Mechanisms of Toll/interleukin1 receptor (TIR) domain function in cell death and immunity - Project Summary Organisms across the tree of life rely on innate immune systems to detect the presence of pathogens and activate appropriate responses, often including cell death. Our research program dissects mechanistic commonalities of cell death and innate immunity across kingdoms. We propose that a deeper understanding of innate immunity powered by comparative biology will enable rational engineering of the plant immune system, provide novel mechanisms for controlling microbes, and will inform pharmaceutical interventions in humans. Over the next 5 years, my research program will mechanistically dissect a conserved domain of innate immune receptors: the Toll/interleukin-1 Receptor (TIR) domain. TIR domains were first discovered in animal Toll-like receptors and in plant intracellular immune receptors in the 1990s, and recently in prokaryotic anti-phage systems. In all of these systems, TIR domains are found in diverse protein architectures that function in cell death and innate immune pathways via a conserved enzymatic activity to process nucleotides such as NAD+. My lab discovered that plant TIR domains are enzymes and defined TIR-produced small molecules that regulate bacterial anti-phage immunity. Critical immediate goals for TIR biology include understanding: the determinants and regulation of enzymatic function; the spectrum of nucleotide-derived small molecule signals; their downstream receptors; and the consequences of NAD+ depletion. Over the longer term, I envision that my research group will leverage a mechanistic understanding of TIR biology across kingdoms to engineer plant immune systems and to understand the basis of bacterial TIR-driven innate immunity. A fuller understanding of TIR biology will have direct impacts on human health, especially mechanism of the SARM1 TIR protein, which shares enzymatic products with plant and bacterial TIRs but regulates damage- induced cell death in neurons. SARM1 is a plausible therapeutic target for traumatic brain injury and neurodegenerative disease. In no system do we fully understand the mechanisms and consequences of TIR function. NAD+ depletion, the diversity of small molecule signals produced, and regulation of immune receptors all represent knowledge gaps that limit TIR-based solutions. TIR biology represents an opportunity for studies across systems to drive creative solutions for engineering innate immunity and cell death in plants, bacteria, and animals.
