Highlights for Dengue Immunopathogenesis: Antibody-Dependent Enhancement, Cytokine Storm, and Beyond

Infection with dengue virus (DENV) can lead to a wide spectrum of clinical presentations, ranging from asymptomatic infection to death. It is estimated that the disease manifests only in 90 million cases out of the total 390 million yearly infections. Even though research has not yet elucidated which are the precise pathophysiological mechanisms that trigger severe forms of dengue, the infection elicits a critical immune response significant for dengue pathogenesis development. Understanding how the immune response to DENV is established and how it can resolve the infection or turn into an immunopathology is of great importance in DENV research. Currently, studies have extensively debated 2 hypotheses involving immune response: antibody-dependent enhancement and cytokine storm. However, despite its undeniable importance in severe forms of the disease, these 2 hypotheses are based on a primed immune status resulting from previous heterologous infection, abstaining them from explaining the severe forms of dengue in naive immune subjects, for example. Thus, it seems that a more intricate arrangement of causes and conditions must be achieved to severe dengue to occur. Among them, the cytokine network signature elicited, in association with viral aspects deserves special attention regarding the establishment of infection and evolution to pathogenesis. In this work, we intend to shed light on how those elements contribute to severe dengue development.