Definition and Symptoms
Human African trypanosomiasis (HAT), also known as African sleeping sickness, is an infectious disease caused by trypanosomes, a type of parasite. The disease is caused by two different trypanosomes: Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Most cases of HAT are caused by Trypanosoma brucei gambiense.
It is a disease of the circulatory and central nervous system (Stich, Abel, & Krishna, 2002).
There are two stages of the disease, characterized by different symptoms. The first stage of the disease is called the hemolymphatic stage. This stage is characterized by symptoms such as intermittent fever (corresponding with cycles of parasite multiplication in the blood) , joint pain, rash, and swollen lymph nodes, particularly at the base of the neck (Stich, Abel, & Krishna, 2002). It can also present as anemia (Pays et al, 2014).
The second stage of disease begins once the parasites have infiltrated the central nervous system. It is characterized by a disruption of sleeping schedule (which is where the disease gets its name), psychosis, headache, and reduced mental function. If left untreated, the disease will kill its victim (Stich, Abel, & Krishna, 2002). The more common, chronic form (caused by T. b. gambiense) can take years to cause death, whereas the rarer, acute form (caused by T.b. rhodesiense) causes death in months (WHO).
The disease is thought to be thousands of years old, originally existing in isolated areas in Africa, then spreading along the Congo river. It was specifically referenced as early as the 14th century, when the Arabian historian Ibn Khaldun gave a report of trypanosomiasis. He discussed an emperor of Mali who had been struck by the disease:
“He told me that Jata [the empreror] had been smitten by the sleeping illness, a disease which frequently afflicts the inhabitants of that climate, especially the chieftains who are habitually affected by sleep. Those afflicted are virtually never awake or alert. The sickness harms the patient and continues until he perishes (Steverding, 2008).”
One of the main impetuses of the quest to determine the cause of HAT was the slave trade. Slavers noticed that the humans they were trafficking were dying of a mysterious sleeping sickness, and wanted to prevent this from happening (Steverding, 2008).
There was an epidemic in Uganda from 1896-1906, an epidemic in Africa in 1920, and one that began in the 1970s, each killing thousands of people (WHO).
In 1903, a scientist named David Bruce identified the vector of the disease: the tsetse fly (Strong, 1944). An effective treatment was not developed until 1910- an arsenic-based drug called atoxyl that had severe side effects. Some older drugs are still used today, such as pentamidine (discovered in 1949) and melarsoprol (also discovered in 1949). Pentamidine is used during stage one of illness. Melarsoprol is used in stage two of the disease. It is arsenic-based like atoxyl, and can have severe side effects, including encephalitis and death (WHO). It is highly preferred to diagnose the disease while it is still in its hemolymphatic stage.
The disease is usually diagnosed by viewing parasites in the blood under a microscope. If one wishes to asses whether the disease has progressed to stage two, a lumbar puncture is performed in order to determine whether parasites can be found in cerebrospinal fluid (WHO). Lately, there is a new, promising technique to diagnose HAT in the field. The typical preparation of a sample involves chilling it at multiple step and much preparation, which can be difficult to perform without a proper lab in less-developed areas. Recently, there has been a promising new protocol applied in the field called LAMP (loop-mediated isothermal amplification of DNA). This protocol cuts out the many chilling steps required: it uses dried blood samples, eliminating the need for temperature control of liquid samples. Also, since the PCR for DNA amplification in LAMP mostly takes place at one temperature, expensive equipment is not needed (Hayashida et al, 2015). Prior to this paper, LAMP kits were available under a company called Eiken Chemical Co Ltd, but they were very expensive, and therefore did not make sense for an under-equipped laboratory to use. Hayashida et al attempted to make their own LAMP protocol without access to the tightly guarded secrets of the company, using their understanding of the process. It looks like they had success, so it is possible that LAMP will be used more often to diagnose HAT more quickly. Still, if one is to be completely confident in a diagnosis of trypanosomiasis, one must see the parasites in the blood.
If one is to understand the mechanism by which trypanosomes cause disease, one should first have an understanding of the non-disease state functions of the biomolecules that HAT affects. These biomolecules include tumor necrosis factor, hemoglobin, and haptoglobin.
Tumor necrosis factor is a cytokine (mostly produced by macrophages) that can cause apoptosis, and is also involved in fever and cachexia (“wasting away”). There are two types of tumor necrosis factor receptors in the body: TNFR1, which is found in all cells and about which we have the most information, and TNFR2, which is found in immune cells only. When TNF binds to its receptor, the receptors form trimers. This causes a conformational change that leads to the release of a molecule called SODD from the receptor’s “intracellular death domain” (Wajant, Pfizenmaier, & Scheurich, 2003). This domain then binds to an adaptor protein called TRADD. In this form, the protein can initiate one of three pathways. The first of these three pathways is the activation of the NF-kB pathway, which ends with the increased production of transcription factors involved in cell survival and proliferation. The second is activation of the MAPK pathways, which end in the production of transcription factors that promote cell differentiation and apoptosis. The third pathway is for TRADD (attached to the TNF receptor) to interact with FADD. FADD is a cysteine protease, that, when activated, can lead to cell death (Chen & Goeddel, 2002). HAT inhibits the production of TNF through a mechanism discussed under the page “Molecular Basis of Disease State.”
Hemoglobin is the molecule that carries oxygen throughout the body via blood. Haptoglobin is a protein that binds hemoglobin with high affinity, and then removes it from circulation. This prevents loss of iron, and inhibits hemoglobin’s oxidative damage potential. Trypanosomes scavenge heme from the hemoglobin-haptoglobin complex (Pays et al, 2014).