The spread of antimicrobial resistance is quickly outstripping the development of novel antibiotics, suggesting a looming danger for human health and well-being. One potential means for avoiding this crisis is the identification of compounds that stimulate the innate immune system, triggering increased microbial clearance by the host. In addition, these compounds are likely to prove a more difficult target for the adaptive genetic processes of microbes, as they unbalance the host-pathogen interaction, rather than simply killing the pathogen or preventing its replication. For this application, we will utilize a simple model organism, C. elegans, which possesses several experimental advantages: amenability to genetic screens, including forward, reverse, and chemical, adaptability to biochemical assays, and an evolutionarily conserved innate immune pathway similar to those of humans. I developed and partially characterized a novel liquid infection assay with this organism and used it to carry out a high-throughput screen to identify immunostimulatory compounds. For this project, infection-alleviating compounds will be tested for their ability to activate several key immune and stress pathways using transcriptional reporters. The compounds will be used to identify novel components of C. elegans immune response pathways and the targets of selected compounds will be determined. In future work, these compounds can be further tested in a variety of invertebrate and vertebrate model organisms, potentially identifying novel targets for the development of human therapeutics.
The expanding threat of antimicrobial resistance is rapidly outstripping the development of novel antibiotics, leading to a burgeoning menace of untreatable bacterial infections. A novel infection assay with a small worm was used to identify compounds that enhance host survival. Drugs will be tested for immunostimulatory activity, and positive hits will be analyzed to determine their mechanisms of function and will be used to identify novel components of innate immune signaling pathways.
| Kirienko, Daniel R; Revtovich, Alexey V; Kirienko, Natalia V (2016) A High-Content, Phenotypic Screen Identifies Fluorouridine as an Inhibitor of Pyoverdine Biosynthesis and Pseudomonas aeruginosa Virulence. mSphere 1: |
| Kirienko, Natalia V; Ausubel, Frederick M; Ruvkun, Gary (2015) Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 112:1821-6 |
| Pellegrino, Mark W; Nargund, Amrita M; Kirienko, Natalia V et al. (2014) Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516:414-7 |
| Riedel, Christian G; Dowen, Robert H; Lourenco, Guinevere F et al. (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol 15:491-501 |
| Kirienko, Natalia V; Kirienko, Daniel R; Larkins-Ford, Jonah et al. (2013) Pseudomonas aeruginosa disrupts Caenorhabditis elegans iron homeostasis, causing a hypoxic response and death. Cell Host Microbe 13:406-16 |
