Human African trypanosomiasis (HAT) was first recorded in the 14th century, when the Arab historian Ibn Khaldun wrote about the death of King Diata II of Mali, by what he described as “…the sleeping sickness, a disease that frequently afflicts the inhabitants of that climate”.
About 500 years later, chaos and instability brought by the colonial adventures of the Europeans, likely contributed to a great expansion of the HAT endemic regions. A massive epidemic followed around the turn of the 19th century, prompting the colonial administrations to solicit for medical research and recruit scientific missions.
The nous of Bruce
As part of this effort, the Scottish microbiologist David Bruce discovered that African trypanosomiasis is a parasitic disease transmitted by Glossina spp., the tsetse fly, which is endemic in large parts of sub-Saharan Africa. The causative agent Trypanosoma brucei, a unicellular flagellated protozoon, was later named after him.
While Bruce anticipated mechanical transmission by the tsetse fly, it was later established that the parasite persistently infects the insect vector and undergoes a complex life cycle: the parasites are taken up into the insect vector midgut during a bloodmeal from an infected host, and differentiate into procyclic trypomastigotes.
These forms migrate to the salivary gland generating metacyclic trypomastigotes ready for delivery to the mammalian bloodstream with the next bite. The metacyclics transform into the proliferating long slender form capable of establishing and maintaining a bloodstream infection rapidly after entering a new mammalian host.
Loss of spirit
Eventually some parasites cross the blood–brain barrier and infection of the central nervous system (CNS) evokes the symptoms described by the common names ‘sleeping sickness’ for HAT or ‘Nagana’ for the animal disease, which translates in ‘loss of spirit’ in Zulu: the host falls into a lethargic state and later becomes comatose which finally leads to death.
Unlike the related kinetoplastid parasites Trypanosoma cruzi and Leishmania spp., which are intracellular pathogens, African trypanosomes have adapted to survive in the mammalian host bloodstream.
While nutrients are readily available in this environment, a direct and full exposure to the innate and acquired immune systems poses an extreme challenge. Key strategies T. brucei has developed for successful immune evasion are the ability to change its surface ‘coat’ to achieve antigenic variation, in combination with a highly efficient endocytotic apparatus.
In the bloodstream stage, the parasite surface is dominated by a single variant surface glycoprotein (VSG) covering approximately 90% of the cell surface. This VSG can be switched to one of the hundreds of different isoforms when overwhelmed by high antibody titres, thereby evading the host acquired immune response and establishing recurrent infection.
In the patient this manifests as waves of parasitaemia where after 5 to 7 days VSG antibodies are raised that eliminate most of the trypanosomes but then a new wave of trypanosomes with a different VSG, unaffected by the antibodies of the previous wave, appears. Extremely rapid clathrin-dependent endocytosis facilitates clearance of antibodies and complement, that would otherwise lead to cell lysis and is likely important in extending the period that a VSG variant can survive as well as protecting against productive antibody recognition of invariant surface molecules.
Trypanosomaiasis is ancient companion of hominids and primates, and one example of the selective pressure exerted by the parasite is manifested by the omnipresent trypanolytic activity in human blood. Arising during late primate evolution, trypanolytic factor (TLF) confers innate immunity to one subspecies of African trypanosome, T. brucei brucei, in humans.
TLF is a subclass of serum high-density lipoprotein that contains Apolipoprotein L1 (ApoL1) and a protein that is essential for haem uptake, which is bound by a surface receptor of the parasite. This TLF/receptor complex is taken up by endocytosis, traffics to the lysosome where ApoL1 forms pores in the lysosomal membrane, which ultimately kills the parasite. However, some subspecies have developed strategies to circumvent TFL toxicity, in what seems like an evolutionary arms race between host and parasite.
Specifically, West African T. brucei gambiense has a modified receptor to avoid uptake of TLF and the East African T. brucei rhodesiense expresses serum resistance-associated antigen, which interacts with ApoL1, preventing its lytic effect. There is mounting evidence that the potency of two trypanocidal drugs, suramin and pentamidine, rely on endocytic uptake and hence entry into the parasite. Indeed, this is reminiscent of TLF uptake and it has been recognized that the specialized endocytotic apparatus can be exploited for drug delivery, by-passing conventional delivery routes altogether.
Despite progress, new therapies are urgently needed as the current rely on very old drugs with severe side effects and the emergence of drug resistance is a major threat. The state-of-the-art treatment for CNS stage HAT is a combination therapy of nifurtimox and eflornithine developed by a consortium led by the Drugs for Neglected Diseases Initiative in 2009, which was a step forward but requires a long and costly course of intravenous administration.
Risk of relapse
The World Health Organization is on track to achieve elimination of HAT as a public health problem. Strengthened control and surveillance have significantly reduced the transmission of the disease in a steady decrease from over 25,000 reported cases in 2000 to a historic low of 2,184 cases in 2016.
Regrettably, a similar success was celebrated in the 1960s when reported cases stabilized under 5,000; however, this was soon followed by the onset of a new epidemic. Hopefully sustained commitment and, perhaps most importantly, political stability will prevent such a relapse in future.
Martin Zoltner- University of Dundee
- Headrick DR (2014). Sleeping sickness epidemics and colonial responses in East and Central Africa, 1900–1940. PLoS Negl Trop Dis 8(4), e2772.
- Hide G (1999). History of sleeping sickness in East Africa. Clin Microbiol Rev 12, 112–125
- Higgins MK, Lane-Serff H, MacGregor P and Carrington M (2017). A receptor’s tale: an eon in the life of a trypanosome receptor. PLoS Pathog 13(1), e1006055
- Zoltner M, Horn D, de Koning HP and Field, MC (2016). Exploiting the Achilles’ heel of membrane trafficking in trypanosomes. Curr Opin Microbiol 34, 97–103
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