A group of diseases caused by infection with the one-celled flagellate parasites of the genus Trypanosoma. There are several species of trypanosomes, at least two of which can be transmitted to humans by insects. Certain types of trypanosomes can be transmitted between humans by transfusion, contaminated hypodermic needles or from a mother to her baby.

In Africa, the tiny, blood-sucking tsetse fly (genus Glossina) spreads Trypanosoma brucei through its saliva. Tsetse flies live south of the Sahara and north of the Kalahari. Infection of the T. brucei causes the disease called African sleeping sickness. Sleeping sickness can occur months or even years after the initial infection, but may be much quicker.

In the New World, American trypanosomiasis (Chagas’ disease) is caused by T. cruzi. This organism is carried by small insects commonly called ‘cone nosed bugs,’ ‘assassin bugs,’ ‘kissing bugs’ or ‘benchuca.’ These are triatomids, of the family reduviidae in the order Hemiptera. These insects reside in the walls and thatched roofs of huts. The parasite rides around in triatomid’s digestive system and enters a vertebrate host through bites. American trypanosomiasis is endemic to South and Central America, where it is one of the major infectious diseases.

Generally speaking, once trypanosomes enter the body, the B cells develop a recognition to the dense coat of glycoproteins around the parasites' cellular membranes. As the immune system begins to recognize the invading organisms, the infection starts to wane. Unfortunately for the vertebrates, however, the trypanosome has a genetic code which causes it to change coats every so often, in a predictable pattern. The human immune system can not adapt quickly enough and overloads just trying to keep up with the little buggers.

Trypanosomes diverged into their two major species sometime after the African and South American continents split apart, some 100 million years ago. Those trypanosomes which existed in South America developed into the cruzi species and lived in that area, moving from arthropod to vertebrate and back again for millions of years. Our ancestors probably evolved with the threat of trypanosomiasis, then left Africa and moved around the world, finally reaching South America many thousands of years later. There, our ancestors were met by the parasite cousins of their old African scourge. Trypanosomiasis has been with humans for a very long time. Specimens of trypanosomes have been found in mummies 4,000 years old from South America.

AFRICAN SLEEPING SICKNESS

There are two varieties of the African parasite, T. brucei rhodesiense and T. brucei gambiense. Both are sources of potentially lethal infections in humans and some other vertebrates, and both are carried by tsetse flies. Early signs of both types of African trypanosomiasis include headache, malaise and intermittent fever. The lymph nodes and liver may enlarge. The rhodesiense variety of trypanosome may rarely cause pancarditis (inflammation of the entire heart) and thus congestive heart failure at early stages. The gambiense is more subtle and may do no more than cause lymphadenopathy (enlargement of the lymph nodes) over the course of several weeks.

Once inside the human body, the parasites travel into the lymphatic system. African sleeping sickness is termed stage one unless the organisms have entered the cerebrospinal fluid, in which case it is termed stage two. When African trypanosomiasis reaches the second stage, it enters the central nervous system. Second stage may occur in a few weeks in the rhodesiense variety of this infection, but the gambiense variety may sometimes take longer to reach second stage.

During the second stage, trypanosomiasis symptoms include headache and sleep disturbance. Personality changes and mental impairment may manifest, frequently accompanied by ataxia and dyskinesia, as the parasites wreak damage upon the central nervous system. This may lead to meningoencephalitis, a devastating, usually lethal, infection of the brain and its coverings. Barring that fate, progressive damage to the central nervous system continues, especially affecting the basal ganglia, which eventually leads to coma and death.

The World Health Organization (WHO) estimates that at any given time, about half a million people in Africa may be carrying trypanosomes in their body. African sleeping sickness claims up to 50,000 lives each year, this number appears to be on the increase in recent years.

CHAGAS’ DISEASE

Initially, a triatomid bite usually forms a hard lump called a chagoma. When T. cruzi enters the bloodstream, it is quickly carried by macrophages, and it divides like crazy. The disease enters an acute phase (especially true in patients under 15 years of age) and often goes unnoticed, being similar in symptoms to general malaise. Even in the acute phase, this infection can be fatal, usually from myocarditis or from meningoencephalitis.

At the end of the acute phase, which usually lasts from one to two weeks, the disease then goes into so-called indeterminate form, when all symptoms go away and the illness seems to disappear. The parasites will stay with the host for life, however. This indeterminate or latent phase of this disease can last for decades. Some patients will develop organ damage 10-25 years after the initial infection, often to the heart. Sudden heart failure due to the trypanosomes is not unknown.

