Department of Biological Sciences
University of Salford
Salford, M54WT, U.K.
frican sleeping sickness (trypanosomiasis) is caused by the extracellular protozoan parasite Trypanosoma brucei (T.b.), one strain of which (T.b. gambiense) produces, if untreated, a chronic disease form with prominent CNS (late-stage) involvement. Symptoms include dysregulation of endogenous rhythms such as sleep and temperature. Sleep patterns take the form of daytime somnolence and nocturnal restlessness with frequent awakenings and disorganisation, leading to permanent somnolence and death.
The complex neuropathology has been extensively studied in man and in the mouse and rat models. In rodents trypanosomes have been observed in some localised brain areas where the blood-brain barrier is reduced, including the pineal gland, median eminence and the area postrema. In both humans and rodents the choroid plexus is damaged and parasites occupy the CSF. The blood-brain barrier is compromised and there is vasogenic oedema with encephalitis consisting of widespread inflammatory changes with perivascular infiltration of B-cells, plasma cells and macrophages. Astrocytes and microglia become activated. Because of damage at other sites in the patient high levels of bacterial breakdown products (endotoxin) and parasite debris have access to the CSF and brain. Not surprisingly, there are marked changes in the cytokine/mediator network both in the brain and elsewhere in the body(1).
In a study using radioimmunassay techniques high levels of PGD2 (up to several thousand pg/ml) were found in the CSF of late-stage patients (2). There were no significant increases of PGE2 or IL-1. These findings have been confirmed by gas chromatography/mass spectroscopy (GC-MS). We have also found high levels of PGE2, in the CSF of some of these patients. All prostaglandin levels were reduced following chemotherapy.
The involvement of astrocytes in PG production following exposure to the parasites and endotoxin was studied in culture (3). The trypanosome material and endotoxin caused astrocyte activation (i.e. altered morphology to stellate shape, increases in glial fibrillary acidic protein, enhanced MHC class I and I expression), and dose and time-dependent increases in PGD2 and PGE2 synthesis. The combination of both mitogens caused synergistic production of PGS to levels higher than caused by each alone. Therefore the CNS changes in late-stage sleeping sickness include enhanced PG production from astrocytes.
1. Pentreath, V.W. (1995) Trypansomiasis and the nervous system. Trans. Roy. Soc. Trop. Med. Hyg. 89, 9-15.
2. Pentreath, V.W., Rees, K., Owolabi, O. A., Philip, K. and Doua, F. (1990). The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in the cerebrospinal fluid of advanced sleeping sickness patients. Trans. Roy. Soc. Trop. Med. Hyg. 84, 795-799.
3. Alafiatayo, R.A., Cookson, M.R. and Pentreath, V.W. (1994) Production of prostaglandins D2 and E2 by mouse fibroblasts and astrocytes in culture caused by Trypansoma bruci bruci products and endotoxin. Parasitol. Res. 80, 223-229.
