Transferrin is a growth factor for the bloodstream form ofTrypanosoma brucei

Schell, Dietmar; Borowy, N.K.; Overath, Peter

doi:10.1007/bf00931012

Cited by 76 publications

(49 citation statements)

References 15 publications

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“…Schell et al (4) found that bloodstream-form trypanosomes grown in calf serum contain around 1.4 ϫ 10 6 iron atoms/cell, and Steverding (36) has calculated that the minimum amount of cellular iron supporting trypanosome growth is ϳ4 ϫ 10 4 iron atoms/cell. We confirmed these values here.…”

Section: Survival Of Trypanosomes With a Tf-r Subunit On Their Surfacmentioning

confidence: 99%

“…It multiplies extracellularly in blood and escapes elimination by the immune system through antigenic variation of its surface coat, which consists of one major protein species, the variant surface glycoprotein (VSG), 1 attached to the plasma membrane by a glycosylphosphatidylinositol anchor (1,2). African trypanosomes cover their iron need by taking up host transferrin (Tf) (3)(4)(5). Uptake occurs in the flagellar pocket (3,6,7), an invagination of the plasma membrane where all endocytosis and traffic to the trypanosome surface takes place (8 -12), and is mediated by a transferrin receptor (Tf-R), a heterodimer consisting of subunits encoded by expression site-associated gene (ESAG) 6 and 7 (13)(14)(15)(16)(17), which are located in the telomeric VSG gene expression sites (for review, see Refs.…”

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confidence: 99%

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Factors Affecting the Level and Localization of the Transferrin Receptor in Trypanosoma brucei

Mußmann

Engstler

Gerrits

et al. 2004

Journal of Biological Chemistry

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Transfer of bloodstream-form Trypanosoma brucei variant 221a from calf serum to dog serum-based medium induces acute iron starvation, as the transferrin receptor (Tf-R) of variant 221a binds dog Tf poorly. We show here that transfer to dog serum induces a 3-5-fold increase in Tf-R mRNA and protein within one doubling time (8 h). Because iron stores are still high 8 h after transfer, we infer that the signal for Tf-R overproduction is the decreased availability of cytosolic iron when cellular iron import drops. Up to 30% of the extra Tf-R spills out of the flagellar pocket onto the pellicular surface. Because the 5-fold increase in Tf-R is accompanied by a 5-fold increase in bovine Tf uptake, the up-regulation of Tf-R levels in response to Tf starvation helps the trypanosome to compete for limiting amounts of Tf. We noted that Tf-R levels also vary in calf serum medium. Cells in dense cultures contain up to 5-fold more Tf-R mRNA and protein than in dilute cultures. Only onetenth of the extra Tf-R reaches the pellicular surface. The increase cannot be explained by a lack of Tf or to cell density sensing but is due to pericellular hypoxia. Our results show that bloodstream-form trypanosomes can regulate the expression of the two Tf-R subunit genes and the localization of their gene products in a flexible manner. This flexibility is made possible by the promoter-proximal position of the two genes in the variant surface glycoprotein expression site.The unicellular protozoan parasite Trypanosoma brucei can infect a broad range of mammals. It multiplies extracellularly in blood and escapes elimination by the immune system through antigenic variation of its surface coat, which consists of one major protein species, the variant surface glycoprotein (VSG), 1 attached to the plasma membrane by a glycosylphosphatidylinositol anchor (1, 2). African trypanosomes cover their iron need by taking up host transferrin (Tf) (3-5). Uptake occurs in the flagellar pocket (3, 6, 7), an invagination of the plasma membrane where all endocytosis and traffic to the trypanosome surface takes place (8 -12), and is mediated by a transferrin receptor (Tf-R), a heterodimer consisting of subunits encoded by expression site-associated gene (ESAG) 6 and 7 (13-17), which are located in the telomeric VSG gene expression sites (for review, see .The ESAG6 subunit of about 400 amino acids is attached to the plasma membrane by a glycosylphosphatidylinositol anchor; ESAG7 of about 340 amino acids remains membraneattached by holding on to ESAG6 (for review, see Ref. 22). The trypanosomal Tf-R resembles VSG dimers in apparent structure and (distantly) in sequence (23), and it is unlike other Tf-Rs in nature.