When Chagas’ disease enters the chronic phase, the parasites are easily detected in the bloodstream. The presence of the parasite, combined with the immune response, often causes damage to the nervous system and the heart muscle. Often, the nerves controlling digestion and circulation will be damaged, causing the esophagus and colon to be shut down (and thus a particularly unpleasant death). At this point, symptoms may vary widely. Among the common symptoms are fever, rash, swelling and hardening of the lymph nodes and enlargement of the liver and spleen.

DRUG THERAPY FOR TRYPANOSOMIASIS

Both African trypanosomiasis and Chagas’ disease are long-term, potentially fatal infections. Treatments exist for all varieties, but none are not consistently effective. It is very difficult to make drugs which work against trypanosomiasis because there are some odd differences in the ways in which different trypanosomes interact with their hosts.

The drugs pentamidine and suramin are used in first stage African sleeping sickness and melarsoprol is used in the later stage. Eflornithine may be used in the later stage of the gambiense variety of this disease. This drug inhibits the synthesis of an enzyme called ornithine decarboxylase, very important in brucei (at least the gambiense, this enzyme is not so important in the rhodesiense variety). T. cruzi does not use this enzyme, so it is not effective in the treatment of Chagas' disease.

Both benznidazole and nifurtimox are used against acute Chagas’ disease. Benznidazole is a nitroimidazole compound and was introduced in the 1970s. Nifurtimox is of the class of organic compounds known as nitrofurans and it was introduced in the 1960s. It is trypanocidal, mostly destroying circulating trypanomastigotes (the form of the parasite which enters the host). Nifurtimox has also shown some limited effect against late-stage African sleeping sickness as well. A drug called DB289 has been developed and manufactured by Immtech. It is being tested for effectiveness against African sleeping sickness (also malaria and a variety of pneumonia).

All of these drugs may have adverse effects. Sometimes, in order to avoid side effects, physicians may shift between two different drugs in limited dosages.

CHALLENGES AND FUTURE DIRECTIONS IN THE TREATMENT OF TRYPANOSOMIASIS

Several promising directions have been presented in recent years for the pharmacological control of trypanosomiasis. Some research is being conducted with drugs that target the surface proteins of the trypanosome’s cell membrane, although not a lot of work has been done on this. There is also some hope in genetic manipulation, as the DNA of most trypanosome subspecies has been sequenced and the hunt is on for how best to use this information.

Some progress has been made by using compounds to block some the unusual enzymes which T. brucei uses in glycolysis. Trypanosomes also possess an enzyme called trypanothione which appears to be unique to this genus. Blocking the synthesis of trypanothione could be a useful pathway for developing a drug which will kill the parasites without harming the human host.

One of the most significant problems faced in controlling the spread of trypanosomiasis is that there is little economic incentive to conduct research in these impoverished parts of the world and it is difficult to get expensive drugs to the people. Some advances have been made through non-governmental organizations such as Médecins Sans Frontières (Doctors Without Borders)and the WHO. In the absence of effective treatments for trypanosomiasis, the most common route is to treat symptoms, which, while better than nothing, is not very effective.

In Africa and the Americas, one of the most effective ways of reducing the number of cases of trypanosomiasis has been to eradicate the insect pests that act as vectors for the parasites. In the areas where systematic insecticide spraying has taken place, the instances of trypanosome infection have dropped dramatically. Additionally, physical barriers such as mosquito netting and removal of the insects' hiding places (for example, improving the rural housing in South and Central America) has shown great promise in eliminating the hosts of these disease-causing organisms. In Africa, scent-baited tsetse traps have proven effective against some of the species. Targeted releasing of sterile male flies to outcompete fertile ones has also aided in managing the pests.

Both Africa and the South/Central American regions where trypanosomes are endemic are tumultuous places in the early 21st century. Political and social upheavals, combined with major environmental and public health crises are all factors which lead to the lack of stability in these areas of the world. As such, it seems unlikely that anyone will have the money or incentive to work on definitive cures for the problem of trypanosomiasis anytime soon. It is probable that these parasites will be with humanity for a while to come.


References:
Columbia Encyclopedia, Ed. 6, p. 38,967
“R & D Directions” Jul-Aug 2004, V10.7 p 62
Barrett, Michael P., et al, “The trypanosomiases,” the Lancet Nov 1, 2003 v.362 i9394 p 1469f
BlueDragon’s superb writeups on Chagas Disease and trypanosomes
Zimmer, Carl “Parasite Rex” (the Free Press, New York, 2000).
Beers & Berkow, eds., “The Merck Manual” seventeenth ed. (Merck Research Laboratories, Whitehouse Station, NJ, 1999).

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