The History of the ABC Proteins in Human Trypanosomiasis Pathogens

Abstract

Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance.

Keywords: ABC transporters; T. brucei; T. cruzi; chagas disease; sleeping sickness.

Figure 1

T. cruzi ABC proteins. ABC proteins share a nucleotide-binding domain (NBD), displaying conserved sequences among organisms. A typical full-size ABC transporter presents, in addition to the two NBDs, two transmembrane domains, which could be rearranged in direct (TMD–NBD) or reverse (NBD–TMD) order. Half-size transporters have only a TMD and an NBD, assuming that they form dimers or oligomers to transport substrates across membranes. The standardized names of ABC proteins in subfamilies according to HUGO nomenclature are represented by the forth letter, followed by number. For example ABCA1 is subfamily A, member 1.

Figure 2

T. brucei ABC proteins. ABC proteins share a nucleotide-binding domain (NBD), displaying conserved sequences among organisms. A typical full-size ABC transporter presents, in addition to the two NBDs, two transmembrane domains, which could be rearranged in direct (TMD–NBD) or reverse (NBD–TMD) order. Half-size transporter has only a TMD and an NBD, assuming that they form dimers or oligomers to transport substrates across membranes. The standardized names of ABC members in subfamilies according to the HUGO nomenclature are represented by forth letter, followed by number. For example, ABCB1 is subfamily B, member 1. RLI, L ribonuclease inhibitor domain. 4Fe-S, iron-sulfur cluster binding domain.