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Section: Survival Of Trypanosomes With a Tf-r Subunit On Their Surfacmentioning

confidence: 99%

mentioning

confidence: 99%

Factors Affecting the Level and Localization of the Transferrin Receptor in Trypanosoma brucei

Mußmann

Engstler

Gerrits

et al. 2004

Journal of Biological Chemistry

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“…It has been demonstrated that T. brucei requires the major serum iron-transport protein, transferrin (TF), for growth (2). In T. brucei, a specific TF-binding protein (TFBP) that could function as a receptor in transferrin uptake was sought using TF-Sepharose as an affinity matrix (3).…”

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confidence: 99%

Expression of a glycosylphosphatidylinositol-anchored Trypanosoma brucei transferrin-binding protein complex in insect cells.

Chaudhri

Steverding

Kittelberger

et al. 1994

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

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The expression site-associated gene ESAG 6 was previously implicated in transferrin binding in the protozoan parasite Trypanosoma brucei. ESAG 6 and the closely related ESAG 7 of T. brucei strain AnTatl.3 have now been expressed in insect cells using the baculovirus expression system. Expression of ESAG 6 alone in insect cells gives rise to a glycosylated protein of =52 kDa, which is cell surfaceassociated through a glycosylphosphatidylnoltol anchor at its C terminus. The ESAG 7 product of about 42 kDa is also glycosylated, but lacks the glycosylphosphatidylinositol modification, and is located intracellularly. No terrm-binding activity is observed when either ESAG is expressed independently. However, their coexpression results in a cell surface complex of ESAG 6 and 7 products that specifically binds trusferrin. This shows that both ESAG 6 and 7 products are necessary and s ent for binding to transferrin.Trypanosoma brucei is widespread in Africa and causes a wasting disease-Nagana-in cattle and sleeping sickness in humans. In the mammalian host the parasite exists extracellularly in the blood and tissues, where it evades the immune response by sequentially expressing a repertoire of antigenically distinct surface proteins, encoded by the variant surface glycoprotein (VSG) genes. Each transcriptionally active VSG gene is located in a so-called expression site, which contains at least eight other cotranscribed expression siteassociated genes (ESAGs) (1). Although highly immunogenic, the VSGs are unsuitable for immunization against the parasitic infection. Potential targets for protective immunization may be surface proteins that deliver essential nutrients to the parasite and that are invariant.Living extracellularly, the parasite has access to the host's serum components. It has been demonstrated that T. brucei requires the major serum iron-transport protein, transferrin (TF), for growth (2). In T. brucei, a specific TF-binding protein (TFBP) that could function as a receptor in transferrin uptake was sought using TF-Sepharose as an affinity matrix (3). N-terminal sequencing of a purified TFBP isolated in extremely small ajnounts from T. brucei strain MITat 1.4 (clone 117a) revealed it to be identical to the products of two highly similar ESAGs, ESAGs 6 and 7 (3, 4). The putative products of these genes share about 85% sequence identity. Both contain a potential signal peptide, suggesting they are secreted or located on the surface. The ESAG 6 but not ESAG 7 product has a potential recognition site for attachment of a glycosylphosphatidylinositol (GPI) anchor at the C-terminal end. ESAG 6 was originally reported as encoding the TFBP (3). Subsequent work, however, has suggested that the data were misinterpreted (M. Ligtenberg and P. Borst, personal communication; this work; refs. 5 and 6) and that ESAG 6 and 7 products are involved in TF binding (this work;refs. 6 and 7).In this paper we report the expression of both proteins individually and together in insect cells and unequivocally demonstrate that in...

