The objective of this proposal is to identify the role of autophagy regulation of innate and adaptive immunity in dengue virus (DENV)-infected cells. Infection with one of the four serotypes of DENV generates long-term homotypic immunity;however, studies have identified an association of preexisting immunity to one DENV serotype with a greater risk of developing more severe disease, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), during subsequent infection with a different DENV serotype. Several studies have also shown DENV strain-related differences in activation of innate immune pathways. Autophagy intersects with both innate and adaptive immune mechanisms. Recent studies have demonstrated DENV-induced activation of autophagy, but have not fully defined its interaction with innate and adaptive immunity and have not considered strain-related factors. This project will investigate the effects of DENV strains with different profiles of induction of type I interferon on autophagy and the effects of infection on innate and adaptive immune responses. This objective will be accomplished through the following Specific Aims: 1. We will investigate the induction of autophagy and signaling through the mitochondrial antiviral signaling (MAVS) pathway in primary human and murine monocytes and dendritic cells infected with different DENV strains. 2. We will investigate the effects of autophagy on dendritic cell activation and expression of co-stimulatory molecules and cytokines induced by different DENV strains and the downstream effects on anfigen presentation and activation of DENV-specific T cells. These studies will elucidate strain-related differences in driving innate and adaptive immune responses that might be targeted as part of immunomodulatory therapies for dengue.
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