African trypanosome infections of the nervous system: Parasite entry and effects on sleep and synaptic functions
Introduction
Human African trypanosomiasis (HAT) is associated with severe disturbances in nervous system functions, which include extrapyramidal and neuropsychiatric symptoms, sensory alterations and characteristic changes in sleep pattern. Due to sleep changes, the disease is also designated with the alternative name, sleeping sickness (Kennedy, 2004).
Two subspecies of the hemoflagellate Trypanosoma brucei (T. b.), transmitted by populations of tsetse flies in sub-Saharan Africa, cause HAT (Fig. 1). Trypanosoma brucei gambiense is the causative agent for the West African or Gambian form of the disease; this subspecies has man as the main host and the disease has a slowly progressive course over months or even years, which increases the chances for transmission of the parasites to the tsetse fly vector. On the other hand, Trypanosoma brucei rhodesiense, which is responsible for the East African or Rhodesian form, has game animals and cattle as main hosts; when humans are infected, the course of disease is faster, its evolution being reduced to weeks or a few months. The geographical demarcation line between the two forms follows roughly the Rift Valley, and in Uganda both forms exist (Welburn et al., 2001) (Fig. 1). A third subspecies, Trypanosoma brucei brucei, is pathogenic for animals, including rodents, whereas humans have a serum factor, apolipoprotein L-I, that kills this parasite subspecies. Thus, T. b. brucei are safer to use in experimental studies than the human pathogenic T. b. gambiense and T. b. rhodesiense, which can capture this trypanolytic molecule and therefore survive in the human organism (Vanhollebeke et al., 2008).
The life cycle of the parasites in the vector and host as well as their immunobiology, mechanisms of transmission, and epidemiology have been extensively studied and reviewed. The focus of the present overview is on the interactions between the parasites and the nervous system of the mammalian host.
African trypanosomes spend their life in the blood and tissues without entering the host's cells. Thus, disturbances of nervous system functions should be caused by factors released either by the parasites or the host's immune response during the infection, or both. We will here review data indicating that spread of T. b. to the nervous system is a multi-step process, which is at least partly regulated by immune response molecules, and that such molecules and trypanosome-derived factors can affect synaptic functions causing nervous system alterations, including the disrupted sleep pattern. In particular, we will address mechanisms for T. b. entry into the nervous system and sleep disturbances during the disease caused by the parasite. Other symptoms of T. b. infection will also be discussed in the context of the effects exerted by the parasite on synaptic functions.
Section snippets
Prevalence
HAT is endemic in foci in sub-Saharan African countries (Fig. 1) and, depending on ecological and socioeconomic factors, the disease expands or contracts in these areas (Welburn et al., 2001). The disease has been known for centuries, but reached levels of sizeable epidemics through migration of people and cattle during the colonization of Africa. The outbreak in Uganda at the beginning of last century claimed the life of about two-thirds of the population. During this epidemic, trypanosomes
Spread of African trypanosomes to the nervous system
Initial multiplication of the parasites at the infection site is followed by a hemo-lymphatic stage with waves of parasitemia (stage 1). Subsequently, trypanosomes invade the nervous system to cause a leukoencephalitis (meningo-encephalitic stage 2).
The disease is invariably lethal if left untreated. Effective stage 1 drugs, suramin and pentamidine, penetrate poorly the blood–brain barrier (BBB), and are therefore ineffective at stage 2. For treatment of the late encephalitic stage of HAT,
Effects of African trypanosome infections on sleep and circadian rhythms
As mentioned previously (see Section 1), T. b. infections in patients and in experimental rodents are hallmarked by disturbances of sleep. The regulation of sleep and endogenous rhythms is here summarized as a premise to the presentation of clinical symptoms and discussion of potential pathogenetic mechanisms.
Involvement of brain regions implicated in sleep–wake regulation
For the discussion of pathogenetic mechanisms, it is first of all worth to emphasize that only minor, if any, signs of degeneration of neuronal cell bodies have been found in the brain of T. b. brucei-infected rats and mice, even in chronic forms of experimental infection (Keita et al., 1997, Mhlanga et al., 1997, Quan et al., 1999), though degenerating fibers have been revealed by silver staining in a few brain sites in T. b. brucei-infected rats (Quan et al., 1999). Glial cell activation is
Other nervous system dysfunctions in African trypanosomiasis
The localization of the inflammatory response to the CVOs, diencephalic cell groups around the third ventricle and white matter (Kristensson and Bentivoglio, 1999) may also account for other signs of disease in HAT patients, which include endocrine disturbances and disorders of muscle tone and movements (Dumas and Bisser, 1999). Impotence, amenorrhea and infertility are frequent and disturbances in sex steroid and gonadotropin levels have been reported in HAT (Dumas and Bisser, 1999).
Concluding remarks
We have here highlighted recent studies showing that passage of trypanosomes and T cells into the brain is a multi-step process and that, like in experimental allergic encephalomyelitis, IFN-γ and IFN-γ-induced chemokines play a crucial to promote this entry, which may provoke the severe morbidity of the disease. We have also pointed out that by localization to basal meninges and CVOs trypanosomes may cause release of molecules that could affect the function of neurons involved in the
Acknowledgments
The study was supported by a grant from the European Commission (FP6-2004-INCO-DEV-3 032324; NEUROTRYP). The authors are grateful to Karolina Kristensson for the preparation of Fig. 2, Fig. 4.
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