DALLAS - Jan. 4, 2018 - Sleeping sickness could use a more encompassing moniker.
An international study from the O'Donnell Brain Institute shows one of Africa's most lethal diseases is actually 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 new therapeutic alternatives to the current toxic treatments that are occasionally fatal to patients.
"Sleeping sickness is really a misnomer," said Dr. Joseph S. Takahashi, Chairman of Neuroscience at UT Southwestern's Peter O'Donnell Jr. Brain Institute and an Investigator with the Howard Hughes Medical Institute (HHMI). "Our work shows that the underlying mechanism of altered sleep in this disease is caused by a circadian disorder."
Sleeping sickness - known formally as 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 delivered by the fly causes such symptoms as inverted sleeping cycles, fever, muscle weakness, and itching. The parasite 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 mouse study 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 similar to those 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.
"How the clocks are changing remains a mystery. We need to study further whether the host is producing a molecule in response to the infection, or if there is a secretion from the parasite," said Dr. Takahashi, who in the 1990s made the landmark discovery of the Clock gene in mice that laid the foundation for a new wave of medical research. "Finding the causative agent could aid in the development of drugs to treat the disease and find molecules that modulate the clock for treatment other circadian disorders."
The study is the second recent collaborative effort between Dr. Luisa Figueiredo at the University of Lisbon in Portugal and Dr. Takahashi, who holds the Loyd B. Sands Distinguished Chair in Neuroscience. It builds upon research they published last year that showed for the first time that parasites have biological clocks. The study further revealed that this circadian cycle renders the sleeping sickness parasite - known as Trypanosoma 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 now 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.
Meanwhile, control efforts have significantly reduced the number of cases over the last decade. However, an unknown number of people still die annually from sleeping sickness as scientists continue seeking vaccines and alternative treatments.
"Although many studies on this subject have tried to understand the causes of sleeping sickness, our multidisciplinary effort between a circadian rhythms and a parasitology laboratory led us to the understanding that the circadian clock is at the core of the symptoms observed. It is important to continue this research to better understand both sleeping sickness and other difficult-to-treat parasitic diseases that impact millions across the globe," said Dr. Filipa Rijo-Ferreira, first author of the study and an Associate with HHMI in Dr. Takahashi's laboratory.
The work was supported by HHMI and Foundation for Science and Technology awards.
5 parasite diseases to watch for in the U.S.
While deadly sleeping sickness is primarily transmitted in rural regions of Africa, millions of people in the US are exposed to other forms of parasitic diseases. Here are five such diseases the US Centers for Disease Control and Prevention lists as public-health priorities.
Chagas disease is most commonly acquired through contact with the feces of an infected kissing bug, a blood-sucking insect. There may be swelling where the parasite enters the body, and in rare cases the disease results in life-threatening inflammation of the heart or brain. If untreated, infection is lifelong. CDC estimates about 300,000 people in the US have the condition.
This condition is a leading cause of death related to food-borne illness in the US. More than 30 million Americans carry the parasite, though few show symptoms because their immune systems protect against the illness. People can become infected by eating undercooked, contaminated meat, and women who are infected during pregnancy sometimes pass the parasite to their unborn children. This transfer can result in a miscarriage, a stillborn child, eye disease or unusual head size.
Toxocariasis is caused by two species of roundworm and is typically spread through the feces of dogs and cats. Most infected people don't show symptoms, though in some cases the parasite can travel through parts of the body such as the liver, lungs, or central nervous system. The larvae can also travel to the eye and cause blindness. Each year about 70 people, mostly children, are blinded by the condition.
Cysticercosis is spread through ingesting larval cysts of a tapeworm, causing infections in the muscles, brain or other tissue. People become infected when they drink water or eat food contaminated with tapeworm eggs, or if they put contaminated fingers in their mouths. Cysts in the brain or spinal cord commonly cause seizures or headaches. The condition may also cause life-threatening brain swelling or strokes. CDC estimates that at least 1,000 people are hospitalized each year with the more severe brain-related form of the disease.
The parasite that causes trichomoniasis is transferred from human to human during sex. About 3.7 million people in the US have the condition, though most do not know they have it. Symptoms may include itching, burning, redness or soreness in the infected areas. The parasite can be eradicated through medications. Without treatment, the infection can last for months or years.
Source: US Centers for Disease Control and Prevention.
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UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.