Publications

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functional characterization of two novel parvulins in trypanosoma brucei.parvulins belong to a family of peptidyl-prolyl cis/trans isomerases (ppiases) that catalyze the cis/trans conformations of prolyl-peptidyl bonds. herein, we characterized two novel parvulins, tbpin1 and tbpar42, in trypanosoma brucei. tbpin1, a 115 amino-acid protein, contains a single ppiase domain but lacks the n-terminal ww domain. using nmr spectroscopy, tbpin1 was found to exhibit ppiase activity toward a phosphorylated substrate. overexpression of tbpin1 can rescue the impaired temperatur ...201020466001
ycf45 protein, usually associated with plastids, is targeted into the mitochondrion of trypanosoma brucei.ycf45 belongs to a family of proteins of unknown function usually located in the chloroplast of plants. its highly conserved homologues were found in the genomes of several trypanosoma and leishmania species. ha(3)-tagging of the ycf45 protein with the start codon as annotated in the gene(db) revealed its cytosolic localization in the cultured procyclic stage of trypanosoma brucei. however, when a more upstream located start codon was used in another ha(3)-tagged construct, the resulting protein ...201020470834
discrimination of thermophilic and mesophilic proteins.there is a considerable literature on the source of the thermostability of proteins from thermophilic organisms. understanding the mechanisms for this thermostability would provide insights into proteins generally and permit the design of synthetic hyperstable biocatalysts.201020487512
target of rapamycin (tor)-like 1 kinase is involved in the control of polyphosphate levels and acidocalcisome maintenance in trypanosoma brucei.target of rapamycin (tor) kinases are highly conserved protein kinases that integrate signals from nutrients and growth factors to coordinate cell growth and cell cycle progression. it has been previously described that two tor kinases control cell growth in the protozoan parasite trypanosoma brucei, the causative agent of african trypanosomiasis. here we studied an unusual tor-like protein named tbtor-like 1 containing a pdz domain and found exclusively in kinetoplastids. tbtor-like 1 localizes ...201020495004
selective delivery of 2-hydroxy apa to trypanosoma brucei using the melamine motif.trypanosoma brucei, the parasite that causes human african trypanosomiasis, is auxotrophic for purines and has specialist nucleoside transporters to import these metabolites. in particular, the p2 aminopurine transporter can also selectively accumulate melamine derivatives. in this letter, we report the coupling of the melamine moiety to 2-hydroxy apa, a potent ornithine decarboxylase inhibitor, with the aim of selectively delivering this compound to the parasite. the best compound described her ...201020615694
trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice.gene knockout and knockdown methods were used to examine essentiality of pteridine reductase (ptr1) in pterin metabolism in the african trypanosome. attempts to generate ptr1 null mutants in bloodstream form trypanosoma brucei proved unsuccessful; despite integration of drug selectable markers at the target locus, the gene for ptr1 was either retained at the same locus or elsewhere in the genome. however, rna interference (rnai) resulted in complete knockdown of endogenous protein after 48 h, fo ...201020545846
molecular diagnostics for sleeping sickness: what is the benefit for the patient?sleeping sickness, or human african trypanosomiasis, is a vector-borne disease caused by two subspecies of the protozoan parasite trypanosoma brucei, and is geographically restricted to sub-saharan africa. although the disease causes major public-health and socioeconomic problems among affected populations, sleeping sickness is one of the world's most neglected diseases. within the rapidly evolving field of biotechnology, many molecular diagnostics have been developed to detect the parasite. the ...201020510283
new discoveries in the transmission biology of sleeping sickness parasites: applying the basics.the sleeping sickness parasite, trypanosoma brucei, must differentiate in response to the changing environments that it encounters during its complex life cycle. one developmental form, the bloodstream stumpy stage, plays an important role in infection dynamics and transmission of the parasite. recent advances have shed light on the molecular mechanisms by which these stumpy forms differentiate as they are transmitted from the mammalian host to the insect vector of sleeping sickness, tsetse flie ...201020526573
computer-aided identification of trypanosoma brucei uridine diphosphate galactose 4'-epimerase inhibitors: toward the development of novel therapies for african sleeping sickness.trypanosoma brucei, the causative agent of human african trypanosomiasis, affects tens of thousands of sub-saharan africans. as current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. udp-galactose 4'-epimerase (tbgale), an enzyme of the leloir pathway of galactose metabolism, is one promising t. brucei drug target. we here use the relaxed complex scheme, an advanced computer-docking methodology that accounts ...201020527952
topo3alpha influences antigenic variation by monitoring expression-site-associated vsg switching in trypanosoma brucei.homologous recombination (hr) mediates one of the major mechanisms of trypanosome antigenic variation by placing a different variant surface glycoprotein (vsg) gene under the control of the active expression site (es). it is believed that the majority of vsg switching events occur by duplicative gene conversion, but only a few dna repair genes that are central to hr have been assigned a role in this process. gene conversion events that are associated with crossover are rarely seen in vsg switchi ...201020628569
trypanosoma brucei modifies the tsetse salivary composition, altering the fly feeding behavior that favors parasite transmission.tsetse flies are the notorious transmitters of african trypanosomiasis, a disease caused by the trypanosoma parasite that affects humans and livestock on the african continent. metacyclic infection rates in natural tsetse populations with trypanosoma brucei, including the two human-pathogenic subspecies, are very low, even in epidemic situations. therefore, the infected fly/host contact frequency is a key determinant of the transmission dynamics. as an obligate blood feeder, tsetse flies rely on ...201020532213
a novel phosphatase cascade regulates differentiation in trypanosoma brucei via a glycosomal signaling pathway.in the mammalian bloodstream, the sleeping sickness parasite trypanosoma brucei is held poised for transmission by the activity of a tyrosine phosphatase, tbptp1. this prevents differentiation of the transmissible "stumpy forms" until entry into the tsetse fly, whereupon tbptp1 is inactivated and major changes in parasite physiology are initiated to allow colonization of the arthropod vector. using a substrate-trapping approach, we identified the downstream step in this developmental signaling p ...201020551176
