title: CLEC5A regulates Japanese encephalitis virus-induced neuroinflammation and lethality.
abstract: CLEC5A/MDL-1, a member of the myeloid C-type lectin family expressed on macrophages and neutrophils, is critical for dengue virus (DV)-induced hemorrhagic fever and shock syndrome in Stat1⁻/⁻ mice and ConA-treated wild type mice. However, whether CLEC5A is involved in the pathogenesis of viral encephalitis has not yet been investigated. To investigate the role of CLEC5A to regulate JEV-induced neuroinflammation, antagonistic anti-CLEC5A mAb and CLEC5A-deficient mice were generated. We find that Japanese encephalitis virus (JEV) directly interacts with CLEC5A and induces DAP12 phosphorylation in macrophages. In addition, JEV activates macrophages to secrete proinflammatory cytokines and chemokines, which are dramatically reduced in JEV-infected Clec5a⁻/⁻ macrophages. Although blockade of CLEC5A cannot inhibit JEV infection of neurons and astrocytes, anti-CLEC5A mAb inhibits JEV-induced proinflammatory cytokine release from microglia and prevents bystander damage to neuronal cells. Moreover, JEV causes blood-brain barrier (BBB) disintegrity and lethality in STAT1-deficient (Stat1⁻/⁻) mice, whereas peripheral administration of anti-CLEC5A mAb reduces infiltration of virus-harboring leukocytes into the central nervous system (CNS), restores BBB integrity, attenuates neuroinflammation, and protects mice from JEV-induced lethality. Moreover, all surviving mice develop protective humoral and cellular immunity against JEV infection. These observations demonstrate the critical role of CLEC5A in the pathogenesis of Japanese encephalitis, and identify CLEC5A as a target for the development of new treatments to reduce virus-induced brain damage.
authors.affiliation: Department and Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Szu-Ting
authors.initials: ST
authors.lastname: Chen
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Se-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: David Tat-Wei
authors.initials: DT
authors.lastname: Tan
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.forename: I-Shuen
authors.initials: IS
authors.lastname: Tsai
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004664:Encephalitis Virus, Japanese / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004672:Encephalitis, Japanese / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007111:Immunity, Cellular / Q000235:genetics; D056724:Immunity, Humoral / Q000235:genetics; D007249:Inflammation; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058846:Antibodies, Monoclonal, Murine-Derived; C509772:Clec5a protein, mouse; D016207:Cytokines; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C484963:Tyrobp protein, mouse