Immunopathogenesis Versus Protection in Dengue Virus Infections

Abstract

Dengue viruses (DENV) are mosquito-borne viruses that cause significant morbidity. The existence of four serotypes of DENV with partial immunologic cross-reactivity creates the opportunity for individuals to experience multiple acute DENV infections over the course of their lifetimes. Research over the past several years has revealed complex interactions between DENV and the human innate and adaptive immune systems that can have either beneficial or detrimental influences on the outcome of infection. Further studies that seek to distinguish protective from pathological immune responses in the context of natural DENV infection as well as clinical trials of candidate DENV vaccines have an important place in efforts to control the global impact of this re-emerging viral disease.

Keywords: DENV vaccine; T lymphocyte; dengue; dengue virus (DENV); immunopathogenesis; innate immunity; vaccine; viral disease; viral tropical medicine.

Figure 1

Innate and adaptive immune responses to dengue virus and their relationships to protection or disease. Text boxes in the figure note immune responses activated in the infected cell (DENV-infected monocyte), in DENV-specific T lymphocytes that recognize DENV epitopes expressed by the infected cell, or in vascular endothelial cells. Green arrows denote those pathways that are primarily protective against infection or disease, red arrows denote those pathways that are primarily associated with more severe disease (pathological immune responses), and yellow arrows denote pathways that can be associated with either protection or pathogenesis, as described in the text. Monocytes (shown here), macrophages, and dendritic cells are the primary targets for dengue virus (DENV) infection; DENV infection of cells is enhanced by DENV-antibody complexes formed in the presence of pre-existing DENV-specific antibodies (not shown) from a previous DENV infection or passive transfer, e.g., in newborn infants. DENV-specific T lymphocytes responding to the current infection include both naïve T cells and serotype-cross-reactive memory T cells from a prior DENV infection. As illustrated in the figure, plasma leakage results from the action of circulating mediators on vascular endothelial cells, whereas direct infection of endothelial cells by DENV is not considered a major contributing factor in vivo.