Endothelial cell sensitization by death receptor fractions of an anti-dengue nonstructural protein 1 antibody induced plasma leakage, coagulopathy, and mortality in mice
Journal
Journal of Immunology
Journal Volume
195
Journal Issue
6
Pages
2743-2753
Date Issued
2015
Author(s)
Sun D.-S.
Chang Y.-C.
Lien T.-S.
King C.-C.
Shih Y.-L.
Huang H.-S.
Wang T.-Y.
Li C.-R.
Lee C.-C.
Chang H.-H.
Abstract
The mechanisms leading to the life-threatening dengue hemorrhagic fever (DHF) remain elusive. DHF preferentially occurs during secondary dengue infections, suggesting that aberrant immune responses are involved in its development. We previously demonstrated that the autoantibodies elicited by dengue virus (DENV) nonstructural protein 1 (NS1; anti-NS1 Igs) induce plasma leakage and mortality in mice with warfarinized anticoagulant suppression. However, the involved pathogenic Ig fractions of anti-NS1 Igs remain unclear. In this study, the autoreactive Igs in patients with DHF and in NS1-immunized rabbits crossreacted with TNFrelated apoptosis-inducing ligand receptor 1 (death receptor [DR]4). Challenges with the DENV in a subcytotoxic dose sensitized endothelial cells to apoptosis. Treatments with the autoantibodies induced proapoptotic activities and suppressed the surface expression of endothelial anticoagulant thrombomodulin. Combined treatments comprising the DENV and DR4 affinity-purified fractions of anti-NS1 IgGs (anti-NS1-DR4 Ig), but not preimmune control IgGs, in subcytotoxic doses led to apoptosis in endothelial cells. Treatments with the anti-NS1-DR4 Ig led to plasma leakage, coagulopathy, and morality in mice with warfarinized anticoagulant suppression. These results suggest that DR4-induced endothelial cell sensitization through NS1-elicited autoantibodies exacerbates anticoagulant suppression, vascular injury, and plasma leakage. Detecting and blocking anti-DR Igs in patients may be novel strategies for managing severe DENV infection. ? 2015 by The American Association of Immunologists, Inc.
SDGs
Other Subjects
autoantibody; death receptor 4; immunoglobulin G; nonstructural protein 1 antibody; protein antibody; thrombomodulin; unclassified drug; antibody; anticoagulant agent; NS1 protein, Dengue virus type 2; small interfering RNA; thrombomodulin; TNFRSF10A protein, human; tumor necrosis factor related apoptosis inducing ligand receptor; virus protein; animal tissue; apoptosis; Article; blood clotting disorder; clinical article; cross reaction; cytotoxicity; dengue; embryo; endothelium cell; hematologic disease; human; human cell; immunoreactivity; male; mouse; nonhuman; plasma leakage; priority journal; protein binding; protein expression; protein function; protein purification; animal; biosynthesis; blood clotting; cell line; cell survival; chick embryo; dengue; Dengue virus; endothelium cell; genetics; immunology; mosquito; pathology; rabbit; RNA interference; Animals; Antibodies; Anticoagulants; Apoptosis; Autoantibodies; Blood Coagulation; Cell Line; Cell Survival; Chick Embryo; Culicidae; Dengue Virus; Endothelial Cells; Humans; Immunoglobulin G; Mice; Rabbits; Receptors, TNF-Related Apoptosis-Inducing Ligand; RNA Interference; RNA, Small Interfering; Severe Dengue; Thrombomodulin; Viral Nonstructural Proteins
Publisher
American Association of Immunologists
Type
journal article