"Mitochondria, the powerhouses of our cells, are remnants of a eubacterial endosymbiont. Because mitochondria retain many hallmarks of their bacterial origin, they have recently been implicated in the etiology of systemic inflammatory response syndrome, a frequent cause of death in intensive care units. Remarkably, mitochondria are immunologically inert under normal homeostatic conditions, raising the fundamental question: how does the immune system distinguish mitochondria from resemblant bacterial pathogens? We hypothesize that mitochondria harbor distinct molecular signatures identifying them to the immune system. To address our hypothesis, we will investigate immune handling of intact mitochondria and mitochondria-derived danger-associated molecular patterns. The research objectives are to examine: 1) if isolated, intact mitochondria in vitro elicit pro-inflammatory signals or are recognized specifically as non-pathogenic by immune cells, 2) immune handling of intact and disrupted mitochondria in vivo by two-photon intravital microscopy, and 3) the role of innate signaling pathways in determining pro- or anti-inflammatory responses to mitochondrial challenges in vivo. The applicant has an international profile and an outstanding track record. He will combine a strong background in immunology with an interdisciplinary approach transcending the boundaries to organelle and symbiosis research. The project entails training in two-photon intravital microscopy at the outgoing host, the Immune Disease Institute, Harvard Medical School. This cutting-edge technique has emerged recently as a powerful tool for studying immune function in real-time in the intact organism. Hence, theoretical developments and technical innovations have converged to pave the way for the implementation of the proposed project, which will address fundamental mechanisms governing the balance between host immunity and autoinflammation, with a significant impact on human health and disease."