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Purification of Extracellular Trypanosomes, Including African, from Blood by Anion-Exchangers (Diethylaminoethyl-cellulose Columns)
Published on: April 6, 2019
Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms
Juma A M Ali1, Daniel N A Tagoe, Jane C Munday
1Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Plos One
|March 19, 2013
Summary
African trypanosomes can synthesize pyrimidines or salvage them from the host. Disrupting pyrimidine synthesis is lethal, making salvage essential for parasite survival and infectivity.
Area of Science:
- Parasitology
- Molecular Biology
- Biochemistry
Background:
- African trypanosomes exhibit both de novo pyrimidine biosynthesis and host pyrimidine salvage pathways.
- The essentiality of these pathways for parasite survival remained undetermined.
Purpose of the Study:
- To investigate the essentiality of pyrimidine biosynthesis and salvage for Trypanosoma brucei brucei growth and infectivity.
- To determine the parasite's preferred pyrimidine source for survival.
Main Methods:
- Culturing Trypanosoma brucei brucei in pyrimidine-free media.
- Gene knockout of the PYR6-5 locus encoding orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase).
- Assessing parasite growth, DNA content, pyrimidine antimetabolite sensitivity, and uracil transport rates.
Main Results:
- Wild-type trypanosomes grew normally in pyrimidine-free medium, indicating salvage is sufficient.
- Knockout of PYR6-5 rendered trypanosomes auxotrophic, strictly dependent on extracellular pyrimidines, with uracil being preferred.
- Pyrimidine starvation was rapidly lethal, causing incomplete DNA replication and reduced infectivity in mice.
Conclusions:
- Pyrimidine salvage is not essential for bloodstream T. b. brucei.
- De novo pyrimidine biosynthesis is essential, with trypanosomes showing a strong preference for uracil.
- While the de novo pathway is essential, its non-viability as a drug target is suggested due to efficient host salvage, yet its interruption is lethal.
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