Neuronal Wnt Signaling and Intestinal Host Defense in Nematodes

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The project focuses on the connection between the nervous and immune systems, an exciting area of active investigation. Emerging evidence indicates that the so-called gut-brain-microbiota axis is very important for health in many different organisms. However, understanding how the nervous system can control host defenses against infection is very limited. Specifically, this research focuses on how neurotransmission in the central nervous system controls gene expression associated with host intestinal defenses in response to pathogens by a well-known molecular signaling pathway (Wnt signaling) in nematodes. Results from this study are expected to elucidate a previously unknown mechanism of neural control of intestinal immunity. The study of nematodes is significant because of their ecological ubiquity and because parasitic nematodes cause severe economic loss (for example, soybean cyst nematodes account for $1.5 billion in crop damage each year in the U.S. alone). In addition, the WNT and nervous system signaling that is the focus of this research using nematodes are conserved in other animals, so that this project will lead to fundamental insights that may be relevant to the nervous system and immune responses of vertebrates, including humans. This project integrates basic science research and a hands-on research experience for a high school teacher as a way to provide experience in the conduct of modern biological research and to have that perspective and understanding communicated to high school students.Neural control of innate immunity is an exciting emerging aspect of host defense, about which little is understood. This is especially true of nematodes, which are the most abundant animals on the planet and are widely used model organisms. The central hypothesis of this proposal is that wingless-Int1 (Wnt) signaling in neurons distally controls the expression of host defense genes in the intestinal epithelium via neuroendocrine signaling. The objective of this proposal is to understand this mechanism of neuroimmune regulation, by defining upstream signaling components that relay Wnt signals in neurons, and downstream mechanisms that mediate neuronal communication with the intestinal epithelium, thereby testing the central hypothesis. To achieve this objective, the Principal Investigator will elucidate the relevant neuronal and Wnt pathway component, specifically which Wnt ligands are induced, the signaling components functioning in neurons, and specific neurons that are involved. The second aim is to elucidate the mechanisms by which Wnt-activated neurons communicate with the intestine to elicit the host response. The researcher will identify neuronal signal(s) that may activate the intestinal response, the role of intestinal muscarinic receptors, and transcription factors controlled by acetylcholine. Because of the novelty of the Wnt-acetylcholine axis, this research has the potential to radically influence our understanding of host-microbe interactions in nematodes. In addition, because the Wnt pathway and muscarinic signaling are evolutionarily conserved, this research has high potential to catalyze advances in neuroimmunity in other organisms.