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1.
PLoS Negl Trop Dis ; 7(3): e2121, 2013.
Article in English | MEDLINE | ID: mdl-23556014

ABSTRACT

The cell surface of Trypanosoma brucei, like many protistan blood parasites, is crucial for mediating host-parasite interactions and is instrumental to the initiation, maintenance and severity of infection. Previous comparisons with the related trypanosomatid parasites T. cruzi and Leishmania major suggest that the cell-surface proteome of T. brucei is largely taxon-specific. Here we compare genes predicted to encode cell surface proteins of T. brucei with those from two related African trypanosomes, T. congolense and T. vivax. We created a cell surface phylome (CSP) by estimating phylogenies for 79 gene families with putative surface functions to understand the more recent evolution of African trypanosome surface architecture. Our findings demonstrate that the transferrin receptor genes essential for bloodstream survival in T. brucei are conserved in T. congolense but absent from T. vivax and include an expanded gene family of insect stage-specific surface glycoproteins that includes many currently uncharacterized genes. We also identify species-specific features and innovations and confirm that these include most expression site-associated genes (ESAGs) in T. brucei, which are absent from T. congolense and T. vivax. The CSP presents the first global picture of the origins and dynamics of cell surface architecture in African trypanosomes, representing the principal differences in genomic repertoire between African trypanosome species and provides a basis from which to explore the developmental and pathological differences in surface architectures. All data can be accessed at: http://www.genedb.org/Page/trypanosoma_surface_phylome.


Subject(s)
Membrane Proteins/genetics , Protozoan Proteins/genetics , Trypanosoma congolense/genetics , Trypanosoma cruzi/genetics , Trypanosoma vivax/genetics , Computational Biology , Evolution, Molecular , Trypanosoma brucei brucei/genetics
2.
Mol Pharmacol ; 83(2): 439-53, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23188714

ABSTRACT

African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form trypanosomes has not been investigated, making it difficult to judge the relative importance of salvage and synthesis or to design a pyrimidine-based chemotherapy. Detailed characterization of pyrimidine transport activities in bloodstream form Trypanosoma brucei brucei found that these cells express a high-affinity uracil transporter (designated TbU3) that is clearly distinct from the procyclic pyrimidine transporters. This transporter had low affinity for uridine and 2'deoxyuridine and was the sole pyrimidine transporter expressed in these cells. In addition, thymidine was taken up inefficiently through a P1-type nucleoside transporter. Of importance, the anticancer drug 5-fluorouracil was an excellent substrate for TbU3, and several 5-fluoropyrimidine analogs were investigated for uptake and trypanocidal activity; 5F-orotic acid, 5F-2'deoxyuridine displayed activity in the low micromolar range. The metabolism and mode of action of these analogs was determined using metabolomic assessments of T. brucei clonal lines adapted to high levels of these pyrimidine analogs, and of the sensitive parental strains. The analysis showed that 5-fluorouracil is incorporated into a large number of metabolites but likely exerts toxicity through incorporation into RNA. 5F-2'dUrd and 5F-2'dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase as 5F-dUMP. We present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes.


Subject(s)
Nucleoside Transport Proteins/metabolism , Pyrimidines/metabolism , Pyrimidines/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/metabolism , Biological Transport/drug effects , Fluorouracil/pharmacology , Genome-Wide Association Study/methods , Glycosylation/drug effects , Uracil/metabolism , Uridine/metabolism
3.
Proc Natl Acad Sci U S A ; 109(9): 3416-21, 2012 Feb 28.
Article in English | MEDLINE | ID: mdl-22331916

ABSTRACT

Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis ("sleeping sickness") across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly co-opted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections.


Subject(s)
Antigenic Variation/genetics , Evolution, Molecular , Genome, Protozoan , Immune Evasion/genetics , Trypanosoma brucei brucei/immunology , Trypanosoma congolense/immunology , Trypanosoma vivax/immunology , Variant Surface Glycoproteins, Trypanosoma/genetics , Amino Acid Sequence , Animals , Base Sequence , DNA, Protozoan/genetics , Humans , Models, Molecular , Molecular Sequence Data , Phylogeny , Protein Conformation , Protozoan Proteins/chemistry , Protozoan Proteins/genetics , Recombination, Genetic , Sequence Alignment , Sequence Homology, Amino Acid , Species Specificity , Trypanosoma brucei brucei/genetics , Trypanosoma congolense/genetics , Trypanosoma vivax/genetics , Variant Surface Glycoproteins, Trypanosoma/chemistry , Variant Surface Glycoproteins, Trypanosoma/immunology
4.
Mol Biochem Parasitol ; 179(2): 51-8, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21763356

ABSTRACT

Most trypanosomatid parasites have both arthropod and mammalian or plant hosts, and the ability to survive and complete a developmental program in each of these very different environments is essential for life cycle progression and hence being a successful pathogen. For African trypanosomes, where the mammalian stage is exclusively extracellular, this presents specific challenges and requires evasion of both the acquired and innate immune systems, together with adaptation to a specific nutritional environment and resistance to mechanical and biochemical stresses. Here we consider the basis for these adaptations, the specific features of the mammalian infective trypanosome that are required to meet these challenges, and how these processes both inform on basic parasite biology and present potential therapeutic targets.


Subject(s)
Antigenic Variation , Immune Evasion , Trypanosoma brucei brucei/pathogenicity , Trypanosomiasis, African/immunology , Animals , Endocytosis , Humans , Mammals , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Protozoan Proteins/genetics , Protozoan Proteins/immunology , Salivary Glands/parasitology , Trypanosoma brucei brucei/genetics , Trypanosoma brucei brucei/immunology , Trypanosomiasis, African/blood , Trypanosomiasis, African/parasitology , Tsetse Flies/immunology , Tsetse Flies/parasitology , Variant Surface Glycoproteins, Trypanosoma/blood , Variant Surface Glycoproteins, Trypanosoma/genetics , Variant Surface Glycoproteins, Trypanosoma/immunology
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