Dengue hemorrhagic fever

The morbidity and mortality associated with severe dengue infections is a major increasing public health problem. The frequency of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) is much greater during secondary infections with dengue virus strains of a different serotype than that which caused the primary infection. The immunopathological data have raised concerns about the safest approach for vaccine development. We hypothesize that the capillary leak syndrome in DHF is the result of intense activation of the numerous precursor dengue virus specific memory CD4(+) and CD8(+) T lymphocytes by dengue-infected monocytes, which are also present in greater numbers in secondary infections due to antibody-dependent enhanced infection. The rapid production of large amounts of cytokines from activated T cells and monocytes disrupts endothelial cell bridges, causing sudden hemoconcentration, and, in severe cases, hypotensive shock. We are examining this and alternative hypotheses in a multifaceted research program which focuses on identifying the virologic and immunologic factors which increase the risk of developing severe dengue infections and DHF.