PROJECT SUMMARY Soil-transmitted parasitic nematodes infect over a billion people around the world and can cause devastating and sometimes fatal illness. Despite this massive health burden, the biology of parasitic nematodes remains almost entirely unexplored. For example, we lack basic knowledge about the physiological specializations and sensory behaviors that enable these gastrointestinal parasites to locate and infect hosts - processes that could be targets for novel therapeutic interventions. Furthermore, virtually nothing is known about how parasitism of mammals arose, multiple times independently, from the evolutionarily conserved genomes, neural circuits, and physiology of nematodes. I have developed the potentially fatal human parasite Strongyloides stercoralis as a powerful new model to investigate the sensory adaptations of species with direct relevance to global health. In this proposal, we aim to understand how temperature cues shape the specialized behavioral and physiological responses of soil-transmitted parasitic nematodes. This proposal is a unique approach that centers the underlying biology the human parasites themselves and lies at the intersection between parasitology, neuroscience, genetics, and molecular biology. Our central hypothesis is that parasitism of mammals requires dramatic shifts in thermal behavior and physiology that arise from an evolutionarily common cluster of molecular and cellular adaptations. First, we leverage high-resolution quantitative behavioral assays to define the role of temperature in driving the parasite-specific behaviors and physiological responses of S. stercoralis across their complex life cycle, experiments we hope will establish a new platform for the development of novel therapies that block the remarkable ability of parasitic worms to locate human hosts and survive the extreme thermal environments of their bodies. Next, we will map the neural circuits underlying thermosensation in S. stercoralis, using newly optimized tools for studying neuronal function in parasitic worms. These experiments will reveal the cellular links between thermal behaviors and molecular substrates and resolve how worm neural circuits evolved to support human parasitism. Finally, we will leverage our expertise in the comparative and functional parasite genomics to identify the genetic and molecular substrates of parasite-specific thermosensory responses in Strongyloides and other parasitic nematode species; a first, critical step towards designing novel and broadly effective anti-parasitic drugs capable of disrupting infections. The results of these studies will reveal key mechanisms underlying the unique thermal adaptability of mammalian parasitic nematodes, providing an essential foundation to enable the development of novel interventional strategies. Although focused on soil-transmitted parasitic nematodes, if successful this work should provide insights into other helminths, such as schistosomes, which also ac...