trypanosoma brucei: two steps to spread out from africa.trypanosoma brucei equiperdum and trypanosoma brucei evansi are typically considered separate species, although a recent study suggested that these organisms can be classified as subspecies of trypanosoma brucei, which we also favor. here we present a scenario that attempts to explain the continuing evolution of the dyskinetoplastic and akinetoplastic strains, as a consequence of loss of selective pressure(s) leading to the loss of kinetoplast dna.201020561822
the fe/s cluster assembly protein isd11 is essential for trna thiolation in trypanosoma brucei.fe/s clusters are part of the active site of many enzymes and are essential for cell viability. in eukaryotes the cysteine desulfurase nfs (iscs) donates the sulfur during fe/s cluster assembly and was thought sufficient for this reaction. moreover, nfs is indispensable for trna thiolation, a modification generally required for trna function and protein synthesis. recently, isd11 was discovered as an integral part of the nfs activity at an early step of fe/s cluster assembly. here we show, using ...201020442400
diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage trypanosoma brucei.the options for treating the fatal disease human african trypanosomiasis are limited to a few drugs that are toxic or facing increasing resistance. new drugs that kill the causative agents, subspecies of trypanosoma brucei, are therefore urgently needed. little is known about the cellular mechanisms that lead to death of the pathogenic bloodstream stage.201020454560
the small gtpase arl2 is required for cytokinesis in trypanosoma brucei.the arf-like (arl) small gtpases have a diverse range of functions in the eukaryotic cell. metazoan arl2 acts as a regulator of microtubule biogenesis, binding to the tubulin-specific chaperone cofactor d. arl2 also has a mitochondrial function through its interactions with bart and ant-1, the only member of the ras superfamily to be found in this organelle to date. in the present study, we describe characterization of the arl2 orthologue in the protozoan parasite trypanosoma brucei. modulation ...201020653091
drug discovery: fat-free proteins kill parasites. 201020360728
cell-free synthesis and functional characterization of sphingolipid synthases from parasitic trypanosomatid protozoa.the trypanosoma brucei genome has four highly similar genes encoding sphingolipid synthases (tbsls1-4). tbslss are polytopic membrane proteins that are essential for viability of the pathogenic bloodstream stage of this human protozoan parasite and, consequently, can be considered as potential drug targets. tbsls4 was shown previously to be a bifunctional sphingomyelin/ethanolamine phosphorylceramide synthase, whereas functions of the others were not characterized. using a recently described lip ...201020457606
genome-wide analysis of mrna abundance in two life-cycle stages of trypanosoma brucei and identification of splicing and polyadenylation sites.transcription of protein-coding genes in trypanosomes is polycistronic and gene expression is primarily regulated by post-transcriptional mechanisms. sequence motifs in the untranslated regions regulate mrna trans-splicing and rna stability, yet where utrs begin and end is known for very few genes. we used high-throughput rna-sequencing to determine the genome-wide steady-state mrna levels ('transcriptomes') for approximately 90% of the genome in two stages of the trypanosoma brucei life cycle c ...201020385579
n-myristoyltransferase inhibitors as new leads to treat sleeping sickness.african sleeping sickness or human african trypanosomiasis, caused by trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suit ...201020360736
mechanism of u insertion rna editing in trypanosome mitochondria: the bimodal tutase activity of the core complex.expression of the trypanosomal mitochondrial genome requires the insertion and deletion of uridylyl residues at specific sites in pre-mrnas. ret2 terminal uridylyl transferase is an integral component of the rna editing core complex (recc) and is responsible for the guide-rna-dependent u insertion reaction. by analyzing rna-interference-based knock-in trypanosoma brucei cell lines, purified editing complex, and individual protein, we have investigated ret2's association with the recc. in additio ...201020362585
processing of a phosphoglycerate kinase reporter mrna in trypanosoma brucei is not coupled to transcription by rna polymerase ii.capping of mrnas is strictly coupled to rna polymerase ii transcription and there is evidence, mainly from metazoans, that other steps in pre-mrna processing show a similar linkage. in trypanosomes, however, the mrna cap is supplied by a trans spliced leader sequence. thus pre-mrnas transcribed by rna polymerase i are capped by trans splicing, and translation-competent transgenic mrnas can be produced by rna polymerase i and t7 rna polymerase so long as the primary transcript has a splice accept ...201020363263
progressive meningoencephalitis in a sudanese immigrant. 201020367592
a target-based high throughput screen yields trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.the parasitic protozoan trypanosoma brucei utilizes glycolysis exclusively for atp production during infection of the mammalian host. the first step in this metabolic pathway is mediated by hexokinase (tbhk), an enzyme essential to the parasite that transfers the gamma-phospho of atp to a hexose. here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed tbhk1, one of two tbhks expressed by t. brucei, using a high throughput screening assay.201020405000
domestic animals as potential reservoir hosts of trypanosoma brucei gambiense in sleeping sickness foci in cameroon.an explanation of the endemic nature and/or the resurgence of human african trypanosomiasis (hat) in the historic foci in west and central africa may be the existence of an animal reservoir. in some hat foci, pigs were found infected by trypanosoma brucei gambiense but the implication of the other domestic animals was not quite evaluated. this study aims to determine the prevalence of t. b. gambiense in domestic animal species (goat, sheep, pig and dog) commonly found in the four active hat foci ...201020387740
anti-parasitic compounds from streptomyces sp. strains isolated from mediterranean sponges.actinomycetes are prolific producers of pharmacologically important compounds accounting for about 70% of the naturally derived antibiotics that are currently in clinical use. in this study, we report on the isolation of streptomyces sp. strains from mediterranean sponges, on their secondary metabolite production and on their screening for anti-infective activities. bioassay-guided isolation and purification yielded three previously known compounds namely, cyclic depsipeptide valinomycin, indolo ...201020390111
