Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model.
Clinical manifestations of severe dengue diseases include thrombocytopenia, vascular leakage, and liver damage. Evidence shows that hepatic injury is involved in the pathogenesis of dengue infection; however, the mechanisms are not fully resolved. Our previous in vitro studies suggested a mechanism of molecular mimicry in which antibodies directed against dengue virus (DV) nonstructural protein 1 (NS1) cross-reacted with endothelial cells and caused inflammatory activation and apoptosis. In this study, the pathogenic effects of anti-DV NS1 antibodies were further examined in a murine model. We found, in liver sections, that anti-DV NS1 antibodies bound to naive mouse vessel endothelium and the binding activity was inhibited by preabsorption of antibodies with DV NS1. Active immunization with DV NS1 resulted in antibody deposition to liver vessel endothelium, and also apoptotic cell death of liver endothelium. Liver tissue damage was observed in DV NS1-immunized mice by histological examination. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were increased in mice either actively immunized with DV NS1 protein or passively immunized with antibodies obtained from DV NS1-immunized mice. Furthermore, histological examination revealed mononuclear phagocyte infiltration and cell apoptosis in mice passively immunized with antibodies obtained from mice immunized with DV NS1. Increased AST and ALT levels were observed in mice passively immunized with purified immunoglobulin G (IgG) from dengue patients compared with normal control human IgG-immunized mice. The increased AST and ALT levels were inhibited when dengue patient serum IgG was preabsorbed with DV NS1. In conclusion, active immunization with DV NS1 protein causes immune-mediated liver injury in mice. Passive immunization provides additional evidence that anti-DV NS1 antibodies may play a role in liver damage, which is a pathologic manifestation in dengue virus disease.
Lin
Chiou-Feng
CF
Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
Wan
Shu-Wen
SW
Chen
Mei-Chun
MC
Lin
Shin-Chao
SC
Cheng
Chu-Chen
CC
Chiu
Shu-Chen
SC
Hsiao
Yu-Ling
YL
Lei
Huan-Yao
HY
Liu
Hsiao-Sheng
HS
Yeh
Trai-Ming
TM
Lin
Yee-Shin
YS
D000818:Animals; D000914:Antibodies, Viral; D003715:Dengue / Q000276:immunology* / Q000473:pathology; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D008107:Liver Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D017361:Viral Nonstructural Proteins / Q000276:immunology*
D000914:Antibodies, Viral; D017361:Viral Nonstructural Proteins