Researchers at the Instituto de Medicina Molecular report that African sleeping sickness is a circadian rhythm disorder caused by the acceleration of biological clocks that control a number of vital functions in addition to sleep. By understanding which clock genes are affected by the parasitic disease, scientists hope the research will ultimately prove useful in developing therapeutic alternatives to the toxic treatments that are sometimes fatal to patients.
“This is not specifically a sleep disorder,” said Luisa Figueiredo, Ph.D., group leader at the Instituto de Medicina Molecular.
The disease known as human African trypanosomiasis is transmitted by the bite of the tsetse fly and threatens tens of millions of people in countries south of the Sahara. Once inside the body, the parasite causes symptoms such as inverted sleep cycles, fever, muscle weakness, and itching. It eventually invades the central nervous system and can kill its host within a few months to several years, depending on the species.
The team’s mouse study (“Sleeping Sickness Is a Circadian Disorder”), published in Nature Communications, shows that symptoms of sleeping sickness can occur shortly after infection, before large numbers of parasites have built up in the brain. Scientists found that infected mice had biological clocks spinning faster after parasites entered the bloodstream, causing reversed sleep cycles, as well as hormone and body temperature abnormalities similarly seen in patients with sleeping sickness.
However, not all parasitic diseases appear to be circadian arrhythmias: the biological clocks of mice infected with malaria were unchanged.
“Sleeping sickness is a deadly disease caused by Trypanosoma brucei, a unicellular parasite that lives in the bloodstream and in the spaces between peripheral tissues and the brain. Patients have altered sleep-wake cycles, body temperature, and endocrine profiles, but the underlying causes are unknown. Here we show that the robust circadian rhythms of mice become out of phase after infection, with abnormal activity occurring during the resting phase. This advanced phase is caused by a shortening of the circadian period both at the behavioral level and at the tissue and cellular level, ”the researchers write.
“The shortening of the period is T. brucei-specific and independent of the host’s immune response, since the cocultivation of parasites with explants or fibroblasts also shortens the clock period, while the malaria infection does not. We suspect that T. brucei causes an advanced circadian rhythm disorder that was previously only associated with mutations in clock genes and leads to changes in the time of sleep. “
“What we still have to find out is what exactly changes the clocks during sleeping sickness. Is it a secretion from the parasite or a molecule the host produces in response to the infection? Knowing the source will help us better understand the disease and possibly block such effects. ”Said Dr. Figueiredo, who recently received a grant from the European Research Council.
The study is the second current collaboration between Dr. Figueiredo and Joseph Takahashi, Ph.D. at Southwestern Medical Center at the University of Texas, Dallas. It builds on research they published last year that first showed that parasites have biological clocks. The study also showed that this circadian cycle made T. brucei more susceptible to medication in the afternoon.
Ultimately, both outcomes could be beneficial for patients whose bodies cannot handle the side effects of the arsenic-based treatments used to eradicate the parasite. In addition to knowing which genes to target when developing new therapies, doctors hope the results will enable them to reduce the duration and dosage of current treatments by knowing the optimal time to give them.