Sleeping sickness begins with a bite — a startling, yet rather insignificant, munch from the tsetse fly, an insect common to sub-saharan Africa. The bite becomes significant when the fly is playing host to single-cell parasite known as Trypanosoma brucei, a harbinger of pain, fever, sleep and death.
Once it’s transferred to a mammalian host, the parasite spreads through the bloodstream and lymphnodes, where it hides from the immune system and cranks out tryptophol, a sleep-inducing chemical compound also found in alcohol. In animals it creates debiliating, but rarely deadly, lethargy. In humans, the early phase of the disease manifests in generalized symptoms like headaches, fever, itching and joint pain. At that stage it's often mistaken for malaria. The confusion dissapears, however, once the parasite enters the cerebrospinal fluid and causes neurological symptoms such as confusion, a rabies-like mania and the classic extreme sleepiness. Untreated, the disease almost always ends in an agonizing death.
In both human and animal forms, sleeping sickness, scientifically known as trypanosomiasis, affects tens of millions of people in 36 countries across sub-Saharan Africa. Efforts from Doctors Without Borders, the World Health Organization and several organizations have reduced human infection rates significantly — from about 30,000 in 1995 to under 8,000 in 2010 — but the disease is still considered one of the most neglected in the world.
Even so, a number of recent breakthroughs suggest the end of the scourge may be in sight, says Susan Welbur, a zoonotic disease specialist at the University of Edinburgh. “For the first time in over 100 years I think we can say: Yes we can.”
A Threat to Both Animal and Man
When David Livingstone published his classic “Missionary Travels and Researches in South Africa” in 1857, the title page bore a large drawing of a fat fly with a wicked-looking proboscis. In his account, the Scottish explorer described these “poisonous insects to ox, horse and dog” which Africans called tsetse.
It was the first time the tsetse fly had been described in the West, but the sleeping sickness it spread had been around long before Europeans arrived.
If not given proper medical attention, someone suffering from sleeping sickness will almost certainly die.. How long it takes depends on which of two subspecies of parasite is involved: more than 98 percent of cases are chronic and can linger for years, while the more acute form can be lethal within months.
The animal version of sleeping sickness isn’t as deadly, but its chronic debilitating symptoms — lethargy, fever, weakness — can be devastating to people who depend on livestock to survive. Nagana, as the animal form is called, affects three million cattle every year across Africa, impacting everything from milk and meat production to food cultivation and transportation.
Arsenic-based compounds have used to treat the disease since Livingstone’s time — he described treating an infected horse with arsenic, which helped it live another six months — but they are so toxic that even today, roughly five percent of patients die from the medicine itself. A more effective treatment called nifurtimox-eflornithine combination therapy, or NECT, was introduced in 2009. Still, it requires repeated injections by skilled staff in a hospital setting, things that are in short supply in rural Africa.
The Drugs for Neglected Diseases initiative (DNDi), which helped develop NECT, currently has two new drugs in the works. One, called Fexinidazole, is in lead stage clinical development. It would involve a ten-day course of pills that patients could take at home, as opposed to having to go to a clinic. “That would be quite a change from what we’ve seen in the past,” says Nathalie Strub-Wougraft, DNDi’s Medical Director, “almost a paradigm shift.” If all goes well, she says, NECT could be available by 2018.
The second drug, called SCYX7-158, would be even more of breakthrough: a dose consisting of a single pill. It has also gone through successful Phase I human clinical trials, which confirmed it can follow the parasite across the blood-brain barrier, a critical hurdle in treating the later stages of disease. Phase IIb and Phase III studies are planned for later this in 2016 in the Democratic Republic of Congo, where nine out of 10 cases of sleeping sickness occur.
Tracking a Moving Target
Trypanosoma brucei is a worthy adversary. But the parasite’s ability to avoid mammalian immune systems makes it especially hard to fight, says Danae Schulz of Rockefeller University. (It’s also why no vaccine has been developed.) In the fly, the parasite expresses one protein on its surface. Once it gets inside a mammal, though, its surface becomes covered with proteins that are constantly changing. This turns it into a moving target that even our adaptive immune systems can’t lock on to.
Schulz led a recent study in PLOS Biology aimed at undermining this defense. “The idea is to trick the parasite into thinking it’s in the fly,” she says, “to get it to stop changing its surface coat and let the mammalian immune system catch up with it.” The study used a drug called I-BET151 on parasites that were then used to infect mice; the mice were able to clear their bodies of the parasites after a few days. Schulz emphasizes that they’re still not sure what the mechanism is, and that clinical trials are still years away. But the results are encouraging, and could have applications in treating other parasitic diseases like malaria, Chagas disease and leishmaniasis.
The one sure way not to catch sleeping sickness is to keep from getting bitten in the first place. That’s why a majority of prevention efforts on the ground have gone toward insecticides, fly traps and clearing brush. At times, people have even been evacuated from heavily affected areas, such as the shores Lake Victoria in Uganda.
Luckily, as flies go the tsetse is, frankly, kind of weird. As opposed to insects like mosquitoes that lay hundreds of eggs, it gives birth to live offspring that grow in a uterus and feed on milk, like a vertebrate. The tsetse finds its victims by smell and is drawn to the colors blue and black. Every idiosyncrasy is a potential weakness, says Seray Aksoy of the Yale School of Public Health — and decoding the fly’s genome could provide the battle plan. Aksoy was part of the team that did just that in 2014, the result of a decade-long effort involving more than 140 researchers in 18 countries.
One target is the fly’s olfactory system. “If you can understand how this process works, what kind of smells they’re able to detect, you can make much better traps,” Aksoy says. Another goal is finding the genes that control the production of the larvae milk proteins; blocking those with chemical inhibitors could effectively sterilize females. Determining which genes affect their color vision could help scientists determine exactly which shade of blue is the flies’ favorite — leading to even better traps — or even how to short-circuit their color vision entirely.
Eventually, Aksoy says, we may at least be able to eradicate flies from regional hotspots — although with 12,000 genes to dig through, the work is just starting.
Approaching a Cure
A study in Uganda showed that treating cattle infected with sleeping sickness can help slash human cases. Cows can carry both the animal and human form of the disease with no ill effects. Add the fact that they can outlive tsetse control programs, and you have a huge reservoir of infection.
In 2005, Welburn participated in a research project that involved injecting 500,000 cattle in Uganda with anti-parasitic drugs and spraying them with long-lasting insecticide. The treatment cut cattle infections by 75 percent — and human cases of the acute form of sleeping sickness by 90 percent
According to Welburn, Cattle are easier and cheaper to work with than their owners. “Finding and treating people is expensive,” he says. “Cows are stationary.” In the Uganda study, the treatment costs $0.50 per treatment. “The beauty of this is that you can approach a human disease via the animal [version],” she says. “It’s a win-win for both.” The concept works with most diseases with animal vectors, like vaccinating pets against rabies.
The National Institutes of Health and the National Institute of Allergy and Infectious Diseases recently pledged $1.1 million toward an effort at West Virginia University to tease out the relationship between the tsetse fly and the trypanosome. For instance, why do some flies carry the disease and others don’t? Do the microbiobes that naturally occur in the fly’s gut have an effect on whether the parasite can survive in its bloodstream and cross over into mammals?
Questions like these will keep researchers busy for the foreseeable future, Welburn says, but hopefully not forever, as long as new tools and enough funding are available. Because remaining on the offensive is extremely advantageous to the cause. “The human infective parasite is quite weak and won’t survive in the system under sustained pressure,” she says.