title: Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1.
abstract: BACKGROUND
  Infection with dengue virus (DENV) may cause life-threatening disease with thrombocytopenia and vascular leakage which are related to dysfunction of platelets and endothelial cells. We previously showed that antibodies (Abs) against DENV nonstructural protein 1 (NS1) cross-react with human platelets and endothelial cells, leading to functional disturbances. Based on sequence homology analysis, the C-terminal region of DENV NS1 protein contains cross-reactive epitopes. For safety in vaccine development, the cross-reactive epitopes of DENV NS1 protein should be deleted or modified.
  
  
  RESULTS
  We tested the protective effects of Abs against full-length DENV NS1, NS1 lacking the C-terminal amino acids (a.a.) 271-352 (designated ΔC NS1), and chimeric DJ NS1 consisting of N-terminal DENV NS1 (a.a. 1-270) and C-terminal Japanese encephalitis virus NS1 (a.a. 271-352). The anti-ΔC NS1 and anti-DJ NS1 Abs showed a lower binding activity to endothelial cells and platelets than that of anti-DENV NS1 Abs. Passive immunization with anti-ΔC NS1 and anti-DJ NS1 Abs reduced DENV-induced prolonged mouse tail bleeding time. Treatment with anti-DENV NS1, anti-ΔC NS1 and anti-DJ NS1 Abs reduced local skin hemorrhage, controlled the viral load of DENV infection in vivo, synergized with complement to inhibit viral replication in vitro, as well as abolished DENV-induced macrophage infiltration to the site of skin inoculation. Moreover, active immunization with modified NS1 protein, but not with unmodified DENV NS1 protein, reduced DENV-induced prolonged bleeding time, local skin hemorrhage, and viral load.
  
  
  CONCLUSIONS
  These results support the idea that modified NS1 proteins may represent an improved strategy for safe and effective vaccine development against DENV infection.
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Wan
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Tien
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Trai-Ming
authors.initials: TM
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Yen
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Betty A
authors.initials: BA
authors.lastname: Wu-Hsieh
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001792:Blood Platelets / Q000187:drug effects; D003429:Cross Reactions / Q000276:immunology; D003715:Dengue / Q000517:prevention & control*; D003716:Dengue Virus / Q000276:immunology*; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D008809:Mice, Inbred C3H; D010446:Peptide Fragments / Q000276:immunology; D014611:Vaccination; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000914:Antibodies, Viral; C079340:NS1 protein, Dengue virus type 2; D010446:Peptide Fragments; D017361:Viral Nonstructural Proteins