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

Abstract

Neuron populations of the lateral hypothalamus which synthesize the orexin (OX)/hypocretin or melanin-concentrating hormone (MCH) peptides play crucial, reciprocal roles in regulating wake stability and sleep. The disease human African trypanosomiasis (HAT), also called sleeping sickness, caused by extracellular Trypanosoma brucei (T. b.) parasites, leads to characteristic sleep-wake cycle disruption and narcoleptic-like alterations of the sleep structure. Previous studies have revealed damage of OX and MCH neurons during systemic infection of laboratory rodents with the non-human pathogenic T. b. brucei subspecies. No information is available, however, on these peptidergic neurons after systemic infection with T. b. gambiense, the etiological agent of 97% of HAT cases. The present study was aimed at the investigation of immunohistochemically characterized OX and MCH neurons after T. b. gambiense or T. b. brucei infection of a susceptible rodent, the multimammate mouse, Mastomys natalensis. Cell counts and evaluation of OX fiber density were performed at 4 and 8 weeks post-infection, when parasites had entered the brain parenchyma from the periphery. A significant decrease of OX neurons (about 44% reduction) and MCH neurons (about 54% reduction) was found in the lateral hypothalamus and perifornical area at 8 weeks in T. b. gambiense-infected M. natalensis. A moderate decrease (21% and 24% reduction, respectively), which did not reach statistical significance, was found after T. b. brucei infection. In two key targets of diencephalic orexinergic innervation, the peri-suprachiasmatic nucleus (SCN) region and the thalamic paraventricular nucleus (PVT), densitometric analyses showed a significant progressive decrease in the density of orexinergic fibers in both infection paradigms, and especially during T. b. gambiense infection. Altogether the findings provide novel information showing that OX and MCH neurons are highly vulnerable to chronic neuroinflammatory signaling caused by the infection of human-pathogenic African trypanosomes.

Sleeping Sickness Disrupts the Sleep-Regulating Adenosine System

“…Of note, the alterations we see in sleep behavior are distinct from the direct wake to REM transitions seen with narcolepsy that are mediated by the orexin system. While there is some indication that T. brucei infection causes orexin and MCH neuronal death in rats (Palomba et al, 2015) of which orexin loss would be expected to result in SOREMs, other studies have shown that only T. brucei gambiense induces significant damage to orexin and MCH neurons (Laperchia et al, 2018) as well as the SCN (Tesoriero et al, 2018) in susceptible organisms. However, these models may not fully recapitulate human sleeping sickness pathophysiology, as postmortem studies do not indicate significant neuronal damage (Kennedy, 2004).…”

Role of T cells during the cerebral infection with Trypanosoma brucei

“…Distinct sleep changes during T.b.b. infection can be due to altered function or damage of the population of neurons that reside in the lateral hypothalamus which releases the orexin peptide pair [55][56][57][58]. A role for T cells in narcolepsy, where sleep dysregulation resembles the one of T.b.…”

Neuropathogenesis caused by Trypanosoma brucei, still an enigma to be unveiled

“…Autoptic analyses had shown diffuse microglial hyperplasia, a proliferation of astrocytes, and the formation of microglial nodules [13,14]. Studies carried on in experimental animal models proved astrocytosis and evidenced neuronal loss in some areas of the brain [15][16][17][18]. Another common feature between HAT patients and animal models is the presence of an inflammatory infiltrate in the parenchyma [19,20].…”