Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies

Running Head: TREATMENT OF HUMAN TRYPANOSOMIASIS IN AFRICA BY
CHEMOTHERAPY STRATEGIES
Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies
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Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies
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Abstract
Chemotherapy continues to majorly impact the reduction of the disease burden caused by
trypanosomatids. But it should be noted that the mode of action of the anti-trypanosomal
drugs remains completely clear and is only partially characterised. There are five current
drugs that are used for the treatment of the Human African Trypanosomiasis (HAT), they are
eflornithine, pentamidine, suramin, melarsoprol and Nifurtimox-eflornithine combination
(NECT). The assays that were exploited to detect the mechanism of action of the current
drugs included DNA staining followed by visualising the results by microscopy as well as
quantitative image analysis, flow cytometry, TUNEL for monitoring the DNA replication.
Eflornithine is an ornithine decarboxylase inhibitor. Melarsoprol inhibits mitosis. Nifurtimox
caused reduction in the abundance of the mitochondrial protein. Pentamidine causes
progressive loss of the kinetoplast DNA as well as perturbs the membrane potential and
suramin inhibits the cytokinesis. Cytology based profiling aids in effective understanding of
the mechanism of action of the drugs.

Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies
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Table of Contents
Introduction...........................................................................................................................3
Background...........................................................................................................................3
Aims......................................................................................................................................4
Discussion.............................................................................................................................4
Pathogenesis of Human African Trypanosomiasis (HAT)................................................4
Chemotherapeutic drugs against Human African Trypanosomiasis (HAT).....................5
NECT: Nifurtimox–Eflornithine Combination Treatment................................................8
Mode of Action of the Chemotherapeutic drugs at the Molecular Level........................10
Perspective...........................................................................................................................16
Conclusion...........................................................................................................................16
Summary.............................................................................................................................17
References...........................................................................................................................18

Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies
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Introduction
Human Africa trypanosomiasis (HAT) also known as sleeping sickness is a centuries-old
disease that negatively impacted the economy as well as the physical suffering in the sub-
Saharan Africa. Statistical data states that approximately 50 million people are at risk of
acquiring the disease considering an area of 10 million square kilometres (Büscher et al.,
2017). The major concern is that there is no effective vaccination for the prevention of the
disease. The creation of vaccines targeting trypanosomes is also a challenge due to the
antigenic variation observed in the species (Keating et al., 2015). This is the reason how the
parasite can evade the immune responses. There is only availability of chemotherapies that
account for the anti-trypanosomiasis measures. This article enlightens on the various
chemotherapeutic drugs exploited for effective treatment of trypanosomiasis.
Human African trypanosomiasis (HAT) also called as sleeping sickness, causes infection
by the parasite Trypanosoma that is transmitted by the vector tsetse fly. The parasite has two
subspecies, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense; and it can
lead to fatal consequences if left untreated (Wangwe et al., 2019). Of late there is an observed
reduction in the number of cases that has been reported of patients affected with African
trypanosomiasis but the treatment is a challenge for the clinicians. The treatment of the CNS
stage disease is considered to be toxic hence, diagnostic staging for differentiating the early
stage from the late stage of the disease when the CNS is invaded is indeed crucial but is
challenging. Eflornithine is combined with nifurtimox drug and acts as the first-line treatment
for late-stage Trypanosoma brucei gambiense. New drugs are in pipeline for the treatment of
CNS human African trypanosomiasis, and is giving rise to the cautious optimism (Santos et
al., 2015).

Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies
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Background
Human Africa trypanosomiasis (HAT) is a disease that is caused by hemoflagellates
belonging of the subgroup of Trypanosoma brusei known as Trypanosoma brusei gambiense
and Trypanosoma brusei rhodesiense which are the Gambian and the Rhodesian form
respectively (Rassi et al., 2017). Trypanosoma brusei gambiense is the first subspecies
responsible for the disease and it accounts for almost of the 98% of the reported cases of
sleeping sickness and is also responsible for cause of chronic infection (Jones and Avery,
2015). Trypanosoma brusei rhodesiense is responsible for causing acute infection and
accounts for only 2% of the cases reported (Kennedy, 2019). The tsetse fly, Glossina sp. is
the vector and aids in transmission of these parasites between the domestic as well as the wild
animals and the human beings. The other modes of infection can be accidental infection in
the laboratory or mother to child infection (Stich, 2015).
Aims
The aim of this article is to understand the action of the chemotherapeutic drugs against
the human African trypanosomiasis at the molecular level and discover the most effective
chemotherapy for the treatment of the disease.
Discussion
Pathogenesis of Human African Trypanosomiasis (HAT)
There are two stages in the clinical course of Human African Trypanosomiasis (HAT),
they are the early stage or the first stage, at this stage the parasite is present in the peripheral
circulation of the infected individual and it has not invaded the central nervous system (CNS)
(World Health Organization, 2019). In the second stage also known as the late stage in which
the parasite invades the blood-brain barrier leading to infection of the central nervous system.
The early stage causes eliciting an immune response against the pathogen (Chappuis, 2018).

Treatment of Human Trypanosomiasis in Africa by Chemotherapy Strategies
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At this stage there are uninterrupted waves of the parasitaemia, which leads to survival of
some parasites that evading the immune response, subsequently. The trypanosomes exploit
antigenic variation to escape the immune response (Bottieau and Clerinx, 2019). In the
process of antigenic variation, the trypanosome switches the variable surface glycoprotein
(VSG) coat to a new VSG coat which is not recognized by the immune system of the host.
This is a continual action that exhausts the defence system of the host. The process of the
evasion also involves the endocytosis of VSG-antibody complexes that allows the complexes
to escape the process of detection by antibodies that are involved in the complement-
mediated killing (Fairlamb and Horn, 2018). The mechanism of antigenic variation ensures
sufficient time for the trypanosomes to spend in the host system promoting the proliferation
and the transmission to other host system through tsetse fly that serves as the vector for
transmission of these trypanosomes. This causes infection of host systems that been already
infected with the trypanosomes and recognises the VSGs (West, 2019). The symptoms of
early stage of the disease involves fever, headaches, joint pain and irritation of the skin at the
site of infection which is a rare case though. The most important symptom is the fever which
lasts for almost about a week and may recur in a span of days or a month. The waves of
parasitaemia and the counter responses of the immune system triggers the fever (Wangwe et
al., 2019) (Santos et al., 2015).
The later stage of the trypanosomal infection is also called as the meningo-encephalitic
stage, which involves parasite invading the blood–brain barrier, entering the CNS and settling
in cerebrospinal fluid (CSF) (Winkelmann and Raether, 2016). The second stage symptoms
of infection involve confusion and poor coordination, tremors, general motor weaknesses,
irritability as well as aggressive behaviour. The most significant symptom of second stage of
the infection is disruption of the natural circadian sleep or the wake rhythm of the body, this
results in irregular and fragmented patterns of sleeping (Docampo and Moreno, 2017). Hence