structure of the trypanosoma brucei p22 protein, a cytochrome oxidase subunit ii-specific rna-editing accessory factor.kinetoplastid rna (k-rna) editing is a complex process in the mitochondria of kinetoplastid protozoa, including trypanosoma brucei, that involves the guide rna-directed insertion and deletion of uridines from precursor-mrnas to produce mature, translatable mrnas. k-rna editing is performed by multiprotein complexes called editosomes. additional non-editosome components termed k-rna-editing accessory factors affect the extent of editing of specific rnas or classes of rnas. the t. brucei p22 prote ...201020392699
antitrypanosomal alkaloids from polyalthia suaveolens (annonaceae): their effects on three selected glycolytic enzymes of trypanosoma brucei.in continuation of our study on medicinal plants of cameroon, stem barks of polyalthia suaveolens were phytochemically studied. this investigation yielded a new indolosesquiterpene alkaloid, named polysin (1) and four hitherto known alkaloids (2-5). polysin (1) appeared as a competitive reversible inhibitor (k(i)=10 microm) of phosphofructo kinase (pfk) of trypanosoma brucei with respect to fructose-6-phosphate (k(i)/k(m)=0.05) and could be used in the design of new trypanocidal drugs. the other ...201020529682
the trypanolytic factor of human serum: many ways to enter the parasite, a single way to kill.humans have developed a particular innate immunity system against african trypanosomes, and only two trypanosoma brucei clones (t. b. gambiense, t. b. rhodesiense) can resist this defence and cause sleeping sickness. the main players of this immunity are the primate-specific apolipoprotein l-i (apol1) and haptoglobin-related protein (hpr). these proteins are both associated with two serum complexes, a minor subfraction of hdls and an igm/apolipoprotein a-i (apoa1) complex, respectively, termed t ...201020398209
late-stage human african trypanosomiasis in a sudanese refugee.a 19-year-old sudanese woman, who had lived for about a decade in ugandan refugee camps, was referred for investigation of a 12-month history of a generalised rash. two months later, her condition had deteriorated to include cachexia and drowsiness. despite initial negative findings on investigation, human african trypanosomiasis (hat) was suspected, and parasites were found in a double-centrifuged sample of cerebrospinal fluid. eflornithine, the appropriate drug for treatment of late-stage dise ...201020367593
lipid metabolism in trypanosoma brucei.trypanosoma brucei membranes consist of all major eukaryotic glycerophospholipid and sphingolipid classes. these are de novo synthesized from precursors obtained either from the host or from catabolised endocytosed lipids. in recent years, substantial progress has been made in the molecular and biochemical characterisation of several of these lipid biosynthetic pathways, using gene knockout or rna interference strategies or by enzymatic characterization of individual reactions. together with the ...201020382188
structural characterization of cyp51 from trypanosoma cruzi and trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole.chagas disease is the leading cause of heart failure in latin america. current drug therapy is limited by issues of both efficacy and severe side effects. trypansoma cruzi, the protozoan agent of chagas disease, is closely related to two other major global pathogens, leishmania spp., responsible for leishmaniasis, and trypansoma brucei, the causative agent of african sleeping sickness. both t. cruzi and leishmania parasites have an essential requirement for ergosterol, and are thus vulnerable to ...201020386598
isolation, phylogenetic analysis and anti-infective activity screening of marine sponge-associated actinomycetes.terrestrial actinomycetes are noteworthy producers of a multitude of antibiotics, however the marine representatives are much less studied in this regard. in this study, 90 actinomycetes were isolated from 11 different species of marine sponges that had been collected from offshore ras mohamed (egypt) and from rovinj (croatia). phylogenetic characterization of the isolates based on 16s rrna gene sequencing supported their assignment to 18 different actinomycete genera representing seven differen ...201020411105
calflagin inhibition prolongs host survival and suppresses parasitemia in trypanosoma brucei infection.african trypanosomes express a family of dually acylated, ef-hand calcium-binding proteins called the calflagins. these proteins associate with lipid raft microdomains in the flagellar membrane, where they putatively function as calcium signaling proteins. here we show that these proteins bind calcium with high affinity and that their expression is regulated during the life cycle stage of the parasite, with protein levels approximately 10-fold higher in the mammalian bloodstream form than in the ...201020418379
tbprmt6 is a type i protein arginine methyltransferase that contributes to cytokinesis in trypanosoma brucei.arginine methylation is a widespread posttranslational modification of proteins catalyzed by a family of protein arginine methyltransferases (prmts). in saccharomyces cerevisiae and mammals, this modification affects multiple cellular processes, such as chromatin remodeling leading to transcriptional regulation, rna processing, dna repair, and cell signaling. the protozoan parasite trypanosoma brucei possesses five putative prmts in its genome. this is a large number of prmts relative to other u ...201020418380
7',8'-dihydroobolactone, a typanocidal alpha-pyrone from the rainforest tree cryptocarya obovata.mass-directed isolation of the ch(2)cl(2)/meoh extract from the leaves of cryptocarya obovata resulted in the purification of a new trypanocidal alpha-pyrone, 7',8'-dihydroobolactone (1). the chemical structure of 1 was determined by 1d/2d nmr, ms and cd data analysis. 7',8'-dihydroobolactone was shown to inhibit trypanosoma brucei brucei with an ic(50) of 2.8 microm.201020558060
glycotyping of trypanosoma brucei variant surface glycoprotein mitat1.8.following a switch from variant surface glycoprotein mitat1.4 to variant surface glycoprotein mitat1.8 expression by lister strain 427 trypanosoma brucei brucei parasites, the latter uncharacterized variant surface glycoprotein was analysed. variant surface glycoprotein mitat1.8 was found to be a disulphide-linked homodimer, containing a complex n-linked glycan at asn58 and a glycosylphosphatidylinositol membrane anchor attached to asp419. mass spectrometric analyses demonstrated that the n-glyc ...201020558211
antitrypanosomal peptaibiotics, trichosporins b-viia and b-viib, produced by trichoderma polysporum fki-4452. 201020431618
cross-resistance to nitro drugs and implications for treatment of human african trypanosomiasis.the success of nifurtimox-eflornithine combination therapy (nect) for the treatment of human african trypanosomiasis (hat) has renewed interest in the potential of nitro drugs as chemotherapeutics. in order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. following selection in vitro by exposure to increasing concentrations of nifurtimox, tryp ...201020439607
