Mast cell responses to antibody-enhanced dengue virus infection

Dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological vascular manifestations of human dengue virus infection. Despite intensive research, it still remains unclear what mechanisms and important cellular players contribute to the observed vascular dysfunction. Mast cells are well recognized inflammatory cells most commonly associated with allergy but have been implicated to play an important sentinel role in innate host protection against infectious agents. It has been shown that human mast cells are capable of antibody-enhanced dengue virus infection resulting in the release of specific inflammatory cytokines and chemokines. The current studies aimed to further investigate the consequences of antibody-enhanced dengue virus infection of human mast cells with regards to Fc receptor usage, apoptosis induction, host gene regulation and cytokine/chemokine production. Additionally, activation of mast cells by dengue virus and the double-stranded (ds) RNA analog polyI:C via pathogen-recognition receptors (PRRs), which has been associated with the release of potent mediators with highly modulatory roles in inflammation, cell recruitment and normal vascular homeostasis was investigated. Studies indicated that primary cord blood-derived human mast cells (CBMCs) and the KU812 and HMC-1 mast cell lines respond to antibody-enhanced dengue virus infection via release of type I interferons, chemokines including CXCL10, CCL4 and CCL5, and upregulation of a number of important interferon-stimulated genes (ISGs), including the dsRNA sensors RIG-I and MDA5. These responses are compared to those obtained following exposure of human mast cells to extracellular or transfected polyl:C. The majority of mast cell responses to antibody-enhanced dengue virus infection were determined to be protein kinase R (PKR)-dependent, while responses to polyl:C were less clear. The mast cell-derived interferon response to dengue virus infection was demonstrated to be protective against subsequent dengue virus infection and apoptosis of target cells. These results demonstrate that mast cells have the ability to respond to "triggers" of virus infection, via apoptosis induction and release of important mediators with the ability to suppress virus infection, the potential to recruit additional immune effector cells, and ultimately influence the cellular environment. These responses have potentially important implications for the deleterious manifestations in vascular integrity and immunopathology which accompany severe dengue disease.