title: CLEC5A is critical for dengue virus-induced osteoclast activation and bone homeostasis.
abstract: Osteoclasts are bone tissue macrophages critical to maintain bone homeostasis. However, whether osteoclasts are susceptible to flaviviral infections and involved in dengue virus (DV)-induced disease pathogenesis is still unknown. In this study, we found that osteoclasts were preferentially susceptible to DV infection and produced similar amounts of cytokines and infectious virions as macrophages. Interestingly, DV-induced cytokine secretion and nuclear translocation of the transcription factor NFATc1 in osteoclast via the Syk-coupled myeloid C-type lectin member 5A (CLEC5A). Moreover, DV caused transient inflammatory reaction in bone tissue and upregulated osteolytic activity to release C-telopeptide of type I collagen (CTX-1) from bone tissue. Furthermore, DV-induced osteolytic activity was attenuated in CLEC5A-deficient mice, and administration of antagonistic anti-CLEC5A mAb inhibited DV-activated osteolytic activity and reduced CTX-1 serum level in vivo. This observation suggests that osteoclasts serve as a novel target for DV, and transient upregulation of osteolytic activity may contribute to the clinical symptoms in dengue patients.
  
  
  
  Cultured osteoclasts were susceptible to DV infection. Osteoclasts produced similar amounts of cytokines and infectious virions as macrophages. DV induced nuclear translocation of NFATc1 in osteoclast via CLEC5A. DV caused transient inflammatory reaction in bone tissue and upregulated osteolytic activity. Antagonistic anti-CLEC5A mAb inhibited DV-activated osteolytic activity in vivo.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ya-Lang
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Taipei Medical University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan.
authors.forename: Szu-Ting
authors.initials: ST
authors.lastname: Chen
authors.affiliation: Molecular and Genetic Imaging Core, Department of Nuclear Medicine, National Yang-Ming University Medical School and Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Yen-Hsu
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Chung-Hao
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Divisions of Infectious Disease, Center for Disease Control, Taipei, Taiwan.
authors.forename: Pei-Yun
authors.initials: PY
authors.lastname: Shu
authors.affiliation: Institute of Infectious Diseases and Vaccinology, National Health Research Institute, Taipei, Taiwan.
authors.forename: Ching-Len
authors.initials: CL
authors.lastname: Liao
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.|Genomics Research Center, Academia Sinica, 128, Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan. slhsieh@gate.sinica.edu.tw.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. slhsieh@gate.sinica.edu.tw.
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D015415:Biomarkers; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003715:Dengue / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D003716:Dengue Virus / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000821:virology*; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism; D000072078:Positron Emission Tomography Computed Tomography; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D000072098:Single Photon Emission Computed Tomography Computed Tomography
chemical_list: D015415:Biomarkers; C509771:CLEC5A protein, human; D016207:Cytokines; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D050778:NFATC Transcription Factors; D011956:Receptors, Cell Surface
keywords: Dengue virus; Osteoclasts; Syk-coupled myeloid C-type lectin member 5A (CLEC5A)