Mechanism of
            <i>Trypanosoma brucei gambiense</i>
            (group 1) resistance to human trypanosome lytic factor

Kieft, Rudo; Capewell, Paul; Turner, C. Michael R.; Veitch, Nicola; MacLeod, Annette; Hajduk, Stephen L.

doi:10.1073/pnas.1007074107

Cited by 84 publications

(128 citation statements)

References 29 publications

(32 reference statements)

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“…Previous studies demonstrated that SRA binds TLF-1 via apoL-1 (39) and that these proteins colocalize in intracellular vesicles (25). Since SRA traffics to the flagellar pocket, which is also the site of receptor- (20). In these cells, SRA-Ty localized to the flagellar pocket, based on localization studies at 3°C with anti-Ty ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Endosomal Localization of the Serum Resistance-Associated Protein in African Trypanosomes Confers Human Infectivity

Stephens

Hajduk

2011

Eukaryot Cell

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Trypanosoma brucei rhodesiense is the causative agent of human African sleeping sickness. While the closely related subspecies T. brucei brucei is highly susceptible to lysis by a subclass of human high-density lipoproteins (HDL) called trypanosome lytic factor (TLF), T. brucei rhodesiense is resistant and therefore able to establish acute and fatal infections in humans. This resistance is due to expression of the serum resistance-associated (SRA) gene, a member of the variant surface glycoprotein (VSG) gene family. Although much has been done to establish the role of SRA in human serum resistance, the specific molecular mechanism of SRA-mediated resistance remains a mystery. Thus, we report the trafficking and steady-state localization of SRA in order to provide more insight into the mechanism of SRA-mediated resistance. We show that SRA traffics to the flagellar pocket of bloodstream-form T. brucei organisms, where it localizes transiently before being endocytosed to its steady-state localization in endosomes, and we demonstrate that the critical point of colocalization between SRA and TLF occurs intracellularly.

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Section: Resultsmentioning

confidence: 99%

Endosomal Localization of the Serum Resistance-Associated Protein in African Trypanosomes Confers Human Infectivity

Stephens

Hajduk

2011

Eukaryot Cell

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“…brucei HpHbR (Leu210) leads to reduced affinity for human Hp-Hb and Hpr-Hb 7,27,28 . In combination with lowlevel expression of HpHbR 26 and the protective effect of TgsGP 22 , this evolutionary amino-acid substitution contributes to T.b. gambiense resistance against the human TLF particles.…”

Section: Structure Determinationmentioning

confidence: 99%

“…T.b. gambiense also exhibits low-level HpHbR expression 26 and harbours a L210S substitution in HpHbR, leading to reduced TLF1 uptake 7,27,28 . These defence mechanisms are not present in the widespread Trypanosoma brucei brucei (T.b.…”

mentioning

confidence: 99%

Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

et al. 2014

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Sleeping sickness is caused by trypanosome parasites, which infect humans and livestock in Sub-Saharan Africa. Haem is an important growth factor for the parasites and is acquired from the host by receptor-mediated uptake of haptoglobin (Hp)-haemoglobin (Hb) complexes. The parasite Hp-Hb receptor (HpHbR) is also a target for a specialized innate immune defence executed by trypanosome-killing lipoprotein particles containing an Hp-related protein in complex with Hb. Here we report the structure of the multimeric complex between human Hp-Hb and Trypanosoma brucei brucei HpHbR. Two receptors forming kinked three-helical rods with small head regions bind to Hp and the b-subunits of Hb (bHb), with one receptor at each end of the dimeric Hp-Hb complex. The Hb b-subunit haem group directly associates with the receptors, which allows for sensing of haem-containing Hp-Hb. The HpHbR-binding region of Hp is conserved in Hp-related protein, indicating an identical recognition of Hp-Hb and trypanolytic particles by HpHbR in human plasma.

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“…Trypanosoma brucei brucei is sensitive to trypanolytic factors present in human serum and therefore fails to establish infection in humans. T. brucei brucei can, however, cause disease in some livestock 2 . The disease runs a complex course leading to death if left untreated in both animals and humans.…”

Section: Introductionmentioning

confidence: 99%

Role of Cytokines in <i>Trypanosoma brucei</i>-Induced Anaemia: A Review of the Literature

Musaya¹,

Matovu²,

Nyirenda³

et al. 2015

Mal. Med. J

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BackgroundAnaemia is an important complication of trypanosomiasis. The mechanisms through which trypanosomal infection leads to anaemia are poorly defined. A number of studies have implicated inflammatory cytokines, but these data are limited and inconsistent. In this article, we reviewed the published literature on cytokines associated with Trypanosoma brucei infections and their role in the immunopathology leading to anaemia. MethodologyArticles were searched in PubMed through screening of titles and abstracts with no limitation on date of publishing and study design. Articles in English were searched using keywords "African trypanosomiasis", "sleeping sickness", "Trypanosoma brucei", in all possible combinations with "anaemia" and/or "cytokines". ResultsTwelve articles examining cytokines and their role in trypanosomeinduced anaemia were identified out of 1095 originally retrieved from PubMed. None of the articles identified were from human-based studies. A total of eight cytokines were implicated, with four cytokines (IFN-γ, IL-10, TNF-α, IL-12) showing an association with anaemia. These articles reported that mice lacking TNF-α were able to control anaemia, and that IFN-γ was linked to severe anaemia given its capacity to suppress erythropoiesis, while IL-10 was shown to regulate IFN-γ and TNF-α, providing a balance that was associated with severity of anaemia. IFN-γ and TNF-α have also been reported to work in concert with other factors such as nitric oxide and iron in order to induce anaemia. ConclusionIFN-γ, IL-10, and TNF-α were the three major cytokines identified to be heavily involved in anaemia caused by Trypanosoma brucei infection. The anti-inflammatory cytokine, IL-10, was shown to counter the effects of proinflammatory cytokines in order to balance the severity of anaemia. The mechanism of anaemia is multifactorial and therefore requires further, more elaborate research. Data from human subjects would also shed more light.

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Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor

Cited by 84 publications

References 29 publications

Endosomal Localization of the Serum Resistance-Associated Protein in African Trypanosomes Confers Human Infectivity

Endosomal Localization of the Serum Resistance-Associated Protein in African Trypanosomes Confers Human Infectivity

Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

Role of Cytokines in <i>Trypanosoma brucei</i>-Induced Anaemia: A Review of the Literature

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