Immunopathogenesis of dengue virus infection.
Dengue virus infection causes dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), whose pathogeneses are not clearly understood. Current hypotheses of antibody-dependent enhancement, virus virulence, and IFN-gamma/TNFalpha-mediated immunopathogenesis are insufficient to explain clinical manifestations of DHF/DSS such as thrombocytopenia and hemoconcentration. Dengue virus infection induces transient immune aberrant activation of CD4/CD8 ratio inversion and cytokine overproduction, and infection of endothelial cells and hepatocytes causes apoptosis and dysfunction of these cells. The coagulation and fibrinolysis systems are also activated after dengue virus infection. We propose a new hypothesis for the immunopathogenesis for dengue virus infection. The aberrant immune responses not only impair the immune response to clear the virus, but also result in overproduction of cytokines that affect monocytes, endothelial cells, and hepatocytes. Platelets are destroyed by crossreactive anti-platelet autoantibodies. Dengue-virus-induced vasculopathy and coagulopathy must be involved in the pathogenesis of hemorrhage, and the unbalance between coagulation and fibrinolysis activation increases the likelihood of severe hemorrhage in DHF/DSS. Hemostasis is maintained unless the dysregulation of coagulation and fibrinolysis persists. The overproduced IL-6 might play a crucial role in the enhanced production of anti-platelet or anti-endothelial cell autoantibodies, elevated levels of tPA, as well as a deficiency in coagulation. Capillary leakage is triggered by the dengue virus itself or by antibodies to its antigens. This immunopathogenesis of DHF/DSS can account for specific characteristics of clinical, pathologic, and epidemiological observations in dengue virus infection.
Lei
H Y
HY
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, ROC. hylei@mail.ncku.edu.tw
Yeh
T M
TM
Liu
H S
HS
Lin
Y S
YS
Chen
S H
SH
Liu
C C
CC
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers; D001769:Blood / Q000821:virology; D003715:Dengue / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology*; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000821:virology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000821:virology
D000998:Antiviral Agents; D015415:Biomarkers; D015850:Interleukin-6