Researchers from the Instituto de Medicina Molecular report that African sleeping sickness is a circadian rhythm disorder caused by the acceleration of biological clocks controlling a range of vital functions besides sleep. By understanding which clock genes are affected by the parasitic disease, scientists hope the research will eventually prove useful in developing therapeutic alternatives to the toxic treatments that are occasionally fatal to patients.
“This is not specifically a sleeping disorder,” said Luisa Figueiredo, Ph.D., group leader at Instituto de Medicina Molecular.
The disease, known as human African trypanosomiasis, is transmitted through the bite of the tsetse fly and threatens tens of millions of people in sub-Saharan African countries. After entering the body, the parasite causes such symptoms as inverted sleeping cycles, fever, muscle weakness, and itching. It eventually invades the central nervous system and, depending on its type, can kill its host in anywhere from a few months to several years.
The team’s mouse study (“Sleeping Sickness Is a Circadian Disorder”), published in Nature Communications, shows sleeping sickness symptoms can occur soon after infection, even before parasites accumulate in large numbers in the brain. Scientists found that the biological clocks in infected mice ran faster after parasites entered the bloodstream, resulting in inverted sleeping 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 rhythm disorders: The biological clocks of mice infected with malaria were unaltered.
“Sleeping sickness is a fatal disease caused by Trypanosoma brucei, a unicellular parasite that lives in the bloodstream and interstitial spaces of 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 phase advanced upon infection, with abnormal activity occurring during the rest phase. This advanced phase is caused by shortening of the circadian period both at the behavioral level as well as at the tissue and cell level,” write the investigators.
“Period shortening is T. brucei specific and independent of the host immune response, as co-culturing parasites with explants or fibroblasts also shortens the clock period, whereas malaria infection does not. We propose that T. brucei causes an advanced circadian rhythm disorder, previously associated only with mutations in clock genes, which leads to changes in the timing of sleep.”
“What we still need to find out is exactly what is causing the clocks to change during sleeping sickness. Is it a secretion from the parasite, or a molecule produced by the host in response to the infection? Knowing the source will help us have a better understanding of the disease and potentially block such effects.” said Dr. Figueiredo, who was recently awarded a grant from the European Research Council.
The study is the second recent collaborative effort between Dr. Figueiredo and Joseph Takahashi, Ph.D., at the University of Texas Southwestern Medical Center, Dallas. It builds upon research they published last year that showed for the first time that parasites have biological clocks. The study further showed that this circadian cycle renders T. brucei more vulnerable to medications during the afternoon.
Both findings could eventually be beneficial for patients whose bodies can't handle 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 findings will allow them to reduce the duration and dosage of current treatments by knowing the optimal time to administer them.