The role of mitochondrial reactive oxygen species in innate immune signaling

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DESCRIPTION (provided by applicant): An essential component of the body's defense against infectious disease is the innate immune system. Macrophages and other white blood cells that comprise this system are the first responders to infection and recognize invading pathogens and initiate an immune response. A central feature of this response is the up- regulation and secretion of host inflammatory mediators and Type I Interferons (IFNs). The molecular basis connecting pathogen recognition to Type I IFN production is unclear, but is dependent upon the mitochondrial- and endoplasmic reticulum-localized adapter protein, Stimulator of Interferon Genes (STING). The objective of the study is to characterize the activation of STING-dependent signaling pathway(s) to further the long-term goal of delineating how Type I IFNs are regulated during intracellular infection of macrophages. Certain intracellular pathogens modulate the function of host mitochondria. It is hypothesized that intracellular infection of macrophages causes mitochondrial dysregulation, prompting generation of Reactive Oxygen Species (ROS), activating STING-dependent innate immune pathways, leading to expression of the prototypical type I IFN, IFN-¿. The small molecule 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a potent activator of STING-dependent signaling in macrophages and will be used as a surrogate for intracellular infection. Additionally, STING-dependent activation in macrophages will be examined in response to an intracellular bacterial (Francisella tularensis) or viral (Respiratory Syncytial Virus (RSV)) infection. The first Aim of the study will be to determine whether mitochondrial ROS generation is sufficient for STING dimerization and activation of downstream signaling components, and establish the necessity of mitochondrial ROS generation for IFN- ¿ expression during infection or chemical treatment. The second Aim will establish how mitochondrial function and mitochondrial ROS is modulated by infection or DMXAA treatment. It is predicted that mitochondrial ROS generated during DMXAA treatment, or infection with F. tularensis or RSV, will be necessary for activation of STING-dependent innate immune signaling pathways following ROS-dependent dimerization of STING. Due to the potential commonality of mitochondrial subversion in infectious disease, the mechanism characterized in this project could have wide-ranging applications to other infectious organisms.