Endothelial Cell Sensitization by Death Receptor Fractions of an Anti–Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice

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 TNF-related 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.

Soluble P-selectin rescues viper venom–induced mortality through anti-inflammatory properties and PSGL-1 pathway-mediated correction of hemostasis

“…Recombinant P-sel IgG-Fc fusion protein (rP-sel-Fc) was purchased from R&D Systems (Minneapolis, MN). Using previously described immunization methods54555657, polyclonal anti-P-sel Igs were obtained from rP-sel-Fc immunized rabbits for neutralization analysis.…”

Risk of stroke in patients with dengue fever: a population-based cohort study

“…20 Moreover, cross-reaction of anti-NS1 antibodies and direct viral infection of endothelial cells and platelets contribute to hemorrhage, thrombocytopenia and plasma leakage. 22,23 These immune-mediated mechanisms of dengue hemorrhagic fever in peripheral blood have also been found in the brain, where they cause breakdown of the bloodbrain barrier, leukocyte infiltration and local inflammation, followed by vasoconstriction, thromboembolism, cerebral edema, ischemia and hemorrhage. 4,21,24 A few case reports have shown atrial fibrillation as a complication of severe dengue, which may predispose these patients to stroke.…”

Suppressed humoral immunity is associated with dengue nonstructural protein NS1-elicited anti-death receptor antibody fractions in mice

“…Anti-TACI antibodies were detected in DHF patients and DENV NS1-immunized rabbits. In our previous study, we found anti-TRAIL receptor (DR4; TNFRSF10A) antibody titers in the serum samples of DHF patients and DENV NS1-immunized rabbits 23 . Because death receptor families share structural similarity among members, in this study, we investigated whether antibody fractions against TACI, BCMA, and BAFFR are present in the serum samples of DHF patients and DENV NS1-immunized rabbits.…”

“…Clinical [15][16][17] , cellular, and animal studies [18][19][20][21][22][23][24][25][26] have found that DENV infections and DENV nonstructural protein 1 (NS1) immunizations elicit autoantibodies against plasma, platelet, and endothelial antigens. Among these autoantigens, our previous report suggest that endothelial TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]; also known as TNFRSF10A) could be a potential autoantibody target leading to plasma leakage in severe DENV infections in our previous study 23 . DR4 is a member of the TNF receptor (TNFR) family and shows certain structural similarities with the TNFR family members of TACI, BCMA, and BAFFR.…”