African sleeping sickness

African sleeping sickness


African sleeping sickness, or Human African trypanosomiasis (HAT), is a parasitic disease caused by the kinetoplastid flagellated protozoa Trypanosoma brucei(). Human African trypanosomiasis is transmitted to humans through bites from infected tsetse flies of the Glossinia species. HAT is endemic in parts of Sub-Saharan Africa and is the only vector borne disease that is limited solely to this continent ().

1.1 Clinical stages of the disease

The disease has two stages of clinical presentation; the hemolymphatic stage and the Mengioencephalitic stage. The hemolymphatic stage of disease is the initial stage; at the site of the tsetse fly bite a chancre develops due to the local infection of trypanosomes. In this stage of the disease the trypanosomes enter the bloodstream, lymph and other tissues where they differentiate and multiply ( ). In east African trypanosomiasis, this stage can be severe, one in ten patients who do not have access to treatment die ( ). The main symptom during this stage is waves of fever, these waves reflect the fluctuating levels of parasites, caused by the immune recognition of new epitopes on the parasite ( ), shown in Figure 1.

The mengioencephalitic stage

1.2 Clinical Variants of the disease

There are two clinical variations of HAT, caused by different sub-species of Trypanosoma brucei. Trypanosoma brucei gambiense causes the chronic form of the disease where the haemolytic stage may last several months or years, in addition to this; the prevalence of disease is specific to Central and Western parts of Africa and is commonly referred to as West African trypanosomiasis ().

Trypanosoma brucei rhodesiense causes the acute form of the disease which is far more virulent and faster developing; the prevalence of this form of the disease is specific to Eastern and Southern parts of Africa and is commonly referred to as East African trypanosomiasis ()

1.3 Trypanosome life cycle

During the Trypanosoma brucei digenetic lifecycle, the trypanosome alternates between the insect vector and the bloodstream of mammalian hosts.. In each of these the trypanosome undergoes different periods of differentiation and proliferation to prepare for the environments of the host and vector.

The trypanosome initially establishes itself in the mid gut of the tsetse fly after ingesting a blood meal from cattle and wild animals that are also hosts for the parasite; however, the parasite migrates to the salivary glands in preparation for transmission to the mammalian host


There are two main virulence factors in the pathogenesis of Trypanosoma brucei; both of these work together in detecting the host environment and evading the immune response.

2.1 Antigenic Variation of VSG protein

The major virulence factor that Trypanosome brucei conveys is the antigenic variation of a protein on the cell membrane, the VSG protein. The variant surface glycoprotein functions as a protective coat that that densely covers the surface of the parasite; each cell containing 107 molecules of identical VSG molecules.

VSG is made up of a 350-400 residue N-terminal domain, a C-terminal domain of 50-100 residues and is attached to the attached to the lipid bilayer of the trypanosome by a C-terminal glycosyl-phosphatidylinositol (GPI) anchor protein

Trypanosomes exploit the high immunogenicity of the VSG coat in order to survive for long periods of time; the parasite can express many different VSG proteins during infection in the mammalian host in a mechanism known as antigenic variation. The trypanosome switches expression of one variant surface glycoprotein present on the cell surface to expression of another immunologically distinct form at a rate fast enough to prevent recognition of the whole population by the immune response.

The rate of switiching expression from one VSG to another is less than 0.01 pre generation; as a consequence, most of the trypanosomes are detected by the immune response and are cleared through VSG-antibody-mediated lysis. However, the benefit of switching allows some parasites to escape the antibody response generated against the previous VSG and a persistent infection can be maintained in the bloodstream. Furthermore, this rate of switching is of benefit to the parasite as there is a symbiotic relationship between the host and parasite; uncontrolled parasitic growth would result in killing of the host.

Antigenic variation of the trypanosome VSG coat can occur by three mechanisms, gene conversion, reciprocal recombination and in situ activation. Over 1000 VSG genes and pseudogenes have been identified in the trypanosome genome; in addition to this, active genes for VSG are located in telomeric expression sites on large chromosomes and 20 expression sites have been identified. However, only one VSG gene is transcriptionally active at any one time, as shown in figure X, below.

