Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis.
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 wild-type but not in Tlr3(-/-) mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor-alpha 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.
Wang
Tian
T
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA.
Town
Terrence
T
Alexopoulou
Lena
L
Anderson
John F
JF
Fikrig
Erol
E
Flavell
Richard A
RA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000821:virology*; D001921:Brain / Q000821:virology*; D004660:Encephalitis / Q000209:etiology* / Q000821:virology; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010539:Permeability; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019562:Viral Load; D014902:West Nile virus / Q000378:metabolism*
D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha