C. elegans to study organismal control of recovery from bacterial infections

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 DESCRIPTION (provided by applicant) This proposal describes experiments designed to understand the mechanisms involved in the control of recovery from bacterial infections. To recover from an infection and return to homeostasis, the host must activate mechanisms capable of controlling the damage caused by pathogen virulence factors, inflammation, and a potentially toxic antibiotic exposure. Failure to properly recover from infections manifests in the form of recurrent infections, inappropriate wound healing, autoimmune diseases, and chronic inflammatory disorders. The mechanisms involved in pathogen recognition and immune activation have been very well studied, but the cellular and systemic responses involved in recovery after an infection is cleared are not well defined. We have established a Caenorhabditis elegans model of acute infection and antibiotic treatment for studying biological changes during the resolution phase of an infection. We found that genes that are markers of innate immunity are downregulated upon recovery, while genes involved in xenobiotic detoxification, redox regulation, and cellular homeostasis are upregulated. Using gene expression profiling, in silico analysis, and reverse genetic approaches, we have linked to the control of recovery from infection to the function of conserved transcription factors, including th GATA transcription factor ELT-2, the FOXO transcription factor DAF-16, and the Nrf transcription factor SKN-1. The proposed experiments will explore the general hypothesis that neural GPCRs and cell non-autonomous signals from different neurons may act on non-neural tissues to regulate recovery from infection at the organismal level. Given the conserved nature of GPCR-mediated signaling and the conservation of the transcription factors involved in the control of recovery, the proposed studies should lead to a better understanding of the mechanisms used by metazoans to control recovery from bacterial infection at the whole animal level.