, Shin Ichiroh Saitoh, Takuma Shibata, Yusuke Murakami, Ryutaro Fukui, Kaiwen Liu, Yun Zhang, Jun Arii, Ge Hong Sun-Wada, Yoh Wada, Tsuneo Ikenoue, Glen N. Barber, Toshiya Manabe, Yasushi Kawaguchi, Kensuke Miyake

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

TLR3 is a sensor of double-stranded RNA that is indispensable for defense against infection with herpes simplex virus type 1 (HSV-1) in the brain. We found here that TLR3 was required for innate immune responses to HSV-1 in neurons and astrocytes. During infection with HSV-1, TLR3 recruited the metabolic checkpoint kinase complex mTORC2, which led to the induction of chemokines and trafficking of TLR3 to the cell periphery. Such trafficking enabled the activation of molecules (including mTORC1) required for the induction of type I interferons. Intracranial infection of mice with HSV-1 was exacerbated by impairment of TLR3 responses with an inhibitor of mTOR and was significantly ‘rescued’ by potentiation of TLR3 responses with an agonistic antibody to TLR3. These results suggest that the TLR3–mTORC2 axis might be a therapeutic target through which to combat herpes simplex encephalitis.

Original languageEnglish (US)
Pages (from-to)1071-1082
Number of pages12
JournalNature Immunology
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sato, R., Kato, A., Chimura, T., Saitoh, S. I., Shibata, T., Murakami, Y., Fukui, R., Liu, K., Zhang, Y., Arii, J., Sun-Wada, G. H., Wada, Y., Ikenoue, T., Barber, G. N., Manabe, T., Kawaguchi, Y., & Miyake, K. (2018). Combating herpesvirus encephalitis by potentiating a TLR3–mTORC2 axis. Nature Immunology, 19(10), 1071-1082. https://doi.org/10.1038/s41590-018-0203-2