Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis

Tian Wang, Terrence Town, Lena Alexopoulou, John F. Anderson, Erol Fikrig, Richard A. Flavell

Research output: Contribution to journalArticle

810 Scopus citations

Abstract

West Nile virus (WNV), a mosquito-borne single-stranded (ss)RNA flavivirus, causes human disease of variable severity. We investigated the involvement of Toll-like receptor (Tlr) 3, which recognizes viral double-stranded (ds)RNA, on WNV infection. Tlr3-deficient (Tlr3-/-) mice were more resistant to lethal WNV infection and had impaired cytokine production and enhanced viral load in the periphery, whereas in the brain, viral load, inflammatory responses and neuropathology were reduced compared to wild-type mice. Peripheral WNV infection led to a breakdown of the blood-brain barrier and enhanced brain infection in wildtype but not in Tlr3-/- mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor-α receptor 1 signaling is vital for blood-brain barrier compromise upon Tlr3 stimulation by dsRNA or WNV. Collectively, WNV infection leads to a Tlr3-dependent inflammatory response, which is involved in brain penetration of the virus and neuronal injury.

Original languageEnglish (US)
Pages (from-to)1366-1373
Number of pages8
JournalNature Medicine
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wang, T., Town, T., Alexopoulou, L., Anderson, J. F., Fikrig, E., & Flavell, R. A. (2004). Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nature Medicine, 10(12), 1366-1373. https://doi.org/10.1038/nm1140