genome-wide in silico screen for ccch-type zinc finger proteins of trypanosoma brucei, trypanosoma cruzi and leishmania major.ccch type zinc finger proteins are rna binding proteins with regulatory functions at all stages of mrna metabolism. the best-characterized member, tritetraproline (ttp), binds to au rich elements in 3' utrs of unstable mrnas, mediating their degradation. in kinetoplastids, ccch type zinc finger proteins have been identified as being involved in the regulation of the life cycle and possibly the cell cycle. to date, no systematic listing of ccch proteins in kinetoplastids is available.201020444260
the trypanosoma brucei life cycle switch tbptp1 is structurally conserved and dephosphorylates the nucleolar protein nopp44/46.trypanosoma brucei adapts to changing environments as it cycles through arrested and proliferating stages in the human and tsetse fly hosts. changes in protein tyrosine phosphorylation of several proteins, including nopp44/46, accompany t. brucei development. moreover, inactivation of t. brucei protein-tyrosine phosphatase 1 (tbptp1) triggers differentiation of bloodstream stumpy forms into tsetse procyclic forms through unknown downstream effects. here, we link these events by showing that nopp ...201020444707
trnasec is transcribed by rna polymerase ii in trypanosoma brucei but not in humans.nuclear-encoded trnas are universally transcribed by rna polymerase iii (pol-iii) and contain intragenic promoters. transcription of vertebrate trna(sec) however requires extragenic promoters similar to pol-iii transcribed u6 snrna. here, we present a comparative analysis of trna(sec) transcription in humans and the parasitic protozoa trypanosoma brucei, two evolutionary highly diverged eukaryotes. rnai-mediated ablation of pol-ii and pol-iii as well as oligo-dt induced transcription termination ...201020444878
discovery of novel orally bioavailable oxaborole 6-carboxamides that demonstrate cure in a murine model of late-stage central nervous system african trypanosomiasis.we report the discovery of novel boron-containing molecules, exemplified by n-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (an3520) and 4-fluoro-n-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (scyx-6759), as potent compounds against trypanosoma brucei in vitro, including the two subspecies responsible for human disease t. b. rhodesiense and t. b. gambiense. these oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis i ...201020660666
histone deacetylases play distinct roles in telomeric vsg expression site silencing in african trypanosomes.african trypanosomes evade the host immune response through antigenic variation, which is achieved by periodically expressing different variant surface glycoproteins (vsgs). vsg expression is monoallelic such that only one of approximately 15 telomeric vsg expression sites (ess) is transcribed at a time. epigenetic regulation is involved in vsg control but our understanding of the mechanisms involved remains incomplete. histone deacetylases are potential drug targets for diseases caused by proto ...201020624217
cd200 receptors are differentially expressed and modulated by minocycline in the brain during trypanosoma brucei infection.infection with trypanosoma brucei, which causes african trypanosomiasis, activates microglia, which are constitutively maintained in a quiescent state through cd200-cd200 receptor interactions. c57bl/6 mice have one inhibitory receptor, cd200r and three activating members, cd200 receptor-like (rl)a-c. infection increased mac-1 (microglia marker), cd200rla and cd200rlb, but not cd200, cd200r or cd200rlc, transcript levels in the brains. minocycline treatment inhibited the infection-induced elevat ...201020627327
echinacea and trypanasomatid parasite interactions: growth-inhibitory and anti-inflammatory effects of echinacea.herbal preparations derived from various species and parts of echinacea (asteraceae) have been advocated for various medical applications, as a result of the many antimicrobial and immunomodulatory activities attributed to them.201020731557
a fluorescence-based assay for the uptake of cpd0801 (db829) by african trypanosomes.drug therapies currently used for second stage human african trypanosomiasis (hat) exhibit problems with toxicity, difficulty of administration, and resistance linked to the loss of transporter function. key to the development of new drugs for hat is a better understanding of the transport properties of candidate compounds. standard methods for studying transport utilize radio-labelled permeant or hplc-ms, however the natural fluorescence of many trypanocidal compounds can be exploited. here we ...201020637807
comparative haematological study of single and mixed infections of mongrel dogs with trypanosoma congolense and trypanosoma brucei brucei.the haematological effects of single and mixed infections of trypanosoma congolense and trypanosoma brucei brucei were compared in experimentally infected mongrel dogs. twenty mongrel dogs of both sexes aged between 3 and 6 months, and weighing between 2.5 and 5.9 kg were used for the study. the dogs were kept in clean metal cages in a fly-proof house and were adequately fed and given water ad libitum. the twenty dogs were divided into four groups of five dogs each. group i dogs were uninfected ...201020638796
the trypanolytic factor-mechanism, impacts and applications.the trypanosoma brucei subspecies t. brucei brucei is non-human infective due to susceptibility to lysis by trypanolytic factor (tlf) in human serum. reviewed here are the advances which have revealed apolipoprotein l1 (apol1), found in high density lipoprotein, as the lysis-inducing component of tlf, the means of uptake via haptoglobin-related protein receptor and the mechanism of resistance in t. b. rhodesiense via its serum resistance-associated (sra) protein. the first practical steps to app ...201020646962
promising lead compounds for novel antiprotozoals. 201020661239
assembly of the flagellum and its role in cell morphogenesis in trypanosoma brucei.eukaryotic flagella are microtubule-based structures required for a variety of functions including cell motility and sensory perception. most eukaryotic flagella grow out from a cell into the surrounding medium, but when the flagellum of the protozoan parasite trypanosoma brucei exits the cell via the flagellar pocket, it is attached along the length of the cell body by a cytoskeletal structure called the flagellum attachment zone (faz). the exact reasons for flagellum attachment have remained e ...201020541452
