Comparative metabolomics of erythroid lineage and Plasmodium life stages reveal novel host and parasite metabolism

Srivastava, Anubhav (2014) Comparative metabolomics of erythroid lineage and Plasmodium life stages reveal novel host and parasite metabolism. PhD thesis, University of Glasgow.

Abstract

Malaria, caused by the Apicomplexan parasite Plasmodium is a deadly disease which poses a huge health and economic burden over many populations in the world, mostly in sub-Saharan Africa and Asia. To design new intervention strategies and to improve upon existing drugs against malaria, it is important to understand the biochemistry of the Plasmodium parasite and its interaction with the host.
We used metabolomics to dissect the biology of the reticulocyte preferring rodent malaria parasite Plasmodium berghei and showed that metabolic reserves in the reticulocytes can aid in survival of malaria parasites when their metabolism is genetically or chemically disrupted, pointing towards a direct role of host cell metabolism in parasite survival. These results have implications for currently used ways of intermediation in malaria infections which target only parasite metabolism against the human malaria parasites, Plasmodium vivax which prefers to infect reticulocytes and Plasmodium falciparum which is capable of infecting all erythrocytes.
We also used metabolomics to show the biochemical differences between the asexual and sexual stages of P. berghei parasites and our data gave additional insights into the preparatory phase of the gametocyte stage at the metabolic level with the discovery of a phosphagen system which plays a role in gametogenesis. Targeted metabolomics of P. berghei life stages using isotopic labelling showed that TCA cycle metabolism is predominant in the mosquito stages. Discovery of a reductive arm of TCA metabolism in reticulocytes pointed towards the existence of rudimentary mitochondria in young erythrocytes. Another surprising discovery was the presence of up regulated γ-Aminobutyric acid (GABA) metabolism in the ookinete stage in P. berghei which may act as an energy source during the ookinete to oocyst transition in the mosquito. This pathway presented novel candidates for transmission blocking.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: malaria, reticulocytes, metabolomics, GABA, gametocytes
• Subjects: Q Science > QH Natural history > QH301 Biology; Q Science > QH Natural history > QH345 Biochemistry
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Parasitology
• Supervisor's Name: Waters, Prof. Andy
• Date of Award: 2014
• Depositing User: Mr Anubhav Srivastava
• Unique ID: glathesis:2014-5725
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 Nov 2014 14:04
• Last Modified: 12 Nov 2014 14:59
• URI: https://theses.gla.ac.uk/id/eprint/5725