Sleeping Sickness: A Tale of Two Clocks

Abstract

Sleeping sickness is caused by a eukaryotic unicellular parasite known to infect wild animals, cattle, and humans. It causes a fatal disease that disrupts many rhythmic physiological processes, including daily rhythms of hormonal secretion, temperature regulation, and sleep, all of which are under circadian (24-h) control. In this review, we summarize research on sleeping sickness parasite biology and the impact it has on host health. We also consider the possible evolutionary advantages of sleep and circadian deregulation for the parasite.

Keywords: circadial rhythm disorders; circadian; infectious disease; parasite; sleep.

Figure 1

Life cycle of Trypanosoma brucei. When a tsetse fly vector has a blood meal from an infected human, parasites enter the midgut where mammalian bloodstream stumpy forms sense the lower temperature and different nutrient environment and differentiate into procyclic forms. These will further differentiate into epimastigotes that journey to and populate the salivary glands. The short epimastigotes in the salivary glands goes through a final differentiation in the fly into the infective metacyclic forms, which are injected during the next blood meal of the fly into the mammalian host. In the bloodstream of the mammalian host, metacyclic parasites differentiate into bloodstream forms, consisting of dividing slender forms and cell-cycle arrested (non-dividing) stumpy forms. These parasites can invade and hide within niche conditions in tissues, such as brain and adipose tissue. Purple cycling circle indicates the parasite forms in which endogenous circadian rhythms have been identified (Rijo-Ferreira et al., 2017a).

Figure 2

Eukaryotic tree of life (Adl et al., ; Burki et al., 2020). Rhythms have been identified in most of the subkingdoms of eukaryotes (colored cycling circles near the organism group). However, only a few of these rhythms have been shown to be endogenous to the organisms themselves (although possibly all these organisms have endogenous clocks), and in even fewer the actual circadian clock genes have been identified (purple cycling circle). Euglenids are free-living, aquatic flagellates; Trypanosomatids are eukaryotic parasites; Chlorarachniophytes are a small group of marine algae; Apicomplexa is a group that includes many parasites including Plasmodium, which causes malaria [it has been recently shown to have an endogenous clock (Rijo-Ferreira et al., ; Smith et al., 2020)]; Gonyaulax is a genus of dinoflagellates that are aquatic organisms with two separate flagella; Nannochloropsis are microalgae living in freshwater and seawater that are related to diatoms and brown algae.

Figure 3

Activity and sleep disruption in sleeping sickness patients. (A) Brain (sagittal section) with many of the sleep-wake regulating regions identified and the circadian master clock, the Suprachiasmatic Nucleus (SCN). Represented with trypanosomes is the parasite distribution across the brain. Wake promoting brain areas are represented in green. Sleep promoting brain areas are represented in blue (Scammell et al., 2017). (B, top panels) Electroencephalogram (EEG) recording of a sleeping sickness patient before and after the first treatment session, showing a clear reversal of the sleeping time to the nighttime upon treatment, similar to healthy individuals (blue line) (adapted with authorization from Buguet et al., 1999). The sleeping sickness patient record shows both increased sleep during the daytime and transitions from wake to REM state (SOREM), highlighted with pink stars. (B, bottom panels) An activity record of a sleeping sickness patient, measured by actigraphy, using activity watches. The same patient had his/her activity measured both before and after pentamidine treatment and show clear reversal of the abnormal activity profile after treatment (adapted with authorization from Njamnshi et al., 2012). The blue line represents the normal profile of a healthy individual.

Figure 4

Activity plots (actograms) of both healthy and T. brucei-infected mice in normal light/dark conditions (left) and in constant darkness (right). Note that this representative infected mouse does not run exclusively during the night period, which is extremely uncommon since mice are nocturnal and light imposes a very strong inhibitory effect on circadian behavior. In constant darkness (monitored with infrared goggles as represented on the top right), it is obvious that the period of activity is shorter in infected mice, especially when noting that the time at which activity starts (phase) becomes earlier every day.

Figure 5

Sleeping sickness is a circadian disorder. Representation of a coronal brain section of a mouse, parasites, and inflammatory cells producing cytokines in response to the parasite presence. Bottom section represents the circadian rhythms of the host, either the behavioral output or molecular clock rhythms in SCN tissue or adipose tissue explant.