a spectrum of disease in human african trypanosomiasis: the host and parasite genetics of virulence.for over 50 years it has been known that there are considerable differences in the severity and rate of progression of both trypanosoma brucei rhodesiense and t. b. gambiense infection between individuals. yet research into the factors, whether parasite or host, which control virulence in human african trypanosomiasis is in its infancy. in this paper we review the clinical evidence for virulence variation and the epidemiological and experimental data that give clues as to the mechanisms involved ...201020663245
aryl phosphoramidates of 5-phospho erythronohydroxamic acid, a new class of potent trypanocidal compounds.rnai and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-pgdh) in trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human african trypanosomiasis. 2,3-o-isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite trypanosoma brucei 6-phosphogluconate dehydrogenase (6-pgdh), the third enzyme of the pentose phosphate pathway. however, this compound does not have trypanocid ...201020666371
basal body movements orchestrate membrane organelle division and cell morphogenesis in trypanosoma brucei.the defined shape and single-copy organelles of trypanosoma brucei mean that it provides an excellent model in which to study how duplication and segregation of organelles is interfaced with morphogenesis of overall cell shape and form. the centriole or basal body of eukaryotic cells is often seen to be at the centre of such processes. we have used a combination of electron microscopy and electron tomography techniques to provide a detailed three-dimensional view of duplication of the basal body ...201020682637
bottlenecks and the maintenance of minor genotypes during the life cycle of trypanosoma brucei.african trypanosomes are digenetic parasites that undergo part of their developmental cycle in mammals and part in tsetse flies. we established a novel technique to monitor the population dynamics of trypanosoma brucei throughout its life cycle while minimising the confounding factors of strain differences or variation in fitness. clones derived from a single trypanosome were tagged with short synthetic dna sequences in a non-transcribed region of the genome. infections were initiated with mixtu ...201020686656
trypanosome alternative oxidase, a potential therapeutic target for sleeping sickness, is conserved among trypanosoma brucei subspecies.trypanosoma brucei rhodesiense and t. b. gambiense are known causes of human african trypanosomiasis (hat), or "sleeping sickness," which is deadly if untreated. we previously reported that a specific inhibitor of trypanosome alternative oxidase (tao), ascofuranone, quickly kills african trypanosomes in vitro and cures mice infected with another subspecies, non-human infective t. b. brucei, in in vivo trials. as an essential factor for trypanosome survival, tao is a promising drug target due to ...201020688188
allicin and derivates are cysteine protease inhibitors with antiparasitic activity.allicin and derivatives thereof inhibit the cac1 cysteine proteases falcipain 2, rhodesain, cathepsin b and l in the low micromolar range. the structure-activity relationship revealed that only derivatives with primary carbon atom in vicinity to the thiosulfinate sulfur atom attacked by the active-site cys residue are active against the target enzymes. some compounds also show potent antiparasitic activity against plasmodium falciparum and trypanosoma brucei brucei.201020692829
functional genome annotation by combined analysis across microarray studies of trypanosoma brucei.functional annotation of trypanosomatid genomes has been a daunting task due to the low similarity of their genes with annotated genes of other organisms. three recent studies have provided gene expression profiles in several different conditions and life stages for one of the main disease-causing trypanosomatids, trypanosoma brucei. these data can be used to study the gene functions and regulatory mechanisms in this organism.201020824174
identification of a κ-opioid agonist as a potent and selective lead for drug development against human african trypanosomiasis.a resazurin-based cell viability assay was developed for phenotypic screening of the lopac 1280 'library of pharmacologically active compounds' against bloodstream forms of trypanosoma brucei in vitro identifying 33 compounds with ec(50) values <1 μm. counter-screening vs. normal diploid human fibroblasts (mrc5 cells) was used to rank these hits for selectivity, with the most potent (<70 nm) and selective (>700-fold) compounds being suramin and pentamidine. these are well-known antitrypanosomal ...201020696141
crystallographic binding studies with an engineered monomeric variant of triosephosphate isomerase.crystallographic binding studies have been carried out to probe the active-site binding properties of a monomeric variant (a-tim) of triosephosphate isomerase (tim). these binding studies are part of a structure-based directed-evolution project aimed towards changing the substrate specificity of monomeric tim and are therefore aimed at finding binders which are substrate-like molecules. a-tim has a modified more extended binding pocket between loop-7 and loop-8 compared with wild-type tim. the a ...201020693693
evaluation of in vitro activity of essential oils against trypanosoma brucei brucei and trypanosoma evansi.essential oils (eos) from cymbopogon citratus (cc), eucalyptus citriodora (ec), eucalyptus camaldulensis (ed), and citrus sinensis (cs) were obtained by hydrodistillation process. the eos were evaluated in vitro for activity against trypanosoma brucei brucei (tbb) and trypanosoma evansi (t. evansi). the eos were found to possess antitrypanosomal activity in vitro in a dose-dependent pattern in a short period of time. the drop in number of parasite over time was achieved doses of 0.4 g/ml, 0.2 g/ ...201020700425
ob-fold domain of krepa4 mediates high-affinity interaction with guide rna and possesses annealing activity.krepa4, also called mp24, is an essential mitochondrial guide rna (grna)-binding protein with a preference for the 3' oligo(u) tail in trypanosomes. structural prediction and compositional analysis of krepa4 have identified a conserved ob (oligonucleotide/oligosaccharide-binding)-fold at the c-terminal end and two low compositional complexity regions (lcrs) at its n terminus. concurrent with these predictions, one or both of these regions in krepa4 protein may be involved in grna binding. to tes ...201020713467
a functional proteomic study of the trypanosoma brucei nuclear pore complex: an informatic strategy.the nuclear pore complex (npc) is the sole mediator of transport between the nucleus and the cytoplasm. the npc is composed of about 30 distinct proteins, termed nucleoporins or nups. the yeast (rout et al., j cell biol 148:635-651, 2000) and mammalian (cronshaw et al., j cell biol 158:915-927, 2002) npc have been extensively studied. however, the two species are relatively closely related. thus, to reveal details about npc evolution, we chose to characterize the npc of a distantly related organ ...201020835803
