Neural Damage in Experimental Trypanosoma brucei gambiense Infection: The Suprachiasmatic Nucleus

Abstract

Trypanosoma brucei (T. b.) gambiense is the parasite subspecies responsible for most reported cases of human African trypanosomiasis (HAT) or sleeping sickness. This severe infection leads to characteristic disruption of the sleep-wake cycle, recalling attention on the circadian timing system. Most animal models of the disease have been hitherto based on infection of laboratory rodents with the T. b. brucei subspecies, which is not infectious to humans. In these animal models, functional, rather than structural, alterations of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), have been reported. Information on the SCN after infection with the human pathogenic T. b. gambiense is instead lacking. The present study was aimed at the examination of the SCN after T. b. gambiense infection of a susceptible rodent, the multimammate mouse, Mastomys natalensis, compared with T. b. brucei infection of the same host species. The animals were examined at 4 and 8 weeks post-infection, when parasites (T. b. gambiense or T. b. brucei) were detected in the brain parenchyma, indicating that the disease was in the encephalitic stage. Neuron and astrocyte changes were examined with Nissl staining, immunophenotyping and quantitative analyses. Interestingly, significant neuronal loss (about 30% reduction) was documented in the SCN during the progression of T. b. gambiense infection. No significant neuronal density changes were found in the SCN of T. b. brucei-infected animals. Neuronal cell counts in the hippocampal dentate gyrus of T. b. gambiense-infected M. natalensis did not point out significant changes, indicating that no widespread neuron loss had occurred in the brain. Marked activation of astrocytes was detected in the SCN after both T. b. gambiense and T. b. brucei infections. Altogether the findings reveal that neurons of the biological clock are highly susceptible to the infection caused by human pathogenic African trypanosomes, which have the capacity to cause permanent partial damage of this structure.

Neural Damage in Experimental Trypanosoma brucei gambiense Infection: Hypothalamic Peptidergic Sleep and Wake-Regulatory Neurons

“…Double immunofluorescence showed in M. natalensis the occurrence of T. b. gambiense and T. b. brucei outside blood vessels within the brain parenchyma, in variable amounts, at both 4 weeks and 8 weeks (Figure 1 ) after infection, as also presented in the companion article (Tesoriero et al, 2018 ). This indicated that in both paradigms the infection was in the encephalitic stage at the sampled time points.…”

“…All efforts were made to minimize animal number and suffering. The present investigation was based on the same brains of the animals used for the study of the SCN presented in a companion article (Tesoriero et al, 2018 ).…”

“…Sleep-wake cycle changes during African trypanosomiasis implicate the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), which drives endogenous biological rhythms in the mammalian brain (van Esseveldt et al, 2000 ; Golombek and Rosenstein, 2010 ; Moore, 2013 ). Findings on neuronal cell loss in the SCN of an animal model of T. b. gambiense infection provided by the multimammate mouse, Mastomys natalensis (Mehlitz, 1975 ; Büscher et al, 2005 ) are presented in a companion article (Tesoriero et al, 2018 ). On the other hand, alterations of sleep architecture in African trypanosomiasis implicate damage to structures of the distributed neural network which regulates sleep and wakefulness (Saper et al, 2010 ; Scammell et al, 2017 ).…”

Circumventricular Organs and Parasite Neurotropism: Neglected Gates to the Brain?

“…The early infection of CVOs by trypanosomes is of interest in view of pathogenetic mechanisms of neural dysfunction. In HAT, which is also called sleeping sickness, functional disturbances include a fragmented sleep pattern and alterations of sleep architecture, documented also in experimental infections in rats (55), and a disruption of the sleep-wake cycle, which is a major circadian rhythm, leading to diurnal somnolence and nocturnal insomnia (56). Other circadian rhythms are also disrupted in HAT patients (56).…”

The Complex Interplay of Parasites, Their Hosts, and Circadian Clocks

“…The multimammate mouse, Mastomys natalensis, was used as a rodent model susceptible to both the human parasite T. brucei gambiense and T. brucei brucei, a pathogen not infectious to humans. Interestingly, infection with T. b. gambiense, but not with T. b. brucei, led to a 30% decrease in SCN neuronal density, while astrocyte activation was noted for both (Tesoriero et al, 2018). This, together with the phase shift of melatonin rhythm in human patients (Claustrat et al, 1998), suggests that the effects on host's circadian clocks also exist in human patients.…”