Comparative analysis of immune response programmes employed by epithelial cells to fight natural infections in C. elegans

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Microsporidia infections cause disease in agriculturally important hosts like fish, honeybees and shrimp, leading to significant economic impacts. Studying immune responses in the simple roundworm C. elegans provides a powerful method to learn more about immune responses against microsporidia. In the wild, C. elegans is subject to infection by the microsporidian pathogen Nematocida parisii (nematode-killer from Paris), which causes a lethal intestinal infection. The proposed work will study how these pathogens are sensed to induce an immune response. It will involve analysis of how specific cells in the intestine turn on gene expression upon infection and includes comparative studies with collaborators in London, UK, who are studying skin infections in C. elegans caused by natural pathogens called oomycetes, which cause diseases like potato blight. These studies will illuminate how skin and intestinal cells fight off infection individually, how they communicate with the entire animal to induce immune responses, and how an ON/OFF switch called PALS-25/PALS-22 controls these immune responses. Given the ubiquity of microsporidia infections, this work may benefit the agriculture and aquaculture industries. It will train graduate students and postdoctoral fellows in interdisciplinary research, as well as provide opportunities for undergraduates and high school students from underrepresented groups to participate in cutting-edge research. Furthermore, because of the opportunities for dissemination that will be available to students and postdocs in this work, there will be broader impacts in training the next generation of scientists in how to effectively communicate scientific results and build scientific community.Microsporidia comprise a phylum containing over 1400 species of obligate intracellular fungal pathogens, and most animal species are thought to be susceptible to infection by one or more microsporidia species. However, almost nothing is known about immune responses against these pathogens, which often infect epithelial cells. Indeed, there is much to be learned about epithelial cell immunity in general, which are on the front lines of defense. The nematode C. elegans relies heavily on epithelial defense, as it has no known professional immune cells like macrophages or T cells. In the wild, microsporidia appear to be a very common cause of infection for C. elegans, and one species in particular called Nematocida parisii (nematode-killer from Paris) is the most common species found naturally infecting C. elegans. N. parisii infects C. elegans intestinal epithelial cells, where it induces a transcriptional immune response named the Intracellular Pathogen Response (IPR). Through genetic screens, an ON/OFF switch for the IPR called PALS-25/PALS-22 was identified both by the Troemel lab, as well as by the lab of collaborator Dr. Barkoulas who independently identified PALS-25/PALS-22 as an ON/OFF switch of an immune response to infection by oomycetes, which are natural pathogens of the C. elegans epidermis. This response has been named the Oomycete Recognition Response or ORR. This study aims to: 1) perform paired genetic screens to compare regulators of the IPR and ORR, 2) analyze tissue-specificity of the IPR and ORR, and 3) assess IPR and ORR triggers for their effects on PALS-22/PALS-25 interactions. This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.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.