Neuropathogenesis of African trypanosomiasis: The use of a mouse model system to elucidate likely mechanisms of the disease process and to design potential therapeutic strategies in man

Human African trypanosomiasis (HAT), also known as sleeping sickness, is prevalent in sub-Saharan Africa. The illness results from infection with the protozoan parasites Trypanosoma brucei (T.b.) gambiense in West and Central Africa and T.b.rhodesiense in East and Central Africa and is spread through the bite of the insect vector of the parasite, the tsetse fly. Both forms of the disease are invariably fatal if not diagnosed and drug treated. During the acute-stage of the infection the trypanosomes spread from the site of the tsetse fly bite, via the lymphatics and bloodstream to invade most of the organs and tissues of the body. As the disease progresses the parasites enter the brain tissue and become established within the CNS and a neuroinflammatory reaction develops. Treatment of the infection once it has reached the CNS-stage is problematic since few trypanocidal drugs can cross the blood-brain barrier (BBB) to clear' the parasites that are sequestered in the brain. The only drug commonly available to treat this stage of the disease is the arsenical derivative melarsoprol but its use is associated with the development of a post-treatment reactive encephalopathy (PTRE) that can in itself prove fatal. The PTRE is characterised by a severe meningoencephalitic reaction with the presence of reactive astrocytes, macrophages, T-cells, B-cells and plasma cells. The pathogenesis of this adverse reaction remains unclear. Since brain tissue can only be obtained from post-mortem cases of HAT, there is a paucity of information regarding the early changes that occur within the CNS following infection and during the development of the PTRE. Therefore, a well-established and highly reproducible murine model, which closely mimics the human disease, was used in the current investigation to elucidate the kinetics of cellular reactivity and the expression of cytokines and chemokines following trypanosome-infection and induction of the PTRE. The mode of action of the ornithine decarboxylase inhibitor, efiornithine, a typanostatic drug used in the treatment of trypanosome infections, was also examined in the possible prevention and amelioration of the severe meningoencephalitic reaction, In addition, the role of the neuropeptide Substance P (SP) in the modulation of the inflammatory response associated with the disease was investigated. In this study eflornithine resistant trypanosomes were used in the infections to isolate the anti-inflammatory effects of the drug treatment from those that arise due to the clearance of the parasites. Therefore, the value of eflornithine treatment as an anti-inflammatory agent, even in cases where trypanosome resistance to the drug is suspected was demonstrated. The identification of the key cellular and functional events resulting in the neuroinflammatory reaction associated with trypanosome infection have allowed a further degree of understanding regarding the mechanisms involved in the development of the CNS inflammation in human disease. Without the existence of the murine model the above conclusions could not have been reached. Furthermore, it is now possible to consider application of the potential novel therapeutic approaches indicated by this study, to prevent and ameliorate the development of the CNS inflammatory reaction, in the management of this devastating disease condition in man. (Abstract shortened by ProQuest.)