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Review
. 2018 Jul 20;9(7):368.
doi: 10.3390/genes9070368.

Adaptation and Therapeutic Exploitation of the Plasma Membrane of African Trypanosomes

Juan F Quintana  1 , Ricardo Canavate Del Pino  2 , Kayo Yamada  3 , Ning Zhang  4
Affiliations
Review

Adaptation and Therapeutic Exploitation of the Plasma Membrane of African Trypanosomes

Juan F Quintana et al. Genes (Basel). .

Abstract

African trypanosomes are highly divergent from their metazoan hosts, and as part of adaptation to a parasitic life style have developed a unique endomembrane system. The key virulence mechanism of many pathogens is successful immune evasion, to enable survival within a host, a feature that requires both genetic events and membrane transport mechanisms in African trypanosomes. Intracellular trafficking not only plays a role in immune evasion, but also in homeostasis of intracellular and extracellular compartments and interactions with the environment. Significantly, historical and recent work has unraveled some of the connections between these processes and highlighted how immune evasion mechanisms that are associated with adaptations to membrane trafficking may have, paradoxically, provided specific sensitivity to drugs. Here, we explore these advances in understanding the membrane composition of the trypanosome plasma membrane and organelles and provide a perspective for how transport could be exploited for therapeutic purposes.

Keywords: Trypanosoma brucei; drug development; endocytosis; endomembrane system; nanobodies; surface proteome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Simplified life cycle of Trypanosoma brucei. Parasites in the stumpy stage differentiate into procyclic forms inside the midgut of the tsetse fly. Procyclic forms of the parasite express a procyclin surface that changes throughout the infection of the midgut. On route to the salivary glands, trypanosomes cross the proventriculus, differentiate into epimastigotes, and switch the procyclin coat to bloodstream stage alanine-rich protein BARP. The final stage of infection in the tsetse fly takes places in the salivary glands; the parasites differentiate into metacyclic forms and express variant surface glycoproteins (VSGs), ready to infect a new host. Through a blood meal, trypanosomes reach the bloodstream of a mammalian host and differentiate into the replicative, long and slender form. This may also involve the skin, lymphatics and adipose tissues, but which are omitted for simplicity. As the levels of parasitemia increase, trypanosomes differentiate into the infective, non-replicative short and stumpy form. Trypanosomes are also able to reach the cerebrospinal fluid and to cross the blood brain barrier into the central nervous system (CNS). It is unclear if this population is in equilibrium with the bloodstream stages. The dominant proteins in each stage of the infection are indicated by colour: VSG; red, BARP; blue and procyclin; teal.
Figure 2
Figure 2
Organization of the endomembrane system of bloodstream form of T. brucei sp. A simplified schematic representation of the trypanosome endomembrane system is shown, with the flagellar pocket at the top of the panel, and including other intracellular organelles, such as the trans-Golgi network (TGN), early, sorting and intermediate endosomes, and the lysosome. Intracellular trafficking routes are indicated by arrows, with the arrowheads pointing towards the destination of traffic. The endocytic route is depicted from the pocket to various intracellular organelles, whereas the exocytic route is depicted from intracellular organelles (TGN, endosomes) to the surface. The cohort of conserved trafficking-related protein between trypanosomes and higher eukaryotes is shown in green, whereas lineage-specific proteins, i.e. those present only in trypanosomes (and possibly a few additional taxa) are indicated in red. Similarly, those components not detected in trypanosomes, and therefore thought to be lost in these organisms (e.g. the adaptor protein 2 complex) are shown in grey. Rab proteins are also shown and positioned based on the step that they mediate as well as localisation data (e.g. Rab5 in early endosomes, Rab11 in sorting/recycling endosomes). Note that not all proteins and complexes shown are discussed in the text but are present for completeness. Abbreviations: ESCRT; endosomal sorting complexes required for transport, CALM; clathrin assembly lymphoid myeloid leukemia, CAP; clathrin-associated proteins, EpsinR; Eps15-interacting protein (Epsin)-related protein. Numbers in endosomal structures (early, sorting, intermediate, and late) represent the corresponding Rab protein (e.g. Rab5A, Rab5B, Rab11, Rab21, Rab28, etc.).
Figure 3
Figure 3
Arrangement of the VSG coat at the cell surface. VSGs form a physical barrier on the plasma membrane to protect the underlying and invariable membrane proteins, thereby preventing the exposure of potentially highly antigenic proteins. During VSG switching and other dynamic conditions, the surface must accommodate a greater number of VSG molecules, which is thought to be achieved by tightly packing VSG under a “compact” conformation. When the VSG switching program is completed and the old VSG is completely removed from the surface, the density of the newly formed VSG coat is reduced, leading to a “relaxed” conformation. It is likely that these conformations are dynamic at the steady-state level, and have important consequences for immune recognition, so that the antibody against invariant determinants (blue) is more likely in the relaxed state. Abbreviations: VSG, Variable Surface Glycoprotein; ISG, Invariant Surface Glycoproteins, Tf, Transferrin; TfR, Transferrin Receptor; Nb, Nanobodies.
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