the transcriptome of the human pathogen trypanosoma brucei at single-nucleotide resolution.the genome of trypanosoma brucei, the causative agent of african trypanosomiasis, was published five years ago, yet identification of all genes and their transcripts remains to be accomplished. annotation is challenged by the organization of genes transcribed by rna polymerase ii (pol ii) into long unidirectional gene clusters with no knowledge of how transcription is initiated. here we report a single-nucleotide resolution genomic map of the t. brucei transcriptome, adding 1,114 new transcripts ...201020838601
tip-dc development during parasitic infection is regulated by il-10 and requires ccl2/ccr2, ifn-gamma and myd88 signaling.the development of classically activated monocytic cells (m1) is a prerequisite for effective elimination of parasites, including african trypanosomes. however, persistent activation of m1 that produce pathogenic molecules such as tnf and no contributes to the development of trypanosome infection-associated tissue injury including liver cell necrosis in experimental mouse models. aiming to identify mechanisms involved in regulation of m1 activity, we have recently documented that during trypanos ...201020714353
in vitro antitrypanosomal activity of 12 low-molecular-weight antibiotics and observations of structure/activity relationships. 201020717119
the role of the kinesin-13 family protein tbkif13-2 in flagellar length control of trypanosoma brucei.tbkif13-2, a member of the microtubule-depolymerising kinesin-13 family was localised at the tip of the flagellum in trypanosoma brucei. its predicted activity suggested a role in the regulation of axonemal length. however, using gene deletion and overexpression of tbkif13-2 we show that, in procyclic t. brucei, this kinesin has only a very limited effect on flagellar length. gene deletion resulted in no significant elongation of the flagellum and overexpression only slightly decreased flagellar ...201020728476
using t. brucei as a biological epitope-display platform to elicit specific antibody responses.the african trypanosome (trypanosoma brucei) is transmitted by the bite of the tsetse vector to the mammalian bloodstream where it exists as a completely extracellular parasite. as a result of this exposure, the parasite elicits a robust immune response that is almost exclusively antibody mediated, and is extremely specific to the trypanosome coat displayed on the surface. this coat is comprised of ~11 million copies of a single gpi-linked molecule (the variable surface glycoprotein or vsg) and ...201020800596
functional characterization of three leishmania poly(a) binding protein homologues with distinct binding properties to rna and protein partners.trypanosomatid protozoans are reliant on posttranscriptional processes to control gene expression. regulation occurs at the levels of mrna processing, stability, and translation, events that may require the participation of the poly(a) binding protein (pabp). here, we have undertaken a functional study of the three distinct leishmania major pabp (lmpabp) homologues: the previously described lmpabp1; lmpabp2, orthologous to the pabp described from trypanosoma species; and lmpabp3, unique to leish ...201020675580
spliced leader trapping reveals widespread alternative splicing patterns in the highly dynamic transcriptome of trypanosoma brucei.trans-splicing of leader sequences onto the 5'ends of mrnas is a widespread phenomenon in protozoa, nematodes and some chordates. using parallel sequencing we have developed a method to simultaneously map 5'splice sites and analyze the corresponding gene expression profile, that we term spliced leader trapping (slt). the method can be applied to any organism with a sequenced genome and trans-splicing of a conserved leader sequence. we analyzed the expression profiles and splicing patterns of blo ...201020700444
α-ketoheterocycles as inhibitors of leishmania mexicana cysteine protease cpb.cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, chagas disease, and leishmaniasis. inspired by the in vivo antiparasitic activity of the vinylsulfone-based cysteine protease inhibitors, a series of α-ketoheterocycles were developed as reversible inhibitors of a recombinant l. mexica ...201020799311
design and synthesis of bioactive adamantanaminoalcohols and adamantanamines.adamantanamines 16, 18, 21, 24, 27, 28, 30, 32, 35, 36, 37, 40, 46 and 48 were synthesized and tested for anti-influenza a virus and trypanocidal activity. the stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. the effect of introducing a hydroxyl group close to the amino group on this class of compounds was examined for the first time. aminoalcohol 24 proved to be the most active of the compounds tested against influenza a virus, being 6-fold more ac ...201020805012
novel naphthalene-based inhibitors of trypanosoma brucei rna editing ligase 1.neglected tropical diseases, including diseases caused by trypanosomatid parasites such as trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. as the current treatments for african trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. rna editing ligase 1 (rel1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.201020808768
ablation of succinate production from glucose metabolism in the procyclic trypanosomes induces metabolic switches to the glycerol 3-phosphate/dihydroxyacetone phosphate shuttle and to proline metabolism.trypanosoma brucei is a parasitic protist that undergoes a complex life cycle during transmission from its mammalian host (bloodstream forms) to the midgut of its insect vector (procyclic form). in both parasitic forms, most glycolytic steps take place within specialized peroxisomes, called glycosomes. here, we studied metabolic adaptations in procyclic trypanosome mutants affected in their maintenance of the glycosomal redox balance. t. brucei can theoretically use three strategies to maintain ...201020702405
prophylactic antiparasitic transgenesis for human parasitic disease? 201020885434
identification and characterization of an unusual class i myosin involved in vesicle traffic in trypanosoma brucei.myosins are a multimember family of motor proteins with diverse functions in eukaryotic cells. african trypanosomes possess only two candidate myosins and thus represent a useful system for functional analysis of these motors. one of these candidates is an unusual class i myosin (tbmyo1) that is expressed at similar levels but organized differently during the life cycle of trypanosoma brucei. this myosin localizes to the polarized endocytic pathway in bloodstream forms of the parasite. this orga ...201020808867
functional characterisation and drug target validation of a mitotic kinesin-13 in trypanosoma brucei.mitotic kinesins are essential for faithful chromosome segregation and cell proliferation. therefore, in humans, kinesin motor proteins have been identified as anti-cancer drug targets and small molecule inhibitors are now tested in clinical studies. phylogenetic analyses have assigned five of the approximately fifty kinesin motor proteins coded by trypanosoma brucei genome to the kinesin-13 family. kinesins of this family have unusual biochemical properties because they do not transport cargo a ...201020808899
