African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions.
The extracellular parasite Trypanosoma brucei causes human African trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes are transmitted by tsetse flies and HAT occurs in foci in sub-Saharan Africa. The disease, which is invariably lethal if untreated, evolves in a first hemo-lymphatic stage, progressing to a second meningo-encephalitic stage when the parasites cross the blood-brain barrier. At first, trypanosomes are restricted to circumventricular organs and choroid plexus in the brain outside the blood-brain barrier, and to dorsal root ganglia. Later, parasites cross the blood-brain barrier at post-capillary venules, through a multi-step process similar to that of lymphocytes. Accumulation of parasites in the brain is regulated by cytokines and chemokines. Trypanosomes can alter neuronal function and the most prominent manifestation is represented by sleep alterations. These are characterized, in HAT and experimental rodent infections, by disruption of the sleep-wake 24h cycle and internal sleep structure. Trypanosome infections alter also some, but not all, other endogenous biological rhythms. A number of neural pathways and molecules may be involved in such effects. Trypanosomes secrete prostaglandins including the somnogenic PGD2, and they interact with the host's immune system to cause release of pro-inflammatory cytokines. From the sites of early localization of parasites in the brain and meninges, such molecules could affect adjacent brain areas implicated in sleep-wakefulness regulation, including the suprachiasmatic nucleus and its downstream targets, to cause the changes characteristic of the disease. This raises challenging issues on the effects of cytokines on synaptic functions potentially involved in sleep-wakefulness alterations.
Kristensson
Krister
K
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm SE-171 77, Sweden. krister.kristensson@ki.se
Nygård
Mikael
M
Bertini
Giuseppe
G
Bentivoglio
Marina
M
D000818:Animals; D001921:Brain / Q000276:immunology; D020808:Central Nervous System Protozoal Infections / Q000276:immunology* / Q000469:parasitology*; D006801:Humans; D012890:Sleep / Q000276:immunology*; D012893:Sleep Wake Disorders / Q000276:immunology* / Q000469:parasitology*; D009435:Synaptic Transmission / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology*