Dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological manifestations of human dengue virus infection. Despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. Mast cells are tissue-resident innate immune cells that play a sentinel cell role 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 cells are susceptible to antibody-enhanced dengue virus infection and respond with selective cytokine and chemokine responses. 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 cell lines were infected with dengue virus in the presence of dengue-immune sera and their responses were evaluated at the mRNA and protein levels. Mast cells responded to antibody-enhanced dengue virus infection or polyinosiniċpolycytidylic acid treatment with the production of type I interferons and the rapid and potent production of chemokines including CCL4, CCL5 and CXCL10. Multiple interferon-stimulated genes were also upregulated as well as mRNA and protein for the RNA sensors PKR, RIG-I and MDA5. Dengue virus-induced chemokine production by KU812 cells was significantly modulated by siRNA knockdown of RIG-I and PKR, in a negative and positive manner, respectively. Pretreatment of fresh KU812 cells with supernatants from dengue virus-infected mast cells provided protection from subsequent infection with dengue virus in a type I interferon-dependent manner. These findings support a role for tissue-resident mast cells in the early detection of antibody-enhanced dengue virus infection via RNA sensors, the protection of neighbouring cells through interferon production and the potential recruitment of leukocytes via chemokine production.
Vascular perturbation is a hallmark of severe forms of dengue disease. We show here that antibodyenhanced dengue virus infection of primary human cord blood-derived mast cells (CBMCs) and the human mast cell-like line HMC-1 results in the release of factor(s) which activate human endothelial cells, as evidenced by increased expression of the adhesion molecules ICAM-1 and VCAM-1. Endothelial cell activation was prevented by pretreatment of mast cell-derived supernatants with a tumor necrosis factor (TNF)-specific blocking antibody, thus identifying TNF as the endothelial cell-activating factor. Our findings suggest that mast cells may represent an important source of TNF, promoting vascular endothelial perturbation following antibody-enhanced dengue virus infection.Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) represent the most life-threatening clinical outcomes of dengue virus infections. The immunopathological mechanisms are significant and include antibody-dependent enhancement of dengue virus infection, a known risk factor in the development of DHF/DSS (18). A major distinguishing feature of DHF/DSS is plasma leakage; therefore, much attention has been directed to mechanisms of vascular endothelial dysfunction. Histological damage to the vascular endothelium in DHF cases is usually limited to swelling and occasional intercellular gaps (41), suggesting that endothelial perturbation is mediated by subtle immunopathological effects rather than by cytopathological virus infection. Dengue virus infection promotes upregulation of membrane-associated and soluble adhesion molecules which are indicative of endothelial cell activation (1, 36). These parameters correlate with disease severity (9,21,25,34,43).Mast cells are connective tissue-associated leukocytes located at areas of external interface, such as the skin and mucous membranes. They are in close proximity to blood vessels, with functional roles in a variety of inflammatory conditions (i.e., asthma and allergy) and innate protection against pathogens. The evidence for mast cell involvement in dengue disease includes observations that dengue patients exhibit increased levels of blood and urinary histamine (a product of mast cells and basophils), which correlates with disease severity (37,47). A large histological study of DHF patients noted that mast cells in the connective tissue around the thymus showed swelling, vacuolation of the cytoplasm, and loss of granule integrity, suggestive of mast cell activation (5). Mast cells are also involved in skin eruptions (rash), a common feature of dengue virus infection (19,35,42,48).We have previously reported that human mast cells are permissive to antibody-enhanced dengue virus infection, occurring in an Fc␥RII-dependent manner (6, 23). Infection of mast cell lines KU812 and HMC-1 results in infectious virus production and the induction of significant levels of cytokines, such as interleukin-1 (IL-1) and IL-6, as well as chemokines CCL3, CCL4, and CCL5, which can recruit additional immune effector...
Despite low levels of infection, human mast cells produce multiple chemokines in response to RSV through mechanisms that include responses to type I interferons. Such mast cell responses might enhance effector cell recruitment during RSV-induced disease.
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