Ribose 5-Phosphate Isomerase B Knockdown Compromises Trypanosoma brucei Bloodstream Form Infectivity

Loureiro, Inês; Faria, Joana; Clayton, Christine; Macedo-Ribeiro, Sandra; Santarém, Nuno; Roy, Nilanjan; Cordeiro-da-Siva, Anabela; Tavares, Joana

doi:10.1371/journal.pntd.0003430

Cited by 21 publications

(28 citation statements)

References 59 publications

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“…Recombinant enzymes from L. donovani 17, T. brucei 18 and T. cruzi 9 have been formally demonstrated to have in vitro isomerase activity, catalyzing the interconversion of R5P and Ru5P. In this paper we have demonstrated that the same applies to L. infantum and L. major homologues.…”

Section: Discussionmentioning

confidence: 63%

Disclosing the essentiality of ribose-5-phosphate isomerase B in Trypanosomatids

Faria

Loureiro

Santarém

et al. 2016

Sci Rep

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Ribose-5-phosphate isomerase (RPI) belongs to the non-oxidative branch of the pentose phosphate pathway, catalysing the inter-conversion of D-ribose-5-phosphate and D-ribulose-5-phosphate. Trypanosomatids encode a type B RPI, whereas humans have a structurally unrelated type A, making RPIB worthy of exploration as a potential drug target. Null mutant generation in Leishmania infantum was only possible when an episomal copy of RPIB gene was provided, and the latter was retained both in vitro and in vivo in the absence of drug pressure. This suggests the gene is essential for parasite survival. Importantly, the inability to remove the second allele of RPIB gene in sKO mutants complemented with an episomal copy of RPIB carrying a mutation that abolishes isomerase activity suggests the essentiality is due to its metabolic function. In vitro, sKO promastigotes exhibited no defect in growth, metacyclogenesis or macrophage infection, however, an impairment in intracellular amastigotes’ replication was observed. Additionally, mice infected with sKO mutants rescued by RPIB complementation had a reduced parasite burden in the liver. Likewise, Trypanosoma brucei is resistant to complete RPIB gene removal and mice infected with sKO mutants showed prolonged survival upon infection. Taken together our results genetically validate RPIB as a potential drug target in trypanosomatids.

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Section: Discussionmentioning

confidence: 63%

Disclosing the essentiality of ribose-5-phosphate isomerase B in Trypanosomatids

Faria

Loureiro

Santarém

et al. 2016

Sci Rep

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“…Biological benefits of multiple alleles at ribose 5‐phosphate isomerase is less obvious; however, the gene has been investigated as a drug target in treating Trypanosoma brucei , the cause of African sleeping sickness (Loureiro et al . ).…”

Section: Discussionmentioning

confidence: 97%

“…Glycogen storage may be important for L3 as during host invasion the L3 worm becomes highly motile as it must migrate from the site of inoculation to the human lymphatics. Biological benefits of multiple alleles at ribose 5-phosphate isomerase is less obvious; however, the gene has been investigated as a drug target in treating Trypanosoma brucei, the cause of African sleeping sickness (Loureiro et al 2015).…”

Section: Regions Of the Genome Possibly Influenced By Natural Selectionmentioning

confidence: 99%

Population genomics of the filarial nematode parasite Wuchereria bancrofti from mosquitoes

et al. 2016

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Wuchereria bancrofti is a parasitic nematode and the primary cause of lymphatic filariasis – a disease specific to humans. W. bancrofti currently infects over 90 million people throughout the tropics and has been acknowledged by the world health organization as a vulnerable parasite. Current research has focused primarily on the clinical manifestations of disease and little is known about the evolutionary history of W. bancrofti. To improve upon knowledge of the evolutionary history of W. bancrofti, we whole genome sequenced 13 W. bancrofti larvae. We circumvent many of the difficulties of multiple infections by sampling larvae directly from mosquitoes that were experimentally inoculated with infected blood. To begin, we used whole genome data to reconstruct the historical population size. Our results support a history of fluctuating population sizes that can be correlated with human migration and fluctuating mosquito abundances. Next, we reconstructed the putative pedigree of W. bancrofti worms within an infection using the kinship coefficient. We deduced that there are full‐sib and half‐sib relationships residing within the same larval cohort. Through combined analysis of the mitochondrial and nuclear genomes we concluded that this is likely a results of polyandrous mating, the first time reported for W. bancrofti. Lastly, we scanned the genomes for signatures of natural selection. Annotation of putative selected regions identified proteins that may have aided in a parasitic life style or may have evolved to protect against current drug treatments. We discuss our results in the greater context of understanding the biology of an animal with a unique life history and ecology.

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“…An adverse phenotype was observed in E. coli [258] and also humans [259] upon RPI deficiency, suggesting a critical conserved role through evolution. Trypanosomatids possess a type B RPI, which is absent from humans that instead have a structurally unrelated type A and therefore possibly an ideal drug target [260][261][262][263][264][265]. Recombinant enzymes from L. donovani [262], L. infantum [261], L. major [261], T. brucei [263] and T. cruzi [263,264] have been formally demonstrated to have in vitro isomerase activity by catalysing the interconversion of R5P and Ru5P.…”

Section: Non-oxidative Branchmentioning

confidence: 99%

“…Trypanosomatids possess a type B RPI, which is absent from humans that instead have a structurally unrelated type A and therefore possibly an ideal drug target [260][261][262][263][264][265]. Recombinant enzymes from L. donovani [262], L. infantum [261], L. major [261], T. brucei [263] and T. cruzi [263,264] have been formally demonstrated to have in vitro isomerase activity by catalysing the interconversion of R5P and Ru5P. The Km values for both R5P and Ru5P were similar between Leishmania and trypanosomes enzymes, however, Kcat values are considerably higher for Leishmania, in both direct and inverse reactions [261][262][263][264].…”

Section: Non-oxidative Branchmentioning

confidence: 99%

Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

Loureiro

Faria

Smith

et al. 2019

CMC

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The trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, are causative agents of important human diseases such African sleeping sickness, Chagas' disease and Leishmaniasis, respectively. The high impact of these diseases on human health and economy worldwide, the unsatisfactory available chemotherapeutic options and the absence of human effective vaccines, strongly justifies the search for new drugs. The pentose phosphate pathway has been proposed to be a viable strategy to defeat several infectious diseases, including those from trypanosomatids, as it includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. This review provides an overview of the available chemotherapeutic options against these diseases and discusses the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets.

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Ribose 5-Phosphate Isomerase B Knockdown Compromises Trypanosoma brucei Bloodstream Form Infectivity

Cited by 21 publications

References 59 publications

Disclosing the essentiality of ribose-5-phosphate isomerase B in Trypanosomatids

Disclosing the essentiality of ribose-5-phosphate isomerase B in Trypanosomatids

Population genomics of the filarial nematode parasite Wuchereria bancrofti from mosquitoes

Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids

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