The innate immune system responds rapidly to virus infection and aims to contain a virus infection in the periphery prior to the initiation of an adaptive immune response that can clear the infection. However, an unintended consequence of innate immune activity is potentially dangerous tissue damage mediated by the cells of the innate response that the proinflammatory mediators that they produce. To prevent or reduce tissue damage an infected host will initiate a number of strategies to reduce the inflammation induced upon innate immune activation, including the downregulation of the innate and adaptive immune systems and the initiation of tissue protective or pro-resolving strategies. Such strategies represent and attractive target for viruses to manipulate to reduce immune activity directed against a virus and to preserve tissue integrity to allow enhanced virus replication. One mechanism used to downregulate the immune response and promote tissue integrity by the host is the production of glucocorticoids. A number of viruses, including influenza and vaccinia (VACV), the virus used here, promote the production of glucocorticoids upon infection. VACV induces glucocorticoid production by expression of the A44L gene product, and deletion of this gene attenuates the virus in vivo and results in a reduction of tissue damage in the skin. However, the mechanisms by which A44L mediates these effects are unknown and are the focus of this application. In Aim 1 we will investigate the effect of A44L-derived glucocorticoids on infiltration of different populations of myeloid cells, including a recently identified population of pro-resolving myeloid cells during VACV infection, and the function (production of cytokines and reactive oxygen species) of these myeloid populations. In Aim 2 we will examine the effects of A44L-derived GC upon dendritic cell heterogeneity, numbers, infiltration, migration, antigen presentation and cytokine production, as our previous results indicate that an effect of GC upon dendritic cells is responsible for a reduction in T cell responsiveness. In both Aim 1 and 2 we will identify the target cell directly affected by A44L-derived glucocorticoids to modulate the immune response. At the conclusion of these studies we will have gained a deeper understanding of the mechanisms that VACV and other viruses deploy to prevent or slow the immune response and preserve tissue integrity, as well as the mechanisms of action of GC upon various components of the innate and adaptive immune response.