Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide.
The onset of vascular leakage and hemorrhagic diathesis is one of the life-threatening complications occurring in dengue patients, yet the pathogenic mechanisms are not well understood. In this study, we demonstrated that Abs against dengue virus nonstructural protein 1 (NS1) generated in mice cross-reacted with human endothelial cells and mouse vessel endothelium. After binding, mouse anti-NS1 Abs induced endothelial cell apoptosis in a caspase-dependent manner. Inducible NO synthase expression could be observed; it showed a time- and dose-dependent correlation with NO production. Endothelial cell apoptosis, characterized by exposure of phosphatidylserine on the cell surface and nuclear DNA fragmentation, was blocked by treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. Further studies demonstrated that the expression of Bcl-2 and Bcl-x(L) decreased in both mRNA and protein levels, whereas p53 and Bax increased after anti-NS1 treatment. Cytochrome c release was also observed. All of these effects could be inhibited by N(omega)-nitro-L-arginine methyl ester. Taken together, anti-NS1 Abs act as autoantibodies that cross-react with noninfected endothelial cells and trigger the intracellular signaling leading to the production of NO and to apoptosis. Endothelial cell damage may cause vascular leakage that contributes to the pathogenesis of dengue disease.
Lin
Chiou-Feng
CF
Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China.
Lei
Huan-Yao
HY
Shiau
Ai-Li
AL
Liu
Hsiao-Sheng
HS
Yeh
Trai-Ming
TM
Chen
Shun-Hua
SH
Liu
Ching-Chuan
CC
Chiu
Shu-Chen
SC
Lin
Yee-Shin
YS
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D003716:Dengue Virus / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000914:Antibodies, Viral; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D003574:Cytochrome c Group; C079340:NS1 protein, Dengue virus type 2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D009569:Nitric Oxide; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases