Rediscovery of Trypanosoma ( Pycnomonas ) suis , a tsetse-transmitted trypanosome closely related to T. brucei

Hutchinson, Rachel; Gibson, Wendy

doi:10.1016/j.meegid.2015.10.018

Cited by 16 publications

(10 citation statements)

References 37 publications

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“…The most probable tree (Supplemental Fig. 1B) is consistent with the evolutionary history of the four species (Hutchinson & Gibson, 2015) and indicates AQP1 as the ancestral AQP present in all trypanosome species. A duplication occurred in the common ancestor of T. suis and T. brucei after divergence from T. congolense and a further duplication, to form AQP2 and AQP3, in the ancestor of T. brucei after divergence from T. suis .…”

Section: Resultssupporting

confidence: 68%

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei

Al-Ghamdi¹,

Munday²,

Campagnaro³

et al. 2020

Preprint

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31Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to 32 pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively 33 selected for increased pore size from a common ancestor aquaporin. We demonstrate that 34 TbAQP2's unique architecture permits pentamidine permeation through its central pore and 35 show how specific mutations in highly conserved motifs affect drug permeation. Introduction 36 of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. 37 Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically 38 favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally 39 strictly impermeable for ionic species. We also identify the structural determinants that make 40 pentamidine a permeant but exclude most other diamidine drugs. Our results have wide-41 ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. 42Moreover, these new insights in aquaporin permeation may allow the pharmacological 43 exploitation of other members of this ubiquitous gene family. 44 45 Keywords: 46 Drug transport / Aquaporin / evolution of membrane proteins / Trypanosoma brucei / 47 109 endocytosis rate and the rate of pentamidine uptake. Our results unequivocally show that 110 pentamidine permeates directly through the central pore of TbAQP2 and that uptake is 111 dependent on the microbial membrane potential. Having identified the essential 112 characteristics that allow the transport of large, flexible molecules through TbAQP2, this 113 should now allow the evaluation of aquaporins in other species for similar adaptations.114 7 Results 115 116 12. Investigation of the structural determinants of AQP2 for pentamidine transport 117 1.1. Positive selection for pore size 118 In T. brucei, the AQP2 and AQP3 genes are arranged as a tandem pair on chromosome 10 119 and have 74% amino acid identity. Whereas TbAQP2 clearly mediates pentamidine uptake, 120 TbAQP3 does not (Baker et al, 2012; Munday et al, 2014), nor do various chimeric AQP2/3 121 rearrangements that give rise to pentamidine resistance (Munday et al, 2014; Graf et al, 122 2015). To investigate the origin of the AQP2 gene, a phylogenetic analysis of AQPs in 123 African trypanosomes was performed. The number of aquaporin genes varies: there is a 124 single aquaporin in T. vivax and T. congolense, two in T. suis and three in T. brucei and its 125 derivatives (Supplemental Fig. 1A). The most probable tree (Supplemental Fig. 1B) is 126 consistent with the evolutionary history of the four species (Hutchinson & Gibson, 2015) and 127 indicates AQP1 as the ancestral AQP present in all trypanosome species. A duplication 128 occurred in the common ancestor of T. suis and T. brucei after divergence from T. 129 congolense and a further duplication, to form AQP2 and AQP3, in the ancestor of T. 130 brucei after divergence from T. suis. Multiple alignment (Supplemental Fig. 1A) shows that 131 the classical NPA/NPA a...

