Plants are fertile sources of nutrients for a variety of microbes. Many of these reduce plant fitness and productivity, and hence are pathogens. Plant pathogens devastate crops, particularly in developing areas where expensive (and often unsustainable) fungicides and pesticides are beyond the economic reach of most farmers. Yield losses due to plant disease are also "water losses", since that resource is often invested before disease decimates a crop. Hence, successfully combating plant diseases through rational deployment of the plant immune system will contribute directly to human and environmental health, and save lots of water. Plants possess a sophisticated immune system anchored in the functions of a family of protein, called NLR receptors, that detect the presence of pathogens and trigger a cascade of events in and around the infected cell that stops pathogen growth. Plant breeding has benefited from the ongoing definition of plant NLR function. A mechanistic understanding of NLR function is a prerequisite for rational deployment of the plant immune system in crops and for the development of treatments for various human diseases. Researchers investigating NLR experimental systems in either plants or animals recognize that it is now vital to understand how signal competent receptors are organized before infection, the precise mechanisms by which they are activated, and how this activation is translated in an appropriate output response. Hence, the broadest impacts of the proposed research project will significantly inform translation to crop species and to human health.<br/><br/>This project focuses on the intracellular receptors of the NLR protein superfamily which are critical for pathogen detection in the innate immune systems of both plants and animals. Originally discovered in plants in the mid-1990s, NLRs are a major basis for disease resistance in plants and have been manipulated, unknowingly at first, by crop breeders as "disease resistance genes" for over a century. NLRs were subsequently discovered in animals, where they play a major role in regulating innate immune signaling in infectious and autoimmune disease. Once activated, NLRs direct a complex output response that ultimately restricts pathogen growth. Despite the central role of NLRs in innate immunity in plants and animals, there is to date no generalizable model describing how NLRs transition from an inactive resting state to an active signaling state after recognition of microbial signals. Filling this gap is the critical unresolved research issue pertaining to NLR biology in both plant and animal innate immune research, and is the focus of this project. This project is aimed at understanding particular mechanistic exemplars that span the wide gamut of NLR modularity in order to illuminate the core principles underlying NLR activation, specifically: (1) as a naturally occurring effector-activated minimal TIR only domain (RBA1); and (2) as a small family of "helper" NLRs called ADR1 proteins that use a canonical mechanism to control cell death but a non-canonical mechanism to enhance sensor NLR function and contribute to the control of salicylic acid levels.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.