Gene conversion involves the insertion of a silent VSG gene in the subtelomeric region into the active expression site on the telomere. This mechanism of antigenic variation frequently occurs in early trypanosome infection. Alternatively, reciprocal recombination involves the switching of a telomeric VSG with the gene present in the active expression site. In situ activation involves the inactivation of the an active expression site and the activation of a previously unactive expression site.

2.2 The flagellum

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The treatment of HAT is dependent on both the stage at which the disease has progressed to and also on the form of disease (acute or chronic). The range of drugs used to treat the two forms of disease is inadequate, with only one new drug discovery in the last 60 years ( ).

4.1 Treatment of Hemolymphaticstage HAT

Suramine was the first drug used to treat Trypanosomiasis in the 1920s and is effective only against the Trypanosoma brucei rhodesiense species, which causes the acute form of the disease ( ).

The drug is administered through intravenous injection over the course of six weeks (Legros et al., 2002). Once administered, the drug binds to host plasma proteins albumin, transferrin and LDL, where it is transported through the bloodstream. LDL and transferrin have been shown to be actively taken up by Trypanosoma brucei rhodesiense through receptor mediated endocytosis ( ). Furthermore, BLAH et al () found that Suramin enters the trypanosome through binding to LDL. Once inside the cell, lysosomal proteases enable Suramin to dissociate from the plasma proteins; facilitating the drug to inhibit enzymes within the parasite ( ).

Pentamidine is an alternative therapy, which is used to treat both forms of HAT ( ). The drug has a direct trypanocidal effect; once administered through intramuscular injection, the drug is taken up by the trypanosome through specific binding to an energy dependent, adenine/adenosine transporter ( ). Once inside the cell the drug binds to DNA to cause

Although these drugs can be used to treat the hemolymphatic stage of HAT they both have severe side effects. Suramin is highly toxic in malnourished patients, usually found in sub-Saharan Africa ( ). Furthermore, Pentamidine causes side effects including tachycardia, shortness of breath and vomiting ( ).

4.2 Treatment of Mengioencephalitic stage HAT

Two drugs are registered for use in the treatment of mengioencephalitic stage HAT; although there has been evidence to suggest a drug used in the treatment of American trypanosomiasis is effective in the African form of disease ().

The first line treatment in the mengioencephalitic stage is with Melarsoprol and is used to treat both forms of the disease.

Eflornithine is the only new drug discovered for the treatment of Trypanosoma brucei gambiense in the last 60 years. The drug has a trypanostatic effect, which inactivates both host and parasite ornithine decarboxylase, an important enzyme in amino acid synthesis which forms the basis of cell multiplication and differentiation.

Due to inhibition of the host and parasite enzyme activity, several side effects can arise, which typically present as seizures and XXX, although this drug is tolerated better than Melarsoprol. However, these side effects are reversible if monitored and managed accordingly.

Although there is a better tolerance of this drug within the HAT infected population, there is a problem in administration. Eflornithine has a short half life and requires infusion every six hours over a two week period. Due to the resource poor setting of sub-Saharan Africa it is clear why this drug is not the first line treatment even though it is more effective and better tolerated ().

Nifurtimox is not registered for the treatment of African trypanosomiasis, only American trypanosomiasis. However, Priotto et al. (2009) have demonstrated that this drug can be used in combination with Eflornithine in the treatment of Trypanosoma brucei gambiense infected patients.

The administration problem arising in Eflornithine monotherapy is reduced when given in combination therapy. When combined, infusions can be increased to 12 hours due to the effect one infusion has on arresting parasite activity, which allows the trypanocidal activity of Nirurtimox through oxidative stress mechanisms to take place before another infusion is required ( )

This combination therapy is easier to administer, poses less problems than Eflornithine monotherapy and requires a shorter stay in hospital. Since Melarsoprol resistance in many parts of sub-Saharan Africa is well established due to the frequency of use of the drug, mengioencephalitic stageWest African trypanosomiasis could effectively be controlled using this combination therapy.

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