The role of long chain fatty acids in the Caenorhabditis elegans innate immune response
- Lipids have long been associated with beneficial and detrimental effects on health and disease. The influence of lipids on the immune system is both complex and diverse, but the mechanisms through which fats modulate innate immune function remain to be clarified. Using the Caenorhabditis elegans-Pseudomonas aeruginosa host-pathogen system, we have attempted to characterize the importance of lipid metabolism to infection responses mediated through the innate immune system. We present evidence for the specific manipulation of lipid metabolism in response to bacterial infection in C. elegans. Infection with Pseudomonas results in altered expression of genes involved in the synthesis of long-chain fatty acids (LCFAs) as well as the breakdown of fats through mitochondrial and peroxisomal beta-oxidation. We demonstrate that two 18-carbon LCFAs, gamma-linolenic acid (GLA) and stearidonic acid (SDA) are required for basal innate immunity in-vivo. Deficiencies in GLA and SDA result in increased susceptibility to bacterial infection, which is associated with reduced basal expression of a number of immune-specific genes. GLA and SDA are required to maintain basal activity of the p38 MAP kinase pathway, which plays important roles in protecting metazoan animals from infection and oxidative stress. Genetic analysis also allowed us to identify a monounsaturated fat, vaccenic acid (VA) that negatively influences C. elegans immune function through its effect on the DAF-2 insulin-like pathway. Decreases in VA levels result in increased resistance to pathogen infection and an associated increase in the expression of antimicrobial peptide and other immune-related genes. Decreased VA levels were also associated with increased nuclear localization of DAF-16, a FOXO transcriptional regulator of the insulin-like immune pathway in C. elegans. Interestingly, we found that the bacterial pathogen Pseudomonas aeruginosa takes advantage of the detrimental effects of VA to compromise the C. elegans host and make it more susceptible to infection. A Pseudomonas mutant defective in the production of VA is attenuated and is compromised in its ability to suppress host immune gene expression. Together we have demonstrated distinct roles for individual fatty acids in innate immune function and pathogen virulence. These results may provide novel avenues for the use of lipids as immune modulators and help identify new targets for potential antimicrobial treatments.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|2009, c2010; 2009
|Stanford University, Program in Immunology.
|Jones, Patricia P
|Jones, Patricia P
|Statement of responsibility
|Submitted to the Program in Immunology.
|Thesis (Ph.D.)--Stanford University, 2010.
- © 2010 by Madhumitha Nandakumar
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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