Toll-like receptor 7 mitigates lethal West Nile encephalitis via interleukin 23-dependent immune cell infiltration and homing.
West Nile virus (WNV), a mosquito-transmitted single-stranded RNA (ssRNA) flavivirus, causes human disease of variable severity. We investigated Toll-like receptor 7-deficient (Tlr7(-/-)) and myeloid differentiation factor 88-deficient (Myd88(-/-)) mice, which both have defective recognition of ssRNA, and found increased viremia and susceptibility to lethal WNV infection. Despite increased tissue concentrations of most innate cytokines, CD45(+) leukocytes and CD11b(+) macrophages failed to home to WNV-infected cells and infiltrate into target organs of Tlr7(-/-) mice. Tlr7(-/-) mice and macrophages had reduced interleukin-12 (IL-12) and IL-23 responses after WNV infection, and mice deficient in IL-12 p40 and IL-23 p40 (Il12b(-/-)) or IL-23 p19 (Il23a(-/-)), but not IL-12 p35 (Il12a(-/-)), responded similarly to Tlr7(-/-) mice, with increased susceptibility to lethal WNV encephalitis. Collectively, these results demonstrate that TLR7 and IL-23-dependent WNV responses represent a vital host defense mechanism that operates by affecting immune cell homing to infected target cells.
Town
Terrence
T
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Bai
Fengwei
F
Wang
Tian
T
Kaplan
Amber T
AT
Qian
Feng
F
Montgomery
Ruth R
RR
Anderson
John F
JF
Flavell
Richard A
RA
Fikrig
Erol
E
D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004198:Disease Susceptibility; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014901:West Nile Fever / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000821:virology
D016207:Cytokines; D053759:Interleukin-23; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7