Emily R. Troemel

Scholar: 2010

Awarded Institution
Assistant Professor
University of California, San Diego
Division of Biological Sciences


Research Interests

Studying Intestinal Immunity Using the C. elegans Model

The human intestinal tract is teeming with microbes, and intestinal cells must discriminate between pathogen and non-pathogen. Similarly, the nematode C. elegans feeds on a diverse array of microbes in its natural environment, and needs to respond appropriately. The C. elegans intestine is composed of 20 epithelial cells that share many characteristics with human intestinal cells. Thus, intestinal cells C. elegans and humans face similar challenges using similar cellular structures. C. elegans is transparent, which allows for visualization of intestinal infections in live animals. In addition, an impressive arsenal of genetic and molecular tools are available for studying the nematode, making it an excellent model for investigating outstanding questions about intestinal immunity. For example, how do intestinal cells discriminate pathogen from non-pathogen? What specific molecular interactions do pathogenic microbes have with intestinal epithelial cells in vivo? To tackle these questions we are pursuing two complementary pathogen models in C. elegans:

Microsporidia are natural intracellular pathogens of C. elegans

In our first model of pathogenesis we are investigating a natural eukaryotic pathogen of C. elegans. This pathogen was isolated from a wild-caught C. elegans strain in Paris and it defines a new genus and species of microsporidia, which are a class of intracellular fungal pathogens that infect a wide range of hosts, from protists to humans. We named this species Nematocida parisii, or nematode-killer from Paris. We have now isolated Nematocida pathogens from wild-caught nematodes in several distinct geographical locations, indicating that microsporidia are a common cause of infection for nematodes in the wild. N. parisii appears to have very specific interactions with C. elegans intestinal cells, including restructuring of the terminal web, a cytoskeletal structure found from worms to humans. This restructuring appears to be part of an exit strategy and we plan to uncover the mechanisms underlying this restructuring, as well as other infection-induced consequences on intestinal structure and function. In unpublished data, we have found natural variation in resistance to this infection. We will determine the basis for this resistance, in combination with genetic screening strategies, to identify the pathways responsible for controlling microsporidia. Almost nothing is known about innate immune control of microsporidia in any system. Our findings will contribute to better understanding of microsporidia infections in agricultural and medical settings, and may also be relevant to infections caused by other intracellular pathogens as well.

Early response to infection by the bacterial pathogen P. aeruginosa

In the second model we are using the bacterial pathogen Pseudomonas aeruginosa, which is a significant cause of hospital-acquired infections and death. P. aeruginosa causes a lethal intestinal infection in C. elegans that requires some of the same virulence factors important for killing mammalian hosts. We have developed GFP reporters in the intestine that are induced specifically by pathogenic P. aeruginosa: these reporters are not induced by other pathogens or by attenuated P. aeruginosa. These reporters provide a window into the early events in intestinal cell response to P. aeruginosa infection in vivo, and offer a unique opportunity to identify both the host response pathways and the pathogen components that trigger this response. To identify host components we are using a full genome RNAi library, together with classical forward mutagenesis. We have already identified ZIP-2, a bZIP transcription factor on the host side that is required specifically for defense against P. aeruginosa, but not other pathogens. We plan to identify the host factors upstream of ZIP-2, to understand how C. elegans detects pathogen infection. On the pathogen side we are taking advantage of an ordered, non-redundant library of P. aeruginosa mutants. We have already found that the global regulator gacA is required to induce the C. elegans response, and we will identify the specific factors that act downstream of gacA. These studies will provide detailed analyses of intestinal epithelial response to pathogen infection in vivo. Our findings will have importance both for the evolutionary insights they may provide into the innate immune system of simple animals, but also for the clinically relevant information they may provide about strategies of host defense and strategies of pathogenesis.