Caenorhabditis Elegans: a Model for Genetic Interaction between the Gut Microbiota and Intestinal Epithelial Cells

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Project Summary Inflammatory and infectious diseases are among the leading causes of death worldwide. Coordination and regulation of immune defenses are essential to combating infection and preventing aberrant inflammatory responses. This is especially important within the gastrointestinal tract where potential pathogens must be differentiated from commensal microbes. Deleterious alterations in our gut microbial community (dysbiosis) are associated with numerous diseases. At the forefront of host-microbe interactions are intestinal cells which act as a critical barrier and interface with our luminal environment. Intestinal cells possess a repertoire of innate immune receptors and defense mechanisms, allowing them to directly respond to and modulate gut bacteria. Thus, they are thought to play a critical role in establishing and maintaining the beneficial symbiotic relationships we develop with our gut microbiota. Remarkably, several fundamental processes underlying these host-microbe interactions remain poorly understood, including how intestinal cells differentiate between commensals and pathogens or which intestinal cell responses promote commensal selection in the gut. The long-term objective of this proposal is to determine how intestinal cells directly contribute to the selection and maintenance of commensal gut bacteria. The proposed research approaches this objective by leveraging the tractability and simplicity of the model organism C. elegans to provide the fine-scale spatial resolution needed to dissect the intricacies underlying host-microbe interactions. C. elegans is a model of intestinal development and innate immunity that also harbors a diverse gut microbiome in natura, making C. elegans an excellent system for studying microbial- induced innate immune responses. Aim 1 will determine how bacteria- and community-specific immune responses are organized in the intestine by evaluating the transcriptional response of intestinal cells to commensal and pathogenic gut bacteria using single-cell RNA-sequencing (scRNA-seq). This will reveal unique innate immune signatures among intestinal cells throughout the gut based on bacterial exposure. Preliminary evidence from our embryo scRNA-seq dataset highlight several spatially distinct immune genes including the C- type lectins (CLECs), which have a well-defined role in bacterial recognition in mammals. Aim 2 will determine how intestinal cells regulate commensal colonization in the gut by testing the role of innate immune receptors, specifically CLECs, in selecting for and maintaining commensal bacteria. Using a combination of molecular biology and microscopy techniques, aim 2 will elucidate the cohorts of CLECs required to recognize and respond to commensal gut bacteria. Results from this proposed investigation will clarify how innate immunity is regulated on a transcriptional level throughout the intestine and how it contributes to the selection and maintenance of host-microbe relationships in the gut. By combining the tractability of C. elegans with innovative mechanistic analysis we will move the C. elegans research community forward and, importantly, reveal conserved pathways enabling the creation of generalizable concepts not limited solely to C. elegans.