RNA Sensors Enable Human Mast Cell Anti-Viral Chemokine Production and IFN-Mediated Protection in Response to Antibody-Enhanced Dengue Virus Infection

Dengue hemorrhagic fever and/or dengue shock syndromerepresent the most serious pathophysiological manifestations of human dengue virusinfection. Despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. Mast cellsare tissue-resident innate immune cells that play a sentinel cellrole in host protection against infectious agents via pathogen-recognition receptors by producing potent mediators that modulate inflammation, cell recruitment and normal vascular homeostasis. Most importantly, mast cellsare susceptible to antibody-enhanced dengue virusinfection and respond with selective cytokine and chemokineresponses. In order to obtain a global view of dengue virus-induced gene regulation in mast cells, primary human cord blood-derived mast cells(CBMCs) and the KU812 and HMC-1 mast celllines were infected with dengue virusin the presence of dengue-immune sera and their responses were evaluated at the mRNA and protein levels. Mast cellsresponded to antibody-enhanced dengue virusinfection or polyinosiniċpolycytidylic acid treatment with the production of type I interferons and the rapid and potent production of chemokinesincluding CCL4, CCL5and CXCL10. Multiple interferon-stimulated geneswere also upregulated as well as mRNA and protein for the RNA sensors PKR, RIG-Iand MDA5. Dengue virus-induced chemokineproduction by KU812 cells was significantly modulated by siRNA knockdown of RIG-Iand PKR, in a negative and positive manner, respectively. Pretreatment of fresh KU812 cells with supernatants from dengue virus-infected mast cellsprovided protection from subsequent infection with dengue virusin a type I interferon-dependent manner. These findings support a role for tissue-resident mast cellsin the early detection of antibody-enhanced dengue virusinfection via RNA sensors, the protection of neighbouring cells through interferon production and the potential recruitment of leukocytes via chemokineproduction.