Specializations in a successful parasite: What makes the bloodstream-form African trypanosome so deadly?

Gadelha, Catarina; Holden, Jennifer; Allison, Harriet C.; Field, Mark C.

doi:10.1016/j.molbiopara.2011.06.006

Cited by 29 publications

(16 citation statements)

References 72 publications

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“…Most trypanosomes have to survive within two hosts, mammalian and insect, necessitating adaption to differing nutritional environments, and remodelling of their surface coat (Gadelha et al, 2011); and must also live within two specialized environments in their mammalian host. In the bloodstream and lymphatic system the parasites evade both the acquired and innate immune systems, predominantly by antigenic variation, changing the variant surface glycoprotein (VSG) expressed on their surface to avoid antibody-mediated responses (Gadelha et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In the bloodstream and lymphatic system the parasites evade both the acquired and innate immune systems, predominantly by antigenic variation, changing the variant surface glycoprotein (VSG) expressed on their surface to avoid antibody-mediated responses (Gadelha et al, 2011). During the second stage of infection, in the CNS, they are more protected from the immune system, and may exist as a reservoir, able to reinfect the bloodstream, for example after treatment with drugs which do not penetrate into the CSF (Mogk et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

2015

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Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (DA; Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (melarsoprol/pentamidine cross resistance, MPXR) is the result of loss of a separate high affinity pentamidine transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this remarkable ability.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

2015

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“…VSG is expressed at early, middle and later stages of infection 26 . Moreover, the VSG antigenicity elicits sufficient level of antibody production in the host against the parasite 34 . In living trypanosomes, the surface epitopes are conformationally labile 35 .…”

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confidence: 99%

Development of ELISA Exploring Recombinant Variable Surface Glycoprotein for Diagnosis of Surra in Animals

et al. 2016

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“…In the mammalian host, T. brucei replicates indefinitely in the bloodstream, where surface proteins must continuously protect against attacks from the host immune system and simultaneously compete with host cells for uptake of essential nutrients (6). The surface of bloodstream-form parasites is dominated by a dense coat of variant surface glycoprotein (VSG) 1 , which shields other parasite surface proteins from host antibodies and allows evasion of the immune system through antigenic variation (7)(8)(9).…”

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confidence: 99%

Cell Surface Proteomics Provides Insight into Stage-Specific Remodeling of the Host-Parasite Interface in Trypanosoma brucei*

Shimogawa

Saada

Vashisht

et al. 2015

Molecular & Cellular Proteomics

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African trypanosomes are devastating human and animal pathogens transmitted by tsetse flies between mammalian hosts. The trypanosome surface forms a critical host interface that is essential for sensing and adapting to diverse host environments. However, trypanosome surface protein composition and diversity remain largely unknown. Here, we use surface labeling, affinity purification, and proteomic analyses to describe cell surface proteomes from insect-stage and mammalian bloodstreamstage Trypanosoma brucei. The cell surface proteomes contain most previously characterized surface proteins. We additionally identify a substantial number of novel proteins, whose functions are unknown, indicating the parasite surface proteome is larger and more diverse than generally appreciated. We also show stage-specific expression for individual paralogs within several protein families, suggesting that fine-tuned remodeling of the parasite surface allows adaptation to diverse host environments, while still fulfilling universally essential cellular needs. Our surface proteome analyses complement existing transcriptomic, proteomic, and in silico analyses by highlighting proteins that are surface-exposed and thereby provide a major step forward in defining the hostparasite interface. Molecular & Cellular

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Specializations in a successful parasite: What makes the bloodstream-form African trypanosome so deadly?

Cited by 29 publications

References 72 publications

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Development of ELISA Exploring Recombinant Variable Surface Glycoprotein for Diagnosis of Surra in Animals

Cell Surface Proteomics Provides Insight into Stage-Specific Remodeling of the Host-Parasite Interface in Trypanosoma brucei*

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