Intestinal epithelial cells are continuously exposed to a wide variety of ingested microbes and must quickly recognize and defend against those that are pathogenic while simultaneously ignoring commensals. If this process fails, it can result in serious and potentially fatal infections and has been linked to multiple disorders including inflammatory bowel disease and metabolic syndrome. Despite this, it is unclear how healthy epithelial cells recognize that they are under attack and are then able to defend themselves. To answer these questions, our laboratory investigates host/pathogen interactions using the small worm Caenorhabditis elegans, which relies primarily on intestinal epithelial immunity to defend against ingested pathogens, including the gram-negative bacterium Pseudomonas aeruginosa. P. aeruginosa is a common nosocomial pathogen that is especially problematic for immunocompromised individuals such as burn victims and patients with cystic fibrosis or those undergoing chemotherapy. P. aeruginosa can be difficult to eradicate using current antibiotics and so detailed characterization of how host cells recognize and respond to this pathogen will be critical for the development of new treatment strategies. Since the mechanisms underlying bacterial invasion and host defense are strongly conserved in evolution, the discoveries I make using the relatively simple and tractable C. elegans model have a high likelihood of being directly applicable to humans. In this application, I will investigate how C. elegans defends against the P. aeruginosa toxin Exotoxin A (ToxA). ToxA is one of the most potent toxins produced by P. aeruginosa and kills animal cells by preventing them from synthesizing new proteins. I previously discovered that C. elegans recognizes the presence of ToxA by indirectly detecting its enzymatic effects (translational inhibition) and reacts by upregulating immune-response genes. Surprisingly, wild-type C. elegans have normal lifespan when continuously fed ToxA but animals defective in immune signaling pathways, including the p38 MAP kinase pathway, die rapidly. Thus, healthy C. elegans animals have a surveillance mechanism that can sense ToxA-mediated translational inhibition and quickly mount an effective response. This application seeks to discover how identifying protein synthesis abnormalities enable C. elegans to survive ToxA and to explore this process in other organisms, including mammalian models.
Intestinal epithelial cells are continuously exposed to ingested bacteria and must quickly recognize and defend against those that are harmful while simultaneously ignoring ones that are beneficial or innocuous. If this process fails, it can result in serious and potentially fatal infections and has been linked to multiple disorders including metabolic syndrome and inflammatory bowel disease. This application will study the mechanisms underlying intestinal epithelial immunity using the small worm Caenorhabditis elegans as a model to understand how human cells guard against infectious bacteria.
|Pukkila-Worley, Read; Feinbaum, Rhonda L; McEwan, Deborah L et al. (2014) The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification. PLoS Pathog 10:e1004143|