title: Distinct dictation of Japanese encephalitis virus-induced neuroinflammation and lethality via triggering TLR3 and TLR4 signal pathways.
abstract: Japanese encephalitis (JE) is major emerging neurologic disease caused by JE virus. To date, the impact of TLR molecules on JE progression has not been addressed. Here, we determined whether each TLR modulates JE, using several TLR-deficient mouse strains (TLR2, TLR3, TLR4, TLR7, TLR9). Surprisingly, among the tested TLR-deficient mice there were contrasting results in TLR3(-/-) and TLR4(-/-) mice, i.e. TLR3(-/-) mice were highly susceptible to JE, whereas TLR4(-/-) mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation characterized by early infiltration of inflammatory CD11b(+)Ly-6Chigh monocytes along with profoundly increased viral burden, proinflammatory cytokine/chemokine expression as well as BBB permeability. In contrast, TLR4(-/-) mice showed mild CNS inflammation manifested by reduced viral burden, leukocyte infiltration and proinflammatory cytokine expression. Interestingly, TLR4 ablation provided potent in vivo systemic type I IFN innate response, as well as ex vivo type I IFN production associated with strong induction of antiviral PRRs (RIG-I, MDA5), transcription factors (IRF-3, IRF-7), and IFN-dependent (PKR, Oas1, Mx) and independent ISGs (ISG49, ISG54, ISG56) by alternative activation of IRF3 and NF-κB in myeloid-derived DCs and macrophages, as compared to TLR3(-/-) myeloid-derived cells which were more permissive to viral replication through impaired type I IFN innate response. TLR4 ablation also appeared to mount an enhanced type I IFN innate and humoral, CD4(+) and CD8(+) T cell responses, which were mediated by altered immune cell populations (increased number of plasmacytoid DCs and NK cells, reduced CD11b(+)Ly-6C(high) monocytes) and CD4(+)Foxp3(+) Treg number in lymphoid tissue. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were closely coupled with reduced JE lethality. Collectively, these results suggest that a balanced triggering of TLR signal array by viral components during JE progression could be responsible for determining disease outcome through regulating negative and positive factors.
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Han
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Erdenebelig
authors.initials: E
authors.lastname: Uyangaa
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Seong Bum
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Biology, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Bum Seok
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, College of Natural Science, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Seong Kug
authors.initials: SK
authors.lastname: Eo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004664:Encephalitis Virus, Japanese / Q000472:pathogenicity*; D004672:Encephalitis, Japanese / Q000150:complications* / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4