African sleeping sickness is also called as Human African Trypanosomiasis (HAT). This disease is fatal if left untreated and is endemic to Africa. HAT is caused by two sub species of the infectious protozoan Trypanosoma brucei. Trypanosoma brucei gambiense (T.b.g) infections are prevalent in western and central Africa, while T.b rhodesiense (T.b.r) infections are common in eastern and southern Africa. The disease spread by the tsetse fly (Glossina spp.). The disease gets its name from one of the major characteristic symptoms of HAT: disruption of sleep cycle. The patient experiences uncontrollable urge to sleep during the day followed by long period of wakefulness at night. Current treatment plans have shown high levels of toxicity and are based on invasive chemotherapy (Malvy & Chappuis, 2011)
HAT occurs in 36 African countries. One-third of continent of Africa is infested with tsetse fly and thus the chances of infection is very high in these regions. The protozoan first attacks the blood cells and then later crosses the blood-brain barrier to attack the central nervous system (CNS). T.b.g infections attack the CNS much later compared to T.b.r. (Kennedy, 2005)
Parasite, vector and host biology
The protozoan Trypanosoma is often referred to as trypanosome. Trypanosomes are unicellular organisms that have a surface coat containing a variable glycoprotein. The variable surface glycoprotein (VSG) gene present in the DNA of the protozoan is thought to be responsible for the production of this glycoprotein. This glycoprotein chain triggers the immune response in the host leading to production of Trypanosoma-specific antibodies. However, the variable nature of the glycoprotein helps the protozoan to escape the immune system until new antibodies for the new glycoprotein are formed. This process continues until the host dies (Malvy & Chappuis, 2011).
The figure explains the life cycle of the parasite between tsetse fly and human host.
Fig 1. Life cycle of Trypanosoma brucei in humans and tsetse fly (Glossina spp.). Image courtesy: Alexander J. da Silva and Melanie Moser, Centers for Disease Control Public Health Image Library
The initial reservoir of the protozoan is thought to be infected animals such as pigs and cattle. The tsetse fly ingests the protozoan during a blood meal. In the next 21 days, the trypanosome undergoes biochemical and morphological changes. First, the trypanosome transforms into slender forms in the midgut. From here, these forms move to the salivary gland and become epimastogotes. These remain in the salivary gland and transform into the infective form called the metacyclic trypanosomes. When a tsetse fly containing these infective form bites a host, such as a human, the trypanosomes enter the bloodstream and cause HAT. An infected fly remains so life-long. The only way to break the infectious cycle would be to eliminate human-fly contact (Malvy & Chappuis, 2011).
Once inside the host the trypanosomes proliferate in two stages:
Early stage (hemolymphatic stage). The trypanosomes multiply through binary fission and remain in the blood and lymphatic system. The onset of infection occurs between 1 and 3 weeks after the bite. Earliest clinical features are onset of fever that last most than a week along with lymphadenopathy. This stage is also characterized by generalized non-neurological symptoms such as skin rashes, chancre at the site of bite, splenomegaly, menstrual disorder, abortions, sterility, loss of hair on skin, lymph node enlargement, etc. Internal organs are also infected in this stage. The patient may feel all right in between and thus, this stage is often misdiagnosed as malaria (Kennedy, 2004; Kennedy, 2005).
Late stage (encephalitic stage). The onset time of the late is unclear. The protozoan crosses the blood-brain barrier by evading the immune system and proliferates in the cerebrospinal fluid (CSF) in the CNS. This results in tissue damage. The second stage is characterized by neurological and psychiatric changes. Urge to sleep, confusion, abnormal reflexes, mood swings, double vision, etc. are some of the common late stage symptoms (Kennedy, 2004; Kennedy, 2005).
Diagnosis of Trypanosoma brucei is done in three steps: 1) screening 2) confirmation of parasitological presence and 3) determining stage.
Screening. A quick and specific test for presence of HAT is the Card Agglutination Test for Trypanosomiasis (CATT). This test uses undiluted blood. Both positive and negative titer values are confirmed by analysis of CSF.
Confirmation of parasitological presence. Microscopic analysis of the blood gives confirmation regarding presence of trypanosomes in the blood. The blood is centrifuged using microhaematocrit centrifuge and analyzed under a microscope. Quantitative buffy coat methods is by far the most sensitive, but very sophisticated to be used in rural Africa.
Staging. To determine the stage of the disease, lumbar puncture is done to obtain CSF. If there are trypanosomes and more than 5 white blood cells in μl of CSF, the patient is said to be in late stage of HAT (Malvy & Chappuis, 2011).
Currently four main drugs are being used for HAT treatment, but they are toxic and are rapidly becoming ineffective due to resistant trypanosome strain development. The four traditional drugs used are Pentamidine isethionate, suramin, melarsoprol and NECT (Eflornithine + Nifurtimox).
Novel drugs such as Benzoxaboroles, Fexinidazole and salinomycin are being examined for effectiveness and possible replacement for current drugs. Benzoxaborole-6-carboxamides has been found to be effective in terminating trypanosomes in mouse models when taken orally (Jacobs et al, 2011). Fexinidazole has been effective against both stages of HAT and both strains of Trypanosoma brucei when taken orally. A 48-hours exposure seems to be optimal for Fexinidazole to initiate trypanocidal activity (Kaiser et al, 2011). Salinomycin is effective only against early stage trypanosomes, but has lower cytotoxic values when compared to current drugs (Steverding & Sexton, 2013).
HAT is one of the most neglected tropical infectious diseases. It is fatal if left untreated and is in need of new non-toxic drugs. Chemotherapy and traditional drugs are losing out in the race and thus there is a dire need for research on this disease that can save lives in rural Africa.
Jacobs, R. T., Plattner, J. J., Nare, B., Wring, S. A., Chen, D., Freund, Y., & Don, R. (2011). Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis. Future medicinal chemistry, 3(10), 1259-1278.
Kaiser, M., Bray, M. A., Cal, M., Trunz, B. B., Torreele, E., & Brun, R. (2011). Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrobial agents and chemotherapy, 55(12), 5602-5608
Kennedy, P. G. (2004). Human African trypanosomiasis of the CNS: current issues and challenges. Journal of Clinical Investigation, 113(4), 496-504.
Kennedy, P. G. (2005). Sleeping sickness–human African trypanosomiasis. Practical Neurology, 5(5), 260-267.
Malvy, D., & Chappuis, F. (2011). Sleeping sickness. Clinical Microbiology and Infection, 17(7), 986-995
Steverding, D., & Sexton, D. W. (2013). Trypanocidal activity of salinomycin is due to sodium influx followed by cell swelling. Parasites & vectors, 6(1), 78.