Nature Medicine
10, 1366 - 1373 (2004)
Published online: 21 November 2004; | doi:10.1038/nm1140
Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitisTian Wang1, 6, Terrence Town2, 3, 6, Lena Alexopoulou2, 5, 6, John F Anderson4, Erol Fikrig1
& Richard A Flavell2, 31
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA. 2
Section of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA. 3
The Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA. 4
Department of Entomology, Connecticut Agricultural Experiment Station, P. O. Box 1106, New Haven, Connecticut 06504, USA. 5
Current address: Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM, Campus de Luminy, Case 906, 13288 Marseille, Cedex 9, France. 6
These authors contributed equally to this work.
Correspondence should be addressed to Erol Fikrig erol.fikrig@yale.eduWest 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 wild-type but not in Tlr3-/- mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor- 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
