RUI: Integration of the Epithelial Innate Immune and Oxidative Stress Responses

Gettysburg College, Gettysburg PA

Investigators

Abstract

Animals interact with diverse microorganisms. Some microbes are pathogenic, and cause disease. Other benign microbes, like the microbiome, are part of the normal flora associated with the animal. The immune system must therefore use a nuanced detection system that discriminates between pathogenic and benign microbes. One way the immune system detects pathogenic microbes is by the presence of host cell damage and stress. This project seeks to dissect the molecular and genetic mechanism of infection that start with the conserved G-protein Coupled Receptor FSHR-1 and how this receptor activation results in oxidative stress. For broader impacts, a portion of the experiments will be performed in the context of an undergraduate course-based research experience, immersing approximately 100 undergraduate students in authentic research projects. This research provides training for the next generation of scientists. Students with substantial research will be co-authors on research-based publications. One type of stress associated with infection is oxidative stress. However, a direct link between oxidative stress and infection recognition has not been established. This is the goal of this research project. The conserved G-protein Coupled Receptor FSHR-1 is a key player in both innate immunity and the response to oxidative stress, and is a primary candidate to coordinate these two critical processes in Caenorhabditis elegans. The experiments will establish the relationship between FSHR-1 and principal molecular components of the oxidative stress response in infected animals using genetic epistasis (Aim 1). Multiple measures of the immune response will assess whether oxidative stress is a necessary and/or sufficient element of infection recognition (Aim 2). Finally, novel genes that connect oxidative stress and immunity will be identified to construct a more complete framework for the integration of these processes (Aim 3). This research project has the potential to transform understanding of the molecular mechanisms by which infection is detected using an experimentally tractable system. Insight into the connection between immunity and oxidative stress, and FSHR-1's role therein, will not only reveal a new means for differentiating pathogenic vs. benign microbes, but will also provide valuable insights into the interaction between animals and their natural microbial milieu. In addition, this research provides a platform that allows undergraduate researchers to perform hypothesis-based research as a means to train the next generation of scientists. 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.