| Human mast cells are tissue-resident, innate immune cells found throughout the body. Their localization in sites where pathogens gain entrance, such as the skin and lungs, place them in a position to respond early in infection. They are classically known as mediators of allergic inflammation, however recent advances have demonstrated they can respond to fungi, bacteria, and viruses. Given their strategic location, and the many mediators they can produce, we hypothesized that mast cells respond to viral infection by producing chemokines and inducing the chemotaxis of effector cells. We used primary cultures of cord blood-derived mast cells (CBMCs) and mast cell lines to investigate these questions. Our data show that mast cells responded to the double-stranded RNA synthetic analogue poly(I:C), reovirus, and antibody-enhanced dengue virus infection, by producing chemokines such as type I IFNs, CCL4, CCL5, CXCL8, and CXCL10. In dengue virus infection, the production of several mediators depended on protein kinase dsRNA dependent (PKR), and IFNs could protect mast cells from infection. A kinetic analysis revealed that mast cells rapidly produce CXCL8, and also CCL4 and CXCL10, in response to reovirus and dengue virus, respectively. To address the biological relevance of such responses, we employed chemotaxis assays to test the ability of mast cell supernatants from poly(I:C) and reovirus stimulation to induce the chemotaxis of freshly isolated peripheral blood NK cells and T cells. We found that poly(I:C) and reovirus infection of mast cells lead to the selective recruitment of NK cells by a CXCL8-dependent mechanism. Supernatants from reovirus-infected mast cells also attracted CD56+ T cells and CD8+CD45RA lo/- memory T cells, of which the former were inhibited by pretreatment with the CCR1/CCR5 antagonist metRANTES. Overall, our data support our hypothesis that mast cells can produce chemokines and attract effector cells in response to viral infection, and imply that mast cells could be an important source of the chemokines necessary for the trafficking of leukocytes into sites of infection. These data could have implications for the involvement of mast cells in virus-induced asthma exacerbations, and alternatively suggest they can be beneficial for the clearance of certain viruses in the lung. |
