Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy

Matovu, Enock; Geiser, Federico; Schneider, V.; Mäser, Pascal; Enyaru, John; Kaminsky, Ronald; Gallati, Sabina; Seebeck, Thomas

doi:10.1016/s0166-6851(01)00332-2

Cited by 90 publications

(110 citation statements)

References 18 publications

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“…Nonetheless, the two-to threefold resistance to melaminophenyl arsenicals observed for this null mutant may still be clinically significant and is consistent with the absence of pronounced arsenical resistance in clinical isolates from melarsoprol-refractory patients (38). Another study of field isolates from distinct parts of Africa (37) revealed that many of the TbAT1 genes isolated from patients with relapsing infections after melarsoprol treatment exhibited the same set of nine mutations and that one relapse isolate was missing the TbAT1 gene altogether, again implicating this gene in drug resistance. It is difficult to fathom how a drug-resistant allele with so many of the same polymorphisms could have arisen independently on multiple occasions.…”

Section: Alterations In Parasite Purine Permeases Leading To Drug Ressupporting

confidence: 72%

Nucleoside and Nucleobase Transporters in Parasitic Protozoa

Landfear¹,

et al. 2004

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PURINE TRANSPORT AND SALVAGE IN PARASITIC PROTOZOAOne distinctive feature of the biochemistry of parasitic protozoa is their absolute reliance upon the salvage of preformed purines from their vertebrate and invertebrate hosts. While many mammalian cells possess the innate ability to synthesize purines de novo, all protozoa so far examined that exhibit a parasitic life style lack these biosynthetic pathways and have therefore elaborated a variety of salvage pathways ( Fig. 1) that enable them to acquire preformed purines from their hosts (14). These nutrients are imported from the host as either nucleosides or nucleobases, either of which can serve as a purine source for the parasite. The first step in these salvage pathways entails the uptake of the purine nucleosides or nucleobases from the host milieu and is mediated by various nucleoside or nucleobase transporters, located in the plasma membrane of the parasite, that provide substrate-specific permeation routes. While the enzymes of purine salvage have been studied in considerable molecular detail (7), the identification of individual purine transporters at the molecular level is a more recent development. However, over the past several years a plethora of genes encoding nucleoside or nucleobase permeases from parasitic protozoa have been identified and functionally expressed. The increasing understanding of these carriers at the molecular level provides an appropriate setting for a timely review of these important transporters and a comparison of their properties to related and distinct purine permeases of other organisms. This article will concentrate primarily on purine transporters from the Kinetoplastid parasites Leishmania and Trypanosoma brucei, since these are the protozoa with which the majority of the studies have been accomplished. However, we will also briefly discuss related work on transporters from the Apicomplexa Plasmodium falciparum and Toxoplasma gondii. This review does not attempt to be exhaustive but focuses rather upon recent results utilizing molecular genetic approaches.A principal reason for the interest in purine transport in these protozoa is the essential nature of purine salvage for this large family of parasites. Thus, while some permeases may provide nutrients that are nonessential, albeit advantageous, to the fitness of the organism in its natural environment, the purine transporters as a group are likely to be required for parasite viability in all life cycle stages. A second compelling reason to study these transporters is that they also mediate the uptake of a variety of cytotoxic drugs, many, but not all, of which are purine homologs (11,13,49). Consequently, the import of subversive substrates that are metabolized, often uniquely, by parasite purine salvage enzymes is absolutely dependent upon the purine permeases. Thus, this family of permeases plays an important role in the delivery of drugs or experimental therapeutic compounds, and mutations in these carriers can cause drug resistance (5, 13, 36). STUDIES OF PURINE TR...

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Section: Alterations In Parasite Purine Permeases Leading To Drug Ressupporting

confidence: 72%

Nucleoside and Nucleobase Transporters in Parasitic Protozoa

Landfear¹,

et al. 2004

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“…AT1 has been found to be mutated, deleted, or down-regulated in melarsoprol-resistant trypanosomes (10,42) but AT1 knockout generated cells with only a twofold increased resistance to both melarsoprol and pentamidine (14), and there is evidence for resistance that is independent of AT1 disruption (43,44). Our results now show that AQP2, when defective, could explain cases of innate MPXR and/or acquired MPXR of clinical relevance.…”

Section: Discussionmentioning

confidence: 58%

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

Baker

Glover

Munday

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

275

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African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of-function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR.

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“…However, all drugs currently registered for use carry significant problems related to administration, toxicity, increasing incidence of treatment failure, and in the case of animal trypanosomiasis, drug resistance (1). Previous work has shown that defects in the P2 aminopurine transporter, encoded by the TbAT1 gene (the same gene in Trypanosoma equiperdum is referred to as TeAT1 [Trypanosoma equiperdum AT1] in this article), are linked to drug resistance in Trypanosoma brucei brucei (11,21), Trypanosoma brucei gambiense (22), and Trypanosoma brucei rhodesiense (28), as well as in Trypanosoma evansi (24,32) and T. equiperdum (3), very close phylogenetic relatives of T. brucei (27). The P2 transporter has been shown to be capable of carrying both melaminophenyl arsenical (11) and diamidine (10,14,15,18) classes of drug into African trypanosomes in the T. brucei group.…”

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confidence: 99%

Multiple Genetic Mechanisms Lead to Loss of Functional TbAT1 Expression in Drug-Resistant Trypanosomes

et al. 2010

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The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [ 3 H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a ⌬Tbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

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Genetic variants of the TbAT1 adenosine transporter from African trypanosomes in relapse infections following melarsoprol therapy

Cited by 90 publications

References 18 publications

Nucleoside and Nucleobase Transporters in Parasitic Protozoa

Nucleoside and Nucleobase Transporters in Parasitic Protozoa

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

Multiple Genetic Mechanisms Lead to Loss of Functional TbAT1 Expression in Drug-Resistant Trypanosomes

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