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“…Variant Surface Glycoprotein expressed was located in the end part of the telomere, the polycistronic transcription unit called VSG expression site (VSGESs) (Hutchinson et al 2016). The polycistronic VSG ESs consisted of a number of Expression Site Associated Genes (ESAGs) which one of it had been characterized as ESAG6/7 involved in the nutrient acquisition (Schell et al 1991).…”

Section: Introductionmentioning

confidence: 99%

Genetic variability of ESAG6/7 gene Trypanosoma evansi

Sawitri¹,

Wardhana²

2018

JITV

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ABSTRAKSawitri DH, Wardhana AH. 2017. Variabilitas genetik dari gen ESAG 6/7 Isolat T. evansi. JITV 22(1): 38-50. DOI: http://dx.doi.org/10.14334/jitv.v22i1.1638Trypanosoma evansi (T. evansi) sebagai agen penyakit Sura merupakan salah satu penyakit parasitik penting untuk diperhatikan karena dapat menimbulkan kerugian ekonomi yang sangat besar di Indonesia. Parasit ini memerlukan zat besi untuk fase propagasi yang diperoleh dari pejamu melalui reseptor transferrin (Tf) yang dikode oleh Expression Site Associated Genees (ESAGs). ESAG6/7 dilaporkan mengkode reseptor transferrin pada afinitas yang berbeda pada pejamu yang berbeda.Adanya perbedaan patogeneitas T. evansi diduga menyebabkan variabilitas pada gene ESAG 6/7. Penelitian ini bertujuan untuk melihat variabilitas gene ESAG6 T. evansi dengan virulensi yang berbeda pada mencit. Penelitian ini dilakukan dengan 2 tahap yaitu uji patogeneitas T. evansi pada mencit dan analisis sekuen gene ESAG6/7. Uji patogeneitas dilakukan dengan melihat median lama hidup mencit setelah masing-masing kelompok diinfeksi dengan 25 T. evansi asal kerbau dari berbagai kondisi geografi. Hasil penelitian uji patogeneitas menunjukkan adanya perbedaan virulensi pada 25 isolat T.evansi pada mencit. Trypanosoma evansi as an agent of Surra is one of the crucial parasitic diseases that cause great economic losses in Indonesia. These parasites need iron for growth and propagation phase which is obtained by receptor-mediated uptake of host transferin. The transferrin receptors are encoded by Expression Site Associated Genees (ESAGs). ESAG6/7 encodes transferrin receptors which reported have different affinities of a different host. The distinction of T. evansi pathogenicity is supposed to cause variability in the ESAG6/7 gene. This research was aimed to investigate the variability of genes ESAG6/7 T. evansi with different virulence in mice. This research was conducted in two steps: bioassay pathogeneicity in mice and analysis of ESAG6/7 gene sequences. The median survival time of mice was investigated after each group of mice infected by 25 T. evansi isolates from buffaloes where its geographically differ. The test results showed a difference of pathogenic virulence on 25 T. evansi isolates in mice. Sequence analysis of the ESAG6/7 gene from 25 T. evansi isolates origin from Indonesia tended to be homogeneous on the transferrin binding site but there was variability in the hypervariable site. These changes are able to separate high and low virulence of the T. evansi isolates. Phylogenetic tree analysis was formed 11 clades of 25 T. evansi. High virulence T. evansi was included in clades 7 and 10, while low virulence T. evansi was included in clade 5 and 11 and the moderate virulence was divided into those four clades.

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Transferrin is a growth factor for the bloodstream form ofTrypanosoma brucei

Cited by 76 publications

References 15 publications

Factors Affecting the Level and Localization of the Transferrin Receptor in Trypanosoma brucei

Factors Affecting the Level and Localization of the Transferrin Receptor in Trypanosoma brucei

Expression of a glycosylphosphatidylinositol-anchored Trypanosoma brucei transferrin-binding protein complex in insect cells.

Genetic variability of ESAG6/7 gene Trypanosoma evansi

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