Abstract

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.

Public Health Relevance

Infections by bacterial pathogens generate substantial tissue damage and alteration in metabolism that have detrimental consequences even after infections have been cleared. Failure to reverse the alterations in host physiology that take place in response to infections may result in recurrent infections, inappropriate wound healing, autoimmune diseases, and chronic inflammatory disorders. We plan to dissect mechanisms of control of recovery from infections that operate at the whole animal level. A better understanding of organismal responses that take place after an infection has been cleared could lead to new therapeutic targets for inflammatory diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI117911-02
Application #
9176010
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Singleton, Kentner L
Project Start
2015-11-05
Project End
2017-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705