New discoveries in the transmission biology of sleeping sickness parasites: applying the basics

Abstract

The sleeping sickness parasite, Trypanosoma brucei, must differentiate in response to the changing environments that it encounters during its complex life cycle. One developmental form, the bloodstream stumpy stage, plays an important role in infection dynamics and transmission of the parasite. Recent advances have shed light on the molecular mechanisms by which these stumpy forms differentiate as they are transmitted from the mammalian host to the insect vector of sleeping sickness, tsetse flies. These molecular advances now provide improved experimental tools for the study of stumpy formation and function within the mammalian bloodstream. They also offer new routes to therapy via high-throughput screens for agents that accelerate parasite development. Here, we shall discuss the recent advances that have been made and the prospects for future research now available.

Fig. 1

A simplified depiction of the T. brucei life cycle. In the bloodstream of the mammalian host, slender forms proliferate. As density increases, the parasites produce stumpy induction factor (SIF) which induces differentiation of a proportion of slender forms to stumpy forms. Stumpy forms are pre-adapted to life in the tsetse vector: they are cell cycle-arrested and have elaborated mitochondrial activity. Upon uptake in a tsetse blood-meal, stumpy forms differentiate into the proliferative procyclic forms in response to cold shock and cis-aconitate or citrate (CCA) in the tsetse midgut. Other signals such as proteases or pH stress may also contribute, as does inhibition of the tyrosine phosphatase, TbPTP1. Further differentiation events occur in the tsetse to produce mature metacyclic forms in the salivary glands. These are pre-adapted to life in the mammalian host

Fig. 2

PAD protein expression and localisation act as checkpoints for differentiation. A summary of the expression of PAD proteins and the consequences for trypanosome differentiation events, based on the predictive model of Engstler and Boshart (2004) [16]. Slender cells proliferate in the bloodstream of the mammalian host. As parasite density increases, slender cells produce SIF which induces production of stumpy forms. Stumpy forms express PAD proteins (denoted by X), whereas slender forms do not. This ensures that only the transmissible stumpy forms are able to detect the differentiation signal. Upon ingestion in a tsetse blood-meal and exposure to a drop in temperature, there is up-regulation and a relocation of at least one PAD protein (PAD2) to the cell surface. Retention of PAD2 within the cell prior to cold shock ensures stumpy forms do not differentiate prematurely. Stumpy forms then differentiate to procyclic forms synchronously in response to CCA. Slender forms do not perceive the signal and are sensitive to proteolytic and potential pH stress in the tsetse midgut and therefore do not survive

Fig. 3

Accelerated parasite development as a route to limiting parasite transmission and parasitaemia. In the normal course of infection, slender cells generate stumpy forms once parasite numbers are sufficient to ensure transmission if taken up during a tsetse blood-meal. By accelerating stumpy formation at a lower parasitaemia, the parasite load in the host would be reduced, potentially reducing pathogenicity. Furthermore, the consequent limitation in parasite numbers would reduce the potential for parasite transmission during a tsetse blood-meal