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

doi:10.1038/nm1140

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 journal › Article › peer-review

837 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 language	English (US)
Pages (from-to)	1366-1373
Number of pages	8
Journal	Nature Medicine
Volume	10
Issue number	12
DOIs	https://doi.org/10.1038/nm1140
State	Published - Dec 2004
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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

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.",

author = "Tian Wang and Terrence Town and Lena Alexopoulou and Anderson, {John F.} and Erol Fikrig and Flavell, {Richard A.}",

note = "Funding Information: We thank F. Manzo for assistance in preparing the manuscript and P. Cresswell for the use of the Zeiss Axioplan 2 fluorescence microscope. All experiments have been approved by the Yale University Animal Care Committee. These studies were supported by grants from the United States National Institutes of Health (AIO55749) and the United States Department of Agriculture. R.A.F. is an investigator of the Howard Hughes Medical Institute. E.F. is the recipient of a Burroughs Wellcome Clinical Scientist Award in Translational Research. T.W. is supported by a J. Kempner Postdoctoral Fellowship from University of Texas Medical Branch at Galveston. T.T. is supported by a Ruth L. Kirschstein NIH/NRSA Postdoctoral Fellowship.",

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AU - Fikrig, Erol

AU - Flavell, Richard A.

N1 - Funding Information: We thank F. Manzo for assistance in preparing the manuscript and P. Cresswell for the use of the Zeiss Axioplan 2 fluorescence microscope. All experiments have been approved by the Yale University Animal Care Committee. These studies were supported by grants from the United States National Institutes of Health (AIO55749) and the United States Department of Agriculture. R.A.F. is an investigator of the Howard Hughes Medical Institute. E.F. is the recipient of a Burroughs Wellcome Clinical Scientist Award in Translational Research. T.W. is supported by a J. Kempner Postdoctoral Fellowship from University of Texas Medical Branch at Galveston. T.T. is supported by a Ruth L. Kirschstein NIH/NRSA Postdoctoral Fellowship.

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

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