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In most eukaryotic organisms, the regulatory processes that take place after the conversion of DNA into RNA are of greater complexity and importance than transcription itself. Trypanosomes take this process to its limits and undertake genome regulation almost entirely at post‐transcriptional level (Queiroz et al. 2009). The formation of proteins in trypanosomes is not regulated by the rate at which mRNA is synthesised but occurs through factors that control the stability of the mRNA molecules (i.e., alter their half‐life and hence concentration) and the rate at which mRNA is translated into protein. RNA binding proteins perform much of this posttranscriptional regulation. Rapid changes in the half‐life of mRNA molecules and translational control regulate adaptions to environmental change such as the movement between vector and mammalian host (Schwede et al. 2012).

Once established within their vertebrate host, the trypanosomes rapidly disseminate about the body via the blood and lymphatic system. Unlike T. cruzi and Leishmania, T. brucei remains an extracellular parasite and never invades cells in its vertebrate host. However, it does invade most of the organs of the body by colonising the intercellular spaces (c.f., T. congolense that tends to remain within the circulatory system). In humans, T. brucei gambiense crosses the blood–brain barrier and colonises the intercellular spaces in the brain. In so doing, it causes the classic symptoms of HAT. By contrast, T. brucei rhodesiense does not usually colonise our nervous system although this may be at least partly because the patient dies before this happens.

The development of HAT depends upon the species of trypanosome and its genetic strain, as well as host health and genetic factors (Kazumba et al. 2018). In the case of gambiense stage 1 HAT, a red sore develops at the site where the tsetse fly bit and over the subsequent weeks or months the patient develops a fever, their lymph glands swell, and they suffer from aches, pains, and headaches. These symptoms are non‐specific, and the disease often remains undiagnosed. In the absence of effective treatment, the disease develops remorselessly to stage 2 HAT in which the symptoms become severe with prolonged fevers, weight loss, anaemia and damage to the central nervous system.

Following their ingestion by a tsetse fly, the parasites differentiate into procyclic trypomastigotes within the midgut region. The main stimulus for the transformation is the drop in temperature (~10 °C) that the parasites experience when they move from the warm mammalian bloodstream to the much cooler insect gut. There are also major changes in the parasite’s metabolism in response to the movement from a hot environment in which glucose is plentiful to a cooler one in which glucose is in much lower concentration. In mammals, the trypanosomes have poorly developed mitochondria since they derive their ATP from glycolysis using the abundantly available glucose obtained from their host and most of their glycolytic enzymes are located within their glycosomes. Trypanosome glycolysis within their mammalian hosts is remarkably inefficient (the metabolism of one mole of glucose yields only two moles of ATP) and the pathway ceases at pyruvate, which they excrete. By contrast, in tsetse flies the trypanosome mitochondrion is a much bigger organelle and has well‐developed cristae. This is because oxidative catabolism becomes more important as a source of ATP.

Having successfully transformed into procyclic trypomastigotes, the parasites reproduce by longitudinal fission. Interestingly, the procyclic forms can undergo apoptosis – a phenomenon that is normally associated with metazoan animals. Apoptosis also occurs in various other parasitic protozoa, including other Trypanosoma, Leishmania and Plasmodium, but its function is uncertain (Proto et al. 2013). The promastigotes penetrate the fly’s peritrophic membrane after which they migrate forward to the proventriculus. At this point, they cease dividing and transform into mesocyclic trypomastigotes, and these penetrate back through the peritrophic membrane and make their way further forward to the salivary glands. Once they reach this point, they transform into epimastigotes. The epimastigotes attach themselves by their flagellum to the epithelial cells lining the tsetse fly salivary gland, multiply by longitudinal fission, and then transform into non‐dividing metacyclic trypomastigotes. Some form of mating involving meiosis often takes place during the epimastigote stage, but it is not obligatory and the extent that it occurs varies between populations. It is also affected by the immune status of the tsetse fly and hybrid matings between trypanosome strains is considered most likely if the fly acquires a mixed infection the first time it feeds (Peacock et al. 2016). Hybridization has relevance for the transfer of genetic traits such as drug resistance between trypanosome lineages.

The metacyclic trypomastigote stage is infective to susceptible mammalian hosts and expresses a specific subset of genes coding for variant surface glycoproteins (VSG). When an infected tsetse fly feeds, it injects the metacyclic trypanosomes into the blood stream and the VSG help protect them from the mammalian immune system. The trypanosome life cycle within the tsetse flies therefore involves a complex sequence of migrations and transformations and typically takes about 3–5 weeks. Consequently, effective transmission depends heavily upon the lifespan of the tsetse fly vector. Male tsetse flies usually only live for about 2–3 weeks in the wild and whilst female tsetse flies survive for up to 4 months, most die within 20–40 days.