Grant: Joint Canada-Israel Health Research Program

The ability of cells in the body to recognize bacteria and viruses is critical to survival. Depending on the type of infection the cell will activate different pathways that generally lead to two distinct responses; first the cell will secrete proteins called cytokines that alert neighbouring cells to the infection, particularly cells of the immune systems. Second, a series of events are triggered to shut down the replication of the pathogen inside the cell. This direct cellular response to infection is called "innate immunity". Over the past few years, researchers have identified a critical role for an intracellular organelle called the mitochondria in the propagation of these signals. The mitochondria are well known as the "energy powerhouse of the cell", however they can also act as a platform to assemble anti-viral and anti-inflammatory signaling complexes. In addition, mitochondria evolved from an alpha-proteobacteria that entered into a symbiotic relationship with a host archeabacteria about 2 billion years ago, giving rise to the eukaryotic cell. Indeed, the mitochondria still retain bacterial signatures, including their own unmethylated DNA, as well as the machinery to translate proteins. It was recently shown that this mitochondrial DNA is released into the cell cytoplasm under certain stress conditions. When this happens, the cellular antiviral responses are initiated, as if the cell was infected with bacteria. In this way the mitochondria play a central role as both a signaling platform to launch the protective response to infection, but also as a direct activator of this response when their own DNA is released. Unfortunately, there is very little known about the specific events that happen at the mitochondria during infection, and we do not understand why or when mtDNA is released. This proposal defines a strategy to address the role of the mitochondria in innate immune responses.