Review
Specializations in a successful parasite: What makes the bloodstream-form African trypanosome so deadly?

https://doi.org/10.1016/j.molbiopara.2011.06.006Get rights and content

Abstract

Most trypanosomatid parasites have both arthropod and mammalian or plant hosts, and the ability to survive and complete a developmental program in each of these very different environments is essential for life cycle progression and hence being a successful pathogen. For African trypanosomes, where the mammalian stage is exclusively extracellular, this presents specific challenges and requires evasion of both the acquired and innate immune systems, together with adaptation to a specific nutritional environment and resistance to mechanical and biochemical stresses. Here we consider the basis for these adaptations, the specific features of the mammalian infective trypanosome that are required to meet these challenges, and how these processes both inform on basic parasite biology and present potential therapeutic targets.

Highlights

► African trypanosomes overcomes many challenges in the mammalian host. ► Firstly, a specialized morphology and biochemical processes adapting to the mammalian bloodstream common to all trypanosomatids. ► Secondly, antigenic variation and accessory immune evasion systems, common to all African trypanosomes. ► Thirdly, specific mechanisms to avoid innate immune defense mechanisms of humans.

Introduction

The trypanosomatids, which formally include African trypanosomes, American trypanosomes and leishmania species, are causative agents of major human, livestock, wild animal and plant diseases. According to WHO statistics, together these organisms directly threaten the health of more than five hundred million people worldwide. African trypanosomes present a dual burden, both directly on human health where they are responsible for tens of thousands of deaths annually, but also on economic wellbeing through human morbidity and agricultural impact. This last aspect is currently unquantified but, given the frequency of trypanosome-mediated disease, it presents a major challenge for public health programs [1]. Moreover, current drugs are highly toxic, require complex dosing regimens and resistance is becoming prevalent [2], [3]. For Trypanosoma brucei subspecies and Trypanosoma congolense specifically, advances over the last two decades in public health programs and monitoring have decreased the death toll substantially. However, the disease that these parasites cause, sleeping sickness or human African trypanosomiasis (HAT) is, as far as it is known, invariably fatal in the absence of therapeutic intervention [4]. The brutal consequence of untreated T. brucei infection in humans contrasts with trypanotolerant animal species such as Bos indicus, and tells us several things about the parasite. Firstly, T. brucei is able to survive and proliferate within many different mammalian hosts. Second, the trypanosome, at the population level, can evade the entirety of the host immune system. Third, there is differential interaction between parasite and host, such that in humans the disease is highly virulent, invariably progressing to death, while by contrast many mammals are able to modulate the infection and co-exist for a protracted period of months or even years, with apparently little negative impact to health [5].

T. brucei cycles between a mammalian and tsetse fly host. Substantial remodeling, of many cellular processes and morphology, accompanies differentiation between the major proliferative stages, the mammalian bloodstream form and the insect procyclic and epimastigote forms. These rapidly proliferating stages are interspersed with additional life cycle intermediates, where cell division appears to halt and essential pre-adaptations to the next host occur [6]. For example, on entering the mammalian host, the parasite must successfully respond to increased temperature, activate [or have activated, see 7] immune evasion mechanisms and be prepared for significant changes to the biochemical composition of the environment, triggering mechanisms required for acquisition of nutrients. Furthermore, the overall architecture of the cell and positioning of the organelles change on transitioning between life cycle stages, which is supported by major alterations in gene expression. Essentially this constitutes a ‘wheel of death’, i.e. a series of interlocking processes that ensure the demise of the human host. In this minireview we consider some of the specializations of the T. brucei bloodstream form, what underpins evolutionary selection for these changes and if there is potential for therapeutic exploitation based on these adaptations (Fig. 1).

Section snippets

Surface coat remodeling

One of the most fundamental changes that occur between the insect vector and mammalian bloodstream forms of T. brucei is that to the parasite cell surface (Fig. 2). The procyclic form, present in the midgut of the tsetse fly, possesses a protease-resistant surface coat composed of the procyclin proteins, while the surface coat of epimastigote forms (a life cycle stage found in the fly salivary gland) consists mainly of an alanine-rich protein called BARP [8]. Ultimately, the bloodstream form

Evasion of innate immune responses

The last ten years or so have seen the characterization of an important and exciting aspect of bloodstream form biology, and one that has a major impact on the ability of trypanosomes to infect humans. A large number of wild mammalian species in Africa are natural trypanosome reservoirs, but many higher primates and humans are resistant to infection by some strains of T. brucei. The identity of at least one primate-specific trypanolytic factor has been demonstrated as the serum protein

Biochemical and morphological adaptations

Immune effectors aside, the bloodstream of the mammalian host is also a very distinct environment to that of the tsetse fly in terms of nutrients, pH, temperature and mechanical stress. In order to meet this challenge, the parasite remodels its surface coat but also triggers large-scale biochemical adjustments to facilitate pre-adaptation. Among these, probably the most intensely studied are those changes that occur in energy metabolism. Upon injection of metacyclic parasites from the fly

Gene expression changes – a whole genome view

Transcriptome analysis, i.e. measurement of levels of all mRNA in a cell at a given time, has the potential to allow very precise definition of pathways and processes altering during life cycle adaptation. Transcriptome analysis is very much influenced by the minor role of promoters in trypanosomes for control of individual transcript levels, with the result that most mRNA are post-transcriptionally regulated [69] (Fig. 3). Early studies identified limited changes to mRNA levels between

Perspectives

The African trypanosome is among the deadliest of human pathogens, with a fatality rate approaching 100% for untreated infections. The high virulence of the East African trypanosome likely represents the fact that it is more often a parasite of non-human mammals. This is supported by the apparently recent evolution of SRA by T. b. rhodesiense as a resistance mechanism against TLF. T. b. gambiense infection is also invariably fatal but does not cause such acute illness. For these and other

Acknowledgements

The authors thank Flavia Fernandes Moreira-Leite (University of Oxford, UK) for the donation of cartoons used in Fig. 2, and Alain Pumir (ENS de Lyon, France) for discussions on flagellar pocket positioning and unpublished data. Work in our laboratory is funded by project and program grants from the Wellcome Trust (to MCF), the MRC (to CG and MCF), and studentships from the MRC (JMH) and BBSRC (HCA), which are gratefully acknowledged.

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