The development of novel experimental strategies for elucidating the role of tryptophan metabolism in the neuropsychopathology of Human African Trypanosomiasis

Fathallah, Nadin and Dawson, Neil and Urbaniak, Mick (2020) The development of novel experimental strategies for elucidating the role of tryptophan metabolism in the neuropsychopathology of Human African Trypanosomiasis. PhD thesis, Lancaster University.

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Abstract

Trypanosoma brucei is an extracellular protozoan parasite that causes Human African Trypanosomiasis. Trypanosomes are found in the blood, lymphatic system, adipose tissue, and skin during the early stage infection, and additionally in the brain in the late stage infection. The late stage is characterised by neuropsychiatric symptoms and sleep disorder that occur through an undefined mechanism. Trypanosomes cultured in vitro significantly deplete tryptophan from the media, using it in both protein synthesis and transamination reactions. In mammals, as well as forming an essential component of the kynurenine pathway, with both neurotoxic and neuroprotective branches, tryptophan is also the precursor of serotonin and melatonin, which are both implicated in sleep regulation. Research has also shown changes in brain tryptophan levels and increased 5-Hydroxytryptophan in stage II clinical samples. In this thesis, I will investigate the connection between parasite localisation, tryptophan metabolism, and behaviour in a murine model of late stage HAT. Ex vivo imaging data using red-shifted luciferase expressing parasites reveals parasite localisation to many organs during early stage infection. HPLC-based analysis of brain tissue confirmed changes in in vivo tryptophan levels across the course of infection. Functional brain imaging found evidence for altered brain glucose metabolism and behavioural characterisation identified impaired locomotor, but not impaired learning and memory, in late stage HAT. Taken together this data suggests a correlation between parasite localisation, tryptophan metabolism and behavioural changes that may be clinically relevant. In addition, in the final chapter of this thesis I outline the development of genetically modified Trypanosomes that will allow future characterisation of the relationship between parasite tryptophan metabolism and the changes seen in host brain function and behaviour.