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Section: Resultssupporting

confidence: 68%

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei

Al-Ghamdi¹,

Munday²,

Campagnaro³

et al. 2020

Preprint

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“…Novel trypanosomes from tsetse flies [7, 25, 26, 29, 30, 44–46] and African ungulates [2, 23, 24, 34] were reported in eastern and central-southern African wildlife conservation areas.…”

Section: Discussionmentioning

confidence: 99%

“…Musubugwe, was molecularly validated using DNA recovered from archived blood smears [46]. Isolates cryopreserved and archived collections of tsetse flies and ungulate blood smears of species of Duttonella can serve as DNA source for comparison with species candidates uncovered in this and other studies.…”

Section: Discussionmentioning

confidence: 99%

New insights from Gorongosa National Park and Niassa National Reserve of Mozambique increasing the genetic diversity of Trypanosoma vivax and Trypanosoma vivax-like in tsetse flies, wild ungulates and livestock from East Africa

et al. 2017

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Background Trypanosoma (Duttonella) vivax is a major pathogen of livestock in Africa and South America (SA), and genetic studies limited to small sampling suggest greater diversity in East Africa (EA) compared to both West Africa (WA) and SA.MethodsMultidimensional scaling and phylogenetic analyses of 112 sequences of the glycosomal glyceraldehyde phosphate dehydrogenase (gGAPDH) gene and 263 sequences of the internal transcribed spacer of rDNA (ITS rDNA) were performed to compare trypanosomes from tsetse flies from Gorongosa National Park and Niassa National Reserve of Mozambique (MZ), wild ungulates and livestock from EA, and livestock isolates from WA and SA.ResultsMultidimensional scaling (MDS) supported Tvv (T. vivax) and TvL (T. vivax-like) evolutionary lineages: 1) Tvv comprises two main groups, TvvA/B (all SA and WA isolates plus some isolates from EA) and TvvC/D (exclusively from EA). The network revealed five ITS-genotypes within Tvv: Tvv1 (WA/EA isolates), Tvv2 (SA) and Tvv3–5 (EA). EA genotypes of Tvv ranged from highly related to largely different from WA/SA genotypes. 2) TvL comprises two gGAPDH-groups formed exclusively by EA sequences, TvLA (Tanzania/Kenya) and TvLB-D (MZ). This lineage contains more than 11 ITS-genotypes, seven forming the lineage TvL-Gorongosa that diverged from T. vivax Y486 enough to be identified as another species of the subgenus Duttonella. While gGAPDH sequences were fundamental for classification at the subgenus, major evolutionary lineages and species levels, ITS rDNA sequences permitted identification of known and novel genotypes.ConclusionsOur results corroborate a remarkable diversity of Duttonella trypanosomes in EA, especially in wildlife conservation areas, compared to the moderate diversity in WA. Surveys in wilderness areas in WA may reveal greater diversity. Biogeographical and phylogenetic data point to EA as the place of origin, diversification and spread of Duttonella trypanosomes across Africa, providing relevant insights towards the understanding of T. vivax evolutionary history.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-017-2241-2) contains supplementary material, which is available to authorized users.

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“…Nas Américas, é transmitido mecanicamente por insetos hematófagos, sendo que o uso de agulhas contaminadas também tem contribuído para sua dispersão (Ventura et al, 2000;. Este parasita é de importância pecuária por estar associado a diminuição na produtividade dos animais, a surtos com alto índice de mortalidade em bovinos e ovinos e, inclusive, a infecções letais em búfalos em condições de estresse Garcia et al, 2016 (Adams et al, 2010;Hutchinson, Gibson, 2015).…”

Section: O Clado T Brucei Compreende Os Tripanossomas Africanos Dos unclassified

Spliced Leader (SL) RNA: análises de genes e regiões intergênicas com aportes na filogenia, taxonomia e genotipagem de <i>Trypanosoma</i> spp. de todas as classes de vertebrados.

Alvarez¹

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Rediscovery of Trypanosoma ( Pycnomonas ) suis , a tsetse-transmitted trypanosome closely related to T. brucei

Cited by 16 publications

References 37 publications

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei

New insights from Gorongosa National Park and Niassa National Reserve of Mozambique increasing the genetic diversity of Trypanosoma vivax and Trypanosoma vivax-like in tsetse flies, wild ungulates and livestock from East Africa

Spliced Leader (SL) RNA: análises de genes e regiões intergênicas com aportes na filogenia, taxonomia e genotipagem de <i>Trypanosoma</i> spp. de todas as classes de vertebrados.

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