The regulation of anti-viral immune responses in the lung is dependent upon the ability to efficiently and appropriately recognize pathogenic signals and promote the proper and non-pathogenic response. Respiratory syncytial virus (RSV) is an especially pathogenic virus that can induce morbidity at all ages, especially in infants and those with underlying lung conditions. Our recent data published from our present funding cycle indicated that a critical innate immune pathway that is functional for regulating pathogenic immune response is autophagy. This omnipresent process provides all cells the ability to not only preserve resources but transport pathogen components to the proper immune recognition molecules. In particular, this process appears to be central for dendritic cell activation, cytokine production, and subsequent T cell activation. In this renewal, we will continue to examine the consequences of altering autophagy, including the regulation of ER stress and inflammasome activation, that leads to a distinct shift in innate cytokine profiles. We will more closely and mechanistically continue to explore the role of an autophagy inducer, Sirtuin 1, a NAD+ deactylase, and its effect on the regulation of not only the autophagy profiles, but also the direct and indirect effect it has on ER stress and inflammasome activation. Using Sirt1 -/- and inhibition along with Sirt1 overexpression and activation we will explore how the absence of Sirt1 along with the reduction of autophagy alters anti-RSV responses in vitro and in vivo. The shift in cytokine patterns induced by increased ER stress in the absence of autophagy and Sirt1 can lead to an altered pathogenic phenotype due to enhanced pathogenic T cell responses, especially IL-17. Thus, these studies will explore several novel and topical pathways that will not only further define the mechanisms that promote pulmonary mucosal immune responses, but expand our understanding of RSV infection and immunity.
The regulation of immune responses is critical for controlling the severity of infectious diseases. This is especially important in vulnerable populations, such as infants and the elderly. This proposal will identify the critical role of innate immune cells and a process of Autophagy. The regulation of dendritic cells will be a primary focus that control the development of T cells during respiratory syncytial virus (RSV) infection, a virus that is particularly detrimental to infants and the elderly. These studies will give important insight into the mechanisms that govern the severity of immunopathology during RSV-induced disease.
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