Ackley Pilot Project Summary

Bacterial pathogens are a significant hazard to human health. This is especially true given the rise of acquired resistance to many commonly used, and even last line, antibiotics. There is a critical need to better understand how hosts and pathogens interact, and how the host defends against the pathogen. The overarching goal of our research is to understand host-specific factors that are important for controlling pathogen infection and, ultimately, to use this information to develop novel approaches to treat infection. To do this we are using a genetically tractable infection model, the free-living soil nematode Caenorhabditis elegans. C. elegans are bacterivores, and, once ingested, bacterial pathogens induce an organismal response in the C. elegans intestine that overlaps with those observed in human cells, validating this as a model to understand infection response. Infections are known to stimulate the release of calcium from intracellular stores, which ultimately leads to innate immune activation. We recently discovered that C. elegans with mutations in a calcium binding protein, PBO-1 have increased susceptibility to pathogen infection. PBO-1 regulates Na+/H+ ion exchange pumps, including PBO-4, which regulates intestinal pH. pH can affect the activity of oxidases and peroxidases that can generate bactericidal reactive oxygen species (ROS), which is a critical component of innate immunity. Here we are seeking to generate new research tools that can enable us to visualize the ROS generated in infected C. elegans. We are also seeking research tools that can help us study the function of a critical enzyme in the clearance of infection, called BLI-3. Chemicals that inhibit BLI-3 will help us to better understand when during infection the enzyme functions.