Date of Award
12-2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biochemistry and Molecular Biology
Committee Chair/Advisor
James Morris
Committee Member
Kimberly Paul
Committee Member
Jennifer Mason
Committee Member
Cheryl Ingram-Smith
Abstract
African trypanosomes are protozoan parasites that cause the diseases African sleeping sickness and nagana, in humans and cattle respectively. These parasites have complex life cycles with infection of a mammalian host, ~5mM glucose, following transmission by an insect vector, essentially zero glucose. With these pathogens being exposed to rapidly changing glucose abundance in a host-dependent manner, the ability to sense and rapidly respond to changes in the availability of the hexose are critical. First, I provide a review of glucose metabolism in Trypanosoma brucei. Then, we explore the role of the catalytic α subunit of AMPK, a eukaryotic master regulator of energy, in procyclic form T. brucei. We found that the larger species of AMPKα1, coined AMPKα1+, was more abundant in the presence of glucose, and other metabolizable sugars. Subcellular location of AMPKα1 was similar regardless of glucose abundance. Phosphorylated AMPKα1 had an association with membranes, hypothesized to connect nutrient sensing and signaling pathways. Lastly, we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites were rapidly killed as glucose concentrations fell, while short stumpy bloodstream form parasites persisted to differentiate into the insect stage procyclic form parasite. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and non-metabolizable glucose analogs and these parasites were found to have upregulated amino acid metabolic pathway component gene expression. In summary, glucose transitions from the primary metabolite of the blood stage infection to a negative regulator of cell development and growth in the insect vector. These data suggest that glucose is not only a key metabolic agent but is also an important signaling molecule and may be signaling through TbAMPK.
Recommended Citation
Jones, Jessica, "Exploring the Role of AMPK in Nutrient Sensing and Signaling in the Human Parasite Trypanosoma brucei" (2021). All Dissertations. 2947.
https://open.clemson.edu/all_dissertations/2947