studies of quinapyramine-resistance of trypanosoma brucei evansi in china.in the present article, we summarize our studies of antrycide-resistance of trypanosoma brucei evansi in four aspects in the last recent several years, the analysis of quinapyramine-sensitive situation of t. b. evansi in china, biological characteristics of t. b. evansi population in quinapyramine-resistance and biological materials of quinapyramine-resistance in t. b. evansi population. firstly, the correlative assays of effective dosage of quinapyramine on t. b. evansi disease between in vivo ...201020813092
the n terminus of phosphodiesterase tbrpdeb1 of trypanosoma brucei contains the signal for integration into the flagellar skeleton.the precise subcellular localization of the components of the cyclic amp (camp) signaling pathways is a crucial aspect of eukaryotic intracellular signaling. in the human pathogen trypanosoma brucei, the strict control of camp levels by camp-specific phosphodiesterases is essential for parasite survival, both in cell culture and in the infected host. among the five cyclic nucleotide phosphodiesterases identified in this organism, two closely related isoenzymes, t. brucei pdeb1 (tbrpdeb1) (pdeb1) ...201020693305
identification, subcellular localization, biochemical properties, and high-resolution crystal structure of trypanosoma brucei udp-glucose pyrophosphorylase.the protozoan parasite trypanosoma brucei is the causative agent of the cattle disease nagana and human african sleeping sickness. glycoproteins play key roles in the parasite's survival and infectivity, and the de novo biosyntheses of the sugar nucleotides udp-galactose (udp-gal), udp-n-acetylglucosamine, and gdp-fucose have been shown to be essential for their growth. the only route to udp-gal in t. brucei is through the epimerization of udp-glucose (udp-glc) by udp-glc 4'-epimerase. udp-glc i ...201020724435
the impact of dietary protein on the pathophysiology of porcine trypanosome infection.the influence of protein nutrition on porcine trypanosomosis was investigated in this study. thirty six landrace/large white cross weanling pigs were used. upon purchase, these were divided into two groups of 18 pigs each and these were housed separately to enable them adapt to our animal house management regimen. post-adaptation, the pigs were divided into 6 groups a(1) and a(2), b(1), and b(2), and c(1) and c(2) (n=6). a(1) and a(2) were fed diet a(1), b(1) and b(2) diet b while c(1) and c(2) ...201020739126
mechanism of trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.human innate immunity against most african trypanosomes, including trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum hdl, called trypanosome lytic factor-1 (tlf-1). this hdl contains two primate specific proteins, apolipoprotein l-1 and haptoglobin (hp)-related protein, as well as apolipoprotein a-1. these assembled proteins provide a powerful defense against trypanosome infection. trypanosoma brucei rhodesiense causes human african sleeping sickness because it has evolve ...201020805508
structure and mechanism of the 6-oxopurine nucleosidase from trypanosoma brucei brucei.trypanosomes are purine-auxotrophic parasites that depend upon nucleoside hydrolase (nh) activity to salvage nitrogenous bases necessary for nucleic acid and cofactor synthesis. nonspecific and purine-specific nhs have been widely studied, yet little is known about the 6-oxopurine-specific isozymes, although they are thought to play a primary role in the catabolism of exogenously derived nucleosides. here, we report the first functional and structural characterization of the inosine-guanosine-sp ...201020825170
developmental regulation and extracellular release of a vsg expression-site-associated gene product from trypanosoma brucei bloodstream forms.trypanosomes evade host immunity by exchanging variant surface glycoprotein (vsg) coats. vsg genes are transcribed from telomeric expression sites, which contain a diverse family of expression-site-associated genes (esags). we have discovered that the mrnas for one esag family, esag9, are strongly developmentally regulated, being enriched in stumpy forms, a life-cycle stage in the mammalian bloodstream that is important for the maintenance of chronic parasite infections and for tsetse transmissi ...201020826456
eupathdomains: the divergent domain database for eukaryotic pathogens.eukaryotic pathogens (e.g. plasmodium, leishmania, trypanosomes, etc.) are a major source of morbidity and mortality worldwide. in africa, one of the most impacted continents, they cause millions of deaths and constitute an immense economic burden. while the genome sequence of several of these organisms is now available, the biological functions of more than half of their proteins are still unknown. this is a serious issue for bringing to the foreground the expected new therapeutic targets. in t ...201020920608
biochemical analysis of piftc3, the trypanosoma brucei orthologue of nematode dyf-13, reveals interactions with established and putative intraflagellar transport components.dyf-13, originally identified in caenorhabditis elegans within a collection of dye-filling chemosensory mutants, is one of several proteins that have been classified as putatively involved in intraflagellar transport (ift), the bidirectional movement of protein complexes along cilia and flagella and specifically in anterograde ift. although genetic studies have highlighted a fundamental role of dyf-13 in nematode sensory cilium and trypanosome flagellum biogenesis, biochemical studies on dyf-13 ...201020923419
centromere-associated topoisomerase activity in bloodstream form trypanosoma brucei.topoisomerase-ii accumulates at centromeres during prometaphase, where it resolves the dna catenations that represent the last link between sister chromatids. previously, using approaches including etoposide-mediated topoisomerase-ii cleavage, we mapped centromeric domains in trypanosomes, early branching eukaryotes in which chromosome segregation is poorly understood. here, we show that in bloodstream form trypanosoma brucei, rnai-mediated depletion of topoisomerase-iiα, but not topoisomerase-i ...201020864447
reliable quantification of cell cycle-dependent mrna abundance using fluorescence-activated cell sorting in trypanosoma brucei.very little is known about cell cycle-dependent regulation of mrna in trypanosoma brucei, the causative agent of african sleeping sickness. methods to synchronize cell cycle progression are inefficient or subject the parasites to non-physiological conditions and stress. we developed a fluorescence-activated cell sorting-based method to analyze steady-state mrna levels in individual cell cycle phases. normalization of the data was the most challenging problem because internal standards for cell c ...201020933544
