title: TLR signaling controls lethal encephalitis in WNV-infected brain.
abstract: Toll-like receptors (TLRs) are known to be activated in Central Nervous System (CNS) viral infections and are recognized to be a critical component in innate immunity. Several reports state a role for particular TLRs in various CNS viral infections. However, excessive TLR activation was previously reported by us in correlation with a pathogenic, rather than a protective, outcome, in a model of SIV encephalitis. Here we aimed at understanding the impact of TLR-mediated pathways by evaluating the early course of pathogenesis in the total absence of TLR signaling during CNS viral infections. We utilized a mouse model of sublethal West Nile virus (WNV) infection. WNV is an emerging neurotropic flavivirus, and a significant global cause of viral encephalitis. The virus was peripherally injected into animals that simultaneously lacked two key adapter molecules of TLR signaling, MyD88 and TRIF. On day 2 pi (post infection), MyD88/Trif-/- mice showed an increased susceptibility to WNV infection, and revealed an impairment in innate immune cytokines, when compared to wild type mice (WT). By day 6 pi, there was an increase in viral burden and robust expression of inflammatory cytokines as well as higher cell infiltration into the CNS in MyD88/Trif-/-, when compared to infected WT. A drastic increase in microglia activation, astrogliosis, and inflammatory trafficking were also observed on day 6 pi in MyD88/Trif-/-. Our observations show a protective role for TLR signaling pathways in preventing lethal encephalitis at early stages of WNV infection.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United States.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Sabouri
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, United States. Electronic address: cmarcond@scripps.edu.
authors.forename: Maria Cecilia Garibaldi
authors.initials: MC
authors.lastname: Marcondes
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United States.
authors.forename: Claudia
authors.initials: C
authors.lastname: Flynn
authors.affiliation: Genetics Department, The Scripps Research Institute, La Jolla, CA, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Genetics Department, The Scripps Research Institute, La Jolla, CA, United States.
authors.forename: Nengming
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, United States.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Fox
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United States.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Sarvetnick
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D002460:Cell Line; D006224:Cricetinae; D018450:Disease Progression; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D014901:West Nile Fever / Q000503:physiopathology*; D014902:West Nile virus / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D012367:RNA, Viral; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse
keywords: MyD88; Toll-like receptors (TLRs); Trif; West Nile Virus