A VSG Expression Site–Associated Gene Confers Resistance to Human Serum in Trypanosoma rhodesiense

Xong, Hoang Van; Vanhamme, Luc; Chamekh, Mustapha; Chimfwembe, Chibeka Evelyn; Abbeele, Jan Van Den; Pays, Annette; Meirvenne, N Van; Hamers, R.; Baetseĺier, Patrick De; Pays, Étienne

doi:10.1016/s0092-8674(00)81706-7

Cited by 331 publications

(132 citation statements)

References 26 publications

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“…The resulting plasmid pkD.Luc was linearized with AvrII and KpnI and transfected into 221 ES .121 tet or Δdot1b.121 tet . pRib.Luc was generated by cloning the luciferase gene between the HindIII and BamHI sites of pTSA-Rib (Xong et al, 1998), in which the tubulin 3′UTR had been replaced by the PARP 3′ region and the hygromycin resistance by puromycin resistance. The resulting plasmid was SphI linearized and transfected into 221 ES .121 tet , creating Luc rPro .221 ES .121 tet .…”

Section: Methodsmentioning

confidence: 99%

Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei

Batram

Jones

Janzen

et al. 2014

eLife

118

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We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness.DOI: http://dx.doi.org/10.7554/eLife.02324.001

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Section: Methodsmentioning

confidence: 99%

Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei

Batram

Jones

Janzen

et al. 2014

eLife

118

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“…The diagnostic feature of Tbr is the presence of the serum resistance associated (SRA) gene (Gibson 2005), which enables Tbr to evade lysis by the Apolipoprotein L-1 ( ApoL-1 ) in human serum (Van Xong et al 1998). Aside from this crucial functional distinction, previous studies, including most recently a kinetoplast CO1 ( Cytochrome Oxidase ) sequence and eight nuclear microsatellites of 142 isolates across Africa (Balmer et al 2011), have shown lack of differentiation between Tbb and Tbr , while finding clear genetic differences between Tbg and Tbb/Tbr (Gibson 2005).…”

Section: Introductionmentioning

confidence: 99%

Comparative Genomics Reveals Multiple Genetic Backgrounds of Human Pathogenicity in the Trypanosoma brucei Complex

Sistrom¹,

Evans²,

Bjornson³

et al. 2014

Genome Biology and Evolution

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The Trypanosoma brucei complex contains a number of subspecies with exceptionally variable life histories, including zoonotic subspecies, which are causative agents of human African trypanosomiasis (HAT) in sub-Saharan Africa. Paradoxically, genomic variation between taxa is extremely low. We analyzed the whole-genome sequences of 39 isolates across the T. brucei complex from diverse hosts and regions, identifying 608,501 single nucleotide polymorphisms that represent 2.33% of the nuclear genome. We show that human pathogenicity occurs across a wide range of parasite genotypes, and taxonomic designation does not reflect genetic variation across the group, as previous studies have suggested based on a small number of genes. This genome-wide study allowed the identification of significant host and geographic location associations. Strong purifying selection was detected in genomic regions associated with cytoskeleton structure, and regulatory genes associated with antigenic variation, suggesting conservation of these regions in African trypanosomes. In agreement with expectations drawn from meiotic reciprocal recombination, differences in average linkage disequilibrium between chromosomes in T. brucei correlate positively with chromosome size. In addition to insights into the life history of a diverse group of eukaryotic parasites, the documentation of genomic variation across the T. brucei complex and its association with specific hosts and geographic localities will aid in the development of comprehensive monitoring tools crucial to the proposed elimination of HAT by 2020, and on a shorter term, for monitoring the feared merger between the two human infective parasites, T. brucei rhodesiense and T. b. gambiense, in northern Uganda.

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“…Reduced TLF binding/uptake operates in T. b. gambiense due to reduced expression of HpHbR and/or mutations in HpHbR [14]–[16]. Endosomal sequestration of APOL1 operates in T. b. rhodesiense due to the expression of a serum resistance-associated protein (SRA) related to a glycosyl-phoshatidylinositol membrane-anchored variant surface glycoprotein (VSG) [2], [17]. Expression of a VSG-related protein also confers TLF-resistance to T. b. gambiense [18], [19], but in this case the VSG-like T. b. gambiense -specific glycoprotein or TgsGP may protect cells from APOL1 by stiffening endosomal membranes rather than through direct interaction with, or sequestration of, APOL1 [19].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin-L Can Resist Lysis by Human Serum in Trypanosoma brucei brucei

et al. 2014

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Closely related African trypanosomes cause lethal diseases but display distinct host ranges. Specifically, Trypanosoma brucei brucei causes nagana in livestock but fails to infect humans, while Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause sleeping sickness in humans. T. b. brucei fails to infect humans because it is sensitive to innate immune complexes found in normal human serum known as trypanolytic factor (TLF) 1 and 2; the lytic component is apolipoprotein-L1 in both TLFs. TLF resistance mechanisms of T. b. gambiense and T. b. rhodesiense are now known to arise through either gain or loss-of-function, but our understanding of factors that render T. b. brucei susceptible to lysis by human serum remains incomplete. We conducted a genome-scale RNA interference (RNAi) library screen for reduced sensitivity to human serum. Among only four high-confidence ‘hits’ were all three genes previously shown to sensitize T. b. brucei to human serum, the haptoglobin-haemoglobin receptor (HpHbR), inhibitor of cysteine peptidase (ICP) and the lysosomal protein, p67, thereby demonstrating the pivotal roles these factors play. The fourth gene identified encodes a predicted protein with eleven trans-membrane domains. Using chemical and genetic approaches, we show that ICP sensitizes T. b. brucei to human serum by modulating the essential cathepsin, CATL, a lysosomal cysteine peptidase. A second cathepsin, CATB, likely to be dispensable for growth in in vitro culture, has little or no impact on human-serum sensitivity. Our findings reveal major and novel determinants of human-serum sensitivity in T. b. brucei. They also shed light on the lysosomal protein-protein interactions that render T. b. brucei exquisitely sensitive to lytic factors in human serum, and indicate that CATL, an important potential drug target, has the capacity to resist these factors.

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A VSG Expression Site–Associated Gene Confers Resistance to Human Serum in Trypanosoma rhodesiense

Cited by 331 publications

References 26 publications

Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei

Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei

Comparative Genomics Reveals Multiple Genetic Backgrounds of Human Pathogenicity in the Trypanosoma brucei Complex

Cathepsin-L Can Resist Lysis by Human Serum in Trypanosoma brucei brucei

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