- Human African Trypanosomiasis
- CNS invasion by African trypanosomes
- Focus-specific clinical phenotypes
- In vitro Blood Brain Barrier Model
My current research focuses on central nervous system (CNS) invasion by African trypanosomes. This work addresses one of the key deficiencies in development of new drugs for late stage African trypanosomiasis: the lack of a robust model for parasite transmission across the blood brain barrier.
I have established foci-specific T.b.rhodesiense HAT clinical phenotypes showing dramatic variation in disease severity and rate of stage progression both between northern and southern East African foci and between geographically close Ugandan HAT foci (Study sites in Uganda and Malawi are shown in Figure 1, active screening for HAT cases in Uganda is shown in Figure 2). Such marked variation in disease severity suggests there are differences in host susceptibility to trypanosome infection and/or genetic variation in trypanosome virulence. Understanding the contribution of host and parasite factors in causing such clinical diversity in HAT is critical for improving management of this neglected disease as well as identifying late stage markers for diagnostics and new candidates for late stage treatment.
Little is known about the mechanism by which trypanosomes cross the BBB but it is thought that both parasite and host factors affect BBB integrity. The BBB is composed of brain microvascular endothelial cells (BMEC) surrounded by basal lamina and astrocytic perivascular endfeet. It has been proposed from studies using an in vitro BBB model that brucipain, a trypanosome cysteine protease, induces calcium activation signals in BMEC via protease-activated receptors (PARs), thereby causing brain endothelial barrier dysfunction allowing trypanosome BBB transmigration. There is also evidence in mouse models that the host neuroinflammatory response plays a role in determining trypanosome entry into the CNS.
I am currently developing a human BMEC in vitro system to mimic events at the human BBB using recently developed cell biological methods with fluorescent transgenic parasites (Figure 3) of different subspecies with known clinical profiles. Availability of a refined in vitro model will facilitate both identification of new diagnostic markers and development of new treatments for late stage HAT infection.