Most of what is known about the biology and function of oxylipins, oxygenated
polyunsaturated fatty acids and metabolites, including the eicosanoids such as
prostaglandins, comes from the study of mammalian biology. These compounds are
ubiquitous in nature and found in all eukaryotic organisms, including the fungal
domain. It is also in this group of organisms that the least is known about the
metabolic pathways leading to the production of oxylipins, including those derived
from arachidonic acid (AA) (n-6 fatty acid), and the functions of these compounds in
the biology of fungi and yeasts. Candida species has the ability to produce proinflammatory
eicosanoids, such as prostaglandin E2 (PGE2), from host derived AA.
Candida albicans is an important opportunistic pathogen in humans causing
systemic infections. An important virulence factor in C. albicans is the ability to
produce pro-inflammatory PGE2, which enhances biofilm formation and influences
host immune responses. Biofilms increase damage in host cells and are more
resistant to antifungal drugs than planktonic yeast cells. This is an important area of
research which may aid in the understanding of the complex interactions between
host and pathogen, leading to the identification of novel antifungals or drug targets.
This study evaluated the production of the prostaglandins, PGE2 and PGF2α, from
exogenous AA, by biofilms of C. albicans and the closely related C. dubliniensis as
well as the effect of different AA metabolism inhibitors on PGE2 production. Candida
albicans and C. dubliniensis biofilms were both capable of producing PGE2 and
PGF2α, from exogenous AA. The use of different inhibitors suggested that
cytochrome P450s and multicopper oxidases are involved in PGE2 production by
these Candida biofilms. It is known that mammalian cells cannot produce PGE2 from
non-methylene interrupted fatty acids (NMIFAs), such as sciadonic acid (SA) (n-6
fatty acid). This property provides these fatty acids with potential anti-inflammatory
activities. This study indicated the incorporation of SA into the lipids of epithelial
cells, which reduced PGE2 production and influenced cytokine profiles in SA
supplemented epithelial cells infected with C. albicans or C. dubliniensis. This
suggest that the incorporation of n-6 NMIFAs, such as SA, might lead to a reduction
in pro-inflammatory prostaglandins, especially PGE2, which could benefit the host
during a Candida infection. Interestingly, both C. albicans and C. dubliniensis
biofilms were unable to produce PGE2 from exogenous SA. Further genomic hybridization studies were used to evaluate the regulation of C. albicans biofilm
genes during incubation in the presence of exogenous AA and SA. Transcriptional
analysis indicated that the genes differentially expressed in the presence of AA had
diverse functions not normally required for cell growth. Genes encoding for
oxidoreductase and hydrolase activity were regulated, but were not clearly involved
in PGE2 synthesis. Interestingly, genes that encode for ABC transporters, as well as
genes associated with filamentous and hyphal growth, carbohydrate metabolic
processes and oxidative stress response were differentially expressed by the
presence of AA. Further studies of these differentially expressed genes are needed
to evaluate how they may be involved in AA metabolism and PGE2 production.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-08142012-160747 |
| Date | 14 August 2012 |
| Creators | Ells, Ruan |
| Contributors | Prof J Albertyn, Prof JLF Kock, Dr CH Pohl-Albertyn |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-08142012-160747/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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