PubMed1996
Human African trypanosomiasis (HAT) is caused by infestation with a flagellate protozoan, the trypanosome which is inoculated by the bite of the tsetse fly Glossina. The particular ecological conditions of parasites and vectors are such that the disease is only found in the intertropical regions of Africa. Although there are many species of trypanosomes, only two, belonging to the brucei group are likely to lead to HAT. These two species are quite similar morphologically but have different pathogenicity. Trypanosoma brucei gambiense found in West and Central Africa leads to a chronic form of the disease or sleeping sickness. T. b. rhodesiense leads to a more virulent and acute condition, although for each species of trypanosome there are strains of different virulence, which account, at least in part, for the interindividual variability in the clinical course. Immediately after penetration into the human organism, the trypanosome multiplies at the point of inoculation, producing a local inflammatory reaction. It then invades the whole organism, and the central nervous system (CNS). The involvement of the CNS leads to an irreversible demyelinating process ending by death without treatment. Apart from the initial stages, it is not easy to determine the phase of the disease that the patient is presenting. The parasite can escape the host immune response by varying the surface glycoprotein coat. Variable surface glycoproteins (VSG) are strongly antigenic and lead to great antibody response with immune lysis. But, some heterologous antigenic variants can survive to repopulate blood and other tissues. This mechanism of antigenic variation is under parasite genetic control. The trypanosome can release numerous pathogenic substances which cause alterations in cytokine/prostaglandin network. A 41-46 kDa molecule termed trypanosome-released lymphocyte trigerring factor may selectively activate CD8+ T cells to produce interferon-gamma which then activates macrophages but also promotes parasite growth. Activated macrophages release tumor necrosis factor alpha and nitric oxide (NO) which are trypanostatic static and other cytokines and prostanglandins. These macrophage relased substances enhance the immunosuppression and alter the blood brain barrier (BBB). So, trypanosomes and inflammatory cells can invade the CNS leading to a progressive meningoencephalitis with typical perivascular cuffings which explain neurological disorders and neuroendocrine alterations. The inflammatory cells (lymphocytes, astrocytes, glial cells) produce cytokines, NO and other mediators and enhance the CNS immunopathological process. The peri-ventricular regions, the tuberoinfundibula and thalamic-hypothalamic regions, are particulary involved. These disturbances lead to a progressively complete disruption of the normal sleep-waking cycle. Antibodies anti-CNS components (galactocerebrosides, neurofilaments, tryptophane) are also described in sera and cerebrospinal fluid (CSF) of HAT patients. Their presence may be due to cross reactions with comon epitopes between host and trypanosomes which can lead to a self-propagating autoimmune reaction, which accounts for the marked demyelination found in the late stage of the disease. The diagnosis of CNS involvement in not easy to establish in the early neurological phase in the absence of neurological signs and in absence of great chnages in CSF. This is an important problem because it is the basis to apply existing available drugs. pentamidine and suramin are effective only in early stages of the disease when CNS is not invaded. Melarsoprol is effective in all-stages: this is the drug of choice when CNS is involved. Unfortunaley, melarsoprol is toxic and, in 5% of treated patients, this drug can lead to arsenical encephalopathy which is often fatal. In the continuing search for new antitrypanosonal drugs, biochemical peculiarities of the trypanosome are used as drug garget, especially glycolysis, trypanothione, sensibil