title: TLR7 is a key regulator of innate immunity against Japanese encephalitis virus infection.
abstract: Toll-like receptor 7 (TLR7) known to recognize guanidine-rich ssRNA has been shown to mount vital host defense mechanism against many viruses including flaviviruses. Signal transduction through TLR7 has been shown to produce type-1 interferon and proinflammatory mediators, thereby initiating essential innate immune response against ssRNA viruses in hosts. Systemic and brain specific TLR7 knock-down mice (TLR7(KD)) were generated using vivo-morpholinos. These mice were then subcutaneously challenged with lethal dose of JEV (GP78 strain) and were subsequently analyzed for survival. Significant difference in susceptibility to JEV between wild-type and systemic TLR7(KD) mice was observed whereas, no difference in susceptibility to JEV infection was seen in brain-specific TLR7(KD) mice. Significant decreases in IFN-α and antiviral proteins were also observed in both TLR7(KD) mice along with increased viral loads in their brain. Owing to increased viral load, increases in levels of various proinflammatory cyto/chemokines, increased microglial activation and infiltration of peripheral immune cells in brain of TLR7(KD) mice were also observed. Immunocytochemistry and RNA co-immunoprecipitation performed with JEV-infected N2a or HT22 cells indicated endosomal localization and confirmed interaction between JEV ssRNA with TLR7. Treatment of mice with imiquimod, a TLR7 agonist, prior to JEV infection resulted in their increased survival. Overall, our results suggest that the TLR7 response following JEV infection promotes type-1 interferon production and generation of antiviral state which might contribute to protective effect in systemic infection.
authors.affiliation: National Brain Research Centre, Manesar, Haryana-122051, India.
authors.forename: Arshed
authors.initials: A
authors.lastname: Nazmi
authors.affiliation: National Brain Research Centre, Manesar, Haryana-122051, India.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: National Brain Research Centre, Manesar, Haryana-122051, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Kundu
authors.affiliation: National Brain Research Centre, Manesar, Haryana-122051, India.
authors.forename: Kallol
authors.initials: K
authors.lastname: Dutta
authors.affiliation: Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore 560029, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Mahadevan
authors.affiliation: Department of Neuropathology, National Institute of Mental Health & Neurosciences, Bangalore 560029, India.
authors.forename: Susarla Krishna
authors.initials: SK
authors.lastname: Shankar
authors.affiliation: National Brain Research Centre, Manesar, Haryana-122051, India. Electronic address: anirban@nbrc.ac.in.
authors.forename: Anirban
authors.initials: A
authors.lastname: Basu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000276:immunology / Q000821:virology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D004195:Disease Models, Animal; D004664:Encephalitis Virus, Japanese / Q000235:genetics; D004672:Encephalitis, Japanese / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D055785:Gene Knockdown Techniques; D006801:Humans; D000077271:Imiquimod; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology; D009474:Neurons / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D004279:DNA, Viral; D007370:Interferon Type I; D008562:Membrane Glycoproteins; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000077271:Imiquimod
keywords: Antiviral; Innate immunity; Japanese encephalitis; Neurons; Neurotrophic virus; Pattern recognition receptors