To see the other types of publications on this topic, follow the link: African trypanosomiasis. Proteins.
Journal articles on the topic 'African trypanosomiasis. Proteins'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'African trypanosomiasis. Proteins.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Bentley, Stephen John, and Aileen Boshoff. "Trypanosoma brucei J-Protein 2 Functionally Co-Operates with the Cytosolic Hsp70 and Hsp70.4 Proteins." International Journal of Molecular Sciences 20, no. 23 (November 21, 2019): 5843. http://dx.doi.org/10.3390/ijms20235843.
Full textAbstract:
The etiological agent of African trypanosomiasis, Trypanosoma brucei (Tb), has been identified to possess an expanded and diverse group of heat shock proteins, which have been implicated in cytoprotection, differentiation, and subsequently progression and transmission of the disease. Heat shock protein 70 (Hsp70) is a highly conserved and ubiquitous molecular chaperone that is important in maintaining protein homeostasis in the cell. Its function is regulated by a wide range of co-chaperones, and inhibition of these functions and interactions with co-chaperones are emerging as potential therapeutic targets for numerous diseases. This study sought to biochemically characterize the cytosolic TbHsp70 and TbHsp70.4 proteins and to investigate if they functionally co-operate with the Type I J-protein, Tbj2. Expression of TbHsp70 was shown to be heat inducible, while TbHsp70.4 was constitutively expressed. The basal ATPase activities of TbHsp70.4 and TbHsp70 were stimulated by Tbj2. It was further determined that Tbj2 functionally co-operated with TbHsp70 and TbHsp70.4 as the J-protein was shown to stimulate the ability of both proteins to mediate the refolding of chemically denatured β-galactosidase. This study provides further insight into this important class of proteins, which may contribute to the development of new therapeutic strategies to combat African Trypanosomiasis.
2
Baral, Toya Nath. "Immunobiology of African Trypanosomes: Need of Alternative Interventions." Journal of Biomedicine and Biotechnology 2010 (2010): 1–24. http://dx.doi.org/10.1155/2010/389153.
Full textAbstract:
Trypanosomiasis is one of the major parasitic diseases for which control is still far from reality. The vaccination approaches by using dominant surface proteins have not been successful, mainly due to antigenic variation of the parasite surface coat. On the other hand, the chemotherapeutic drugs in current use for the treatment of this disease are toxic and problems of resistance are increasing (see Kennedy (2004) and Legros et al. (2002)). Therefore, alternative approaches in both treatment and vaccination against trypanosomiasis are needed at this time. To be able to design and develop such alternatives, the biology of this parasite and the host response against the pathogen need to be studied. These two aspects of this disease with few examples of alternative approaches are discussed here.
3
Ayed, Zoulikha, Michel Dumas, Dismand Houinato, Marie-Odile Jauberteau, Bernard Bouteille, Isabelle Brindel, Felix Doua, and Nestor Van Meirvenne. "Detection and Characterization of Autoantibodies Directed against Neurofilament Proteins in Human African Trypanosomiasis." American Journal of Tropical Medicine and Hygiene 57, no. 1 (July 1, 1997): 1–6. http://dx.doi.org/10.4269/ajtmh.1997.57.1.tm0570010001.
Full text
4
Imboden, M., N. Müller, A. Hemphill, R. Mattioli, and T. Seebeck. "Repetitive proteins from the flagellar cytoskeleton of African trypanosomes are diagnostically useful antigens." Parasitology 110, no. 3 (April 1995): 249–58. http://dx.doi.org/10.1017/s0031182000080835.
Full textAbstract:
SUMMARYTrypanosome infection of mammalian hosts leads, within days, to a strong early response against a small, distinct number of parasite proteins. One of these proteins is the variable surface glycoprotein (VSG). Most of the others are apparently non-variable, intracellular trypanosome proteins. Two of these antigens I2and I17are now characterized at the molecular level. Both exhibit a highly repetitive amino acid sequence organization, but they show no sequence similarity either to each other or to any other proteins known to date. Preliminary serological analyses indicate that both allow the early, sensitive and specific detection of infections with different species of trypanosomatids, making them interesting candidates for the development of diagnostic tools for trypanosomiasis detection.
5
Abry, Muna F., Kelvin M. Kimenyi, Daniel K. Masiga, and Benard W. Kulohoma. "Comparative genomics identifies male accessory gland proteins in five Glossina species." Wellcome Open Research 2 (August 30, 2017): 73. http://dx.doi.org/10.12688/wellcomeopenres.12445.1.
Full textAbstract:
Accessory gland proteins (ACPs) are important reproductive proteins produced by the male accessory glands (MAGs) of most insect species. These proteins are essential for male insect fertility, and are transferred alongside semen to females during copulation. ACPs are poorly characterized in Glossina species (tsetse fly), the principal vector of the parasite that causes life-threatening Human African Trypanosomiasis and Animal trypanosomiasis in endemic regions in Africa. The tsetse fly has a peculiar reproductive cycle because of the absence of oviposition. Females mate once and store sperm in a spermathecal, and produce a single fully developed larva at a time that pupates within minutes of exiting their uterus. This slow reproductive cycle, compared to other insects, significantly restricts reproduction to only 3 to 6 larvae per female lifespan. This unique reproductive cycle is an attractive vector control strategy entry point. We exploit comparative genomics approaches to explore the diversity of ACPs in the recently available whole genome sequence data from five tsetse fly species (Glossina morsitans, G. austeni, G. brevipalpis, G. pallidipes