Immunopathogenesis of dengue virus infection

Abstract

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.

Correlation of disease spectrum among four Dengue serotypes: a five years hospital based study from India

“…26 Liver dysfunction might be responsible for the decreased synthesis of specifi c factors of the intrinsic pathway, an unbalance of which may consequently cause hemorrhage. 26 In our fi nding, mean values of both the transaminases were signifi cantly raised in all four serotype groups, when compared with control groups. Elevation of liver aminotransferase levels was maximum in Den-2 patients (app.…”

The pathogenesis of dengue

“…This occurs as a result of both reduced production and increased destruction of platelets. [107][108][109] It has been suggested that the degree of thrombocytopenia correlates with clinical severity and complement activation. 110 As a result of reduced platelet counts and increased complement activation there is increased vascular fragility and thus an increased risk of haemorrhage.…”

“…112 Elevations of IL-6 and IL-8 have been associated with disordered coagulation and fibrinolysis in dengue. 109,111 Data from children in Vietnam has shown that increased APTT and reduced fibrinogen are consistently observed in patients with dengue. 113 The same study showed minor elevations in prothrombin time (PT).…”

Clinical and laboratory findings in patients with dengue associated with hepatopathy

“…Liver is one of the target organs of dengue virus, and it can be diagnosed hepatomegaly and an increased hepatic protein in serum after infection 14 , therefore, by the range release of inflammatory mediators such as cytokines, which can both protect and damage the body according to individual variations or numbers of infections 17 . These are able to perform their actions by acting on specific receptors present in the membranes of the target cells.…”