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The Genetics of Immune Activation and Regulation in Intestinal Epithelial Cells
Intestinal epithelial cells are the primary interface with commensal microorganisms, potential pathogens and ingested xenobiotic toxins, and function to maintain mucosal homeostasis. Immune regulation is particularly complex in intestinal epithelial cells, since these cells must perform the dual roles of protecting the host from potential pathogens while preventing exaggerated inflammatory responses that can cause collateral injury to the host. What are the mechanisms that ensure immune homeostasis in the intestinal epithelium? How do these cells distinguish between beneficial microbes and invasive pathogens, and mount targeted immune responses only in the context of infection? 

Research 1

Our laboratory approaches these problems by focusing on conserved mechanisms of immune activation. The major hypothesis of our work is that the mechanisms that act in intestinal epithelial cells to distinguish pathogens from commensals have evolutionarily ancient origins, the fundamental principals of which can be elucidated using a simple model host (Pukkila-Worley 2016; Anderson et al 2020). In nature, the genetically tractable soil nematode Caenorhabditis elegans consumes microorganisms for food and thus, their evolution has been shaped by interactions with microbial pathogens and ingested toxins (Peterson et al. 2018). We therefore take advantage of the powerful molecular and genetic tools that are available in C. elegans, together with immunostimulatory probe molecules we have identified (Pukkila-Worley et al., 2012), to define conserved mechanisms of pathogen detection and immune regulation. 

These genetic studies in C. elegans have revealed that immune defenses and small molecule detoxification programs are linked via a conserved transcriptional regulator (Pukkila-Worley et al. 2014); immune pathway activity is tightly controlled to ensure nematode development (Cheesman et al. 2016); and that a conserved nuclear hormone receptor can activate an anti-pathogen transcriptional program in C. elegans (Peterson et al. 2019). In addition, we characterized an interesting connection between nutrient stores, metabolism, and host susceptibility to bacterial infection (Anderson et al., 2019), and found that transcriptional re-direction of a conserved cytoprotective transcrption factor alleivates negative metabolic outcomes of pathogen infection (Nhan et al. 2019). We have also uncovered a new mechanism of innate immune homeostasis that involves signaling from the sensory nervous system to the intestine (Foster et al. 2020).

These studies have led us to focus on three principal areas of current interest:  1) Immune pathway activation in IECs by nuclear hormone receptors. Our data suggest that the expansion of the nuclear hormone family in C. elegans has been fueled, at least in part, by the roles of these proteins in the activation of host defense responses.  2) Neuronal control of intestinal immune responses. We are using forward genetics to define the cellular mechanisms that control host immune pathway function and have identified an ancient mechanism that utilizes inputs from the sensory nervous to promote intestinal immune homeostsis.  3) Cellular energy stores and immune activation. We are defining the genetic links between energy sufficiency and the activation of protective immune defenses. Together, these efforts are uncovering fundamental principles of immune homeostasis involving conserved immune regulators that we are applying to mammalian biology using cell culture and mouse genetics.