the hsp70 chaperones of the tritryps are characterized by unusual features and novel members.proteins belonging to the hsp70 class of molecular chaperones are highly conserved and ubiquitous, performing an essential role in the maintenance of cellular homeostasis in almost all known organisms. trypanosoma brucei, trypanosoma cruzi and leishmania major are human parasites collectively known as the tritryps. the tritryps undergo extensive morphological changes during their life cycles, largely triggered by the marked differences between conditions in their insect vector and human host. hs ...201020816852
regulation of camp-dependent protein kinases: the human protein kinase x (prkx) reveals the role of the catalytic subunit alphah-alphai loop.camp-dependent protein kinases are reversibly complexed with any of the four isoforms of regulatory (r) subunits, which contain either a substrate or a pseudosubstrate autoinhibitory domain. the human protein kinase x (prkx) is an exemption as it is inhibited only by pseudosubstrate inhibitors, i.e. riα or riβ but not by substrate inhibitors riiα or riiβ. detailed examination of the capacity of five prkx-like kinases ranging from human to protozoa (trypanosoma brucei) to form holoenzymes with hu ...201020819953
structures of a key interaction protein from the trypanosoma brucei editosome in complex with single domain antibodies.several major global diseases are caused by single-cell parasites called trypanosomatids. these organisms exhibit many unusual features including a unique and essential u-insertion/deletion rna editing process in their single mitochondrion. many key rna editing steps occur in ∼20s editosomes, which have a core of 12 proteins. among these, the "interaction protein" krepa6 performs a central role in maintaining the integrity of the editosome core and also binds to ssrna. the use of llama single do ...201020969962
the kinetoplastid chemotherapy revisited: current drugs, recent advances and future perspectives.leishmaniasis, african sleeping sickness and chagas disease, caused by the kinetoplastid parasites leishmania spp, trypanosoma brucei and trypanosoma cruzi, respectively, are among the most important parasitic diseases, affecting millions of people and considered to be within the most relevant group of neglected tropical diseases. the main alternative to control such parasitosis is chemotherapy. nevertheless, the current chemotherapeutic treatments are far from being satisfactory. this review ou ...201020939823
the dithiol glutaredoxins of african trypanosomes have distinct roles and are closely linked to the unique trypanothione metabolism.trypanosoma brucei, the causative agent of african sleeping sickness, possesses two dithiol glutaredoxins (grx1 and grx2). grx1 occurs in the cytosol and catalyzes protein deglutathionylations with k(cat)/k(m)-values of up to 2 × 10(5) m(-1) s(-1). it accelerates the reduction of ribonucleotide reductase by trypanothione although less efficiently than the parasite tryparedoxin and has low insulin disulfide reductase activity. despite its classical cpyc active site, grx1 forms dimeric iron-sulfur ...201020826822
quercetin, a fluorescent bioflavanoid, inhibits trypanosoma brucei hexokinase 1.hexokinases from the african trypanosome, trypanosoma brucei, are attractive targets for the development of anti-parasitic drugs, in part because the parasite utilizes glycolysis exclusively for atp production during the mammalian infection. here, we have demonstrated that the bioflavanoid quercetin (qcn), a known trypanocide, is a mixed inhibitor of trypanosoma brucei hexokinase 1 (tbhk1) (ic(50) = 4.1 ± 0.8μm). spectroscopic analysis of qcn binding to tbhk1, taking advantage of the intrinsical ...201020971104
a novel protein kinase localized to lipid droplets is required for droplet biogenesis in trypanosomes.ubiquitous among eukaryotes, lipid droplets are organelles that function to coordinate intracellular lipid homeostasis. their morphology and abundance is affected by numerous genes, many of which are involved in lipid metabolism. in this report we identify a trypanosoma brucei protein kinase, ldk, and demonstrate its localization to the periphery of lipid droplets. association with lipid droplets was abrogated when the hydrophobic domain of ldk was deleted, supporting a model in which the hydrop ...201020833891
ultrastructural investigation methods for trypanosoma brucei.trypanosoma brucei is a unicellular parasite causing african sleeping sickness in cattle and humans. due to the ease with which these cells can be cultured and genetically manipulated, it has emerged as a model organism for the kinetoplastids.in this chapter we describe the preparation of t. brucei for transmission electron microscopy. a thorough explanation of conventional sample preparation through chemical fixation of whole cells and detergent extracted cytoskeletons followed by dehydration a ...201020869523
silencing of a putative inner arm dynein heavy chain results in flagellar immotility in trypanosoma brucei.the trypanosoma brucei flagellum controls motility and is crucial for cell polarity and division. unique features of trypanosome motility suggest that flagellar beat regulation in this organism is unusual and worthy of study. the flagellar axoneme, required for motility, has a structure that is highly conserved among eukaryotes. of the several dyneins in the axonemal inner arm complex, dynein f is thought to control flagellar waveform shape. a t. brucei gene predicted to encode the dynein f alph ...201020888370
genome-wide rnai screens in african trypanosomes identify the nifurtimox activator ntr and the eflornithine transporter aat6.to be effective, therapeutic compounds must typically enter target cells and, in some cases, must be concentrated or modified. thus, uptake and activation mechanisms often form the basis of selectivity against infectious agents. loss-of-function screens can be used to identify proteins involved in drug uptake and metabolism and may also identify clinically relevant potential resistance mechanisms. we used a genome-scale rna interference (rnai) library to identify loss-of-function resistance mech ...201021093499
potential new drugs for human african trypanosomiasis: some progress at last.this review covers recent developments towards novel treatments for human african trypanosomiasis (hat).201020844428
design and preparation of sterol mimetics as potential antiparasitics.we have previously shown that azasterols have activity against trypanosoma brucei, trypanosoma cruzi and leishmania species, which are the causative agents of various neglected tropical diseases. in this paper, we discuss the replacement of the sterol core of the azasterols with sterol mimics. various mimics were designed, and the structures were minimised to see if they could adopt a similar conformation to that of the azasterols. from this, two series of mimics were synthesised and then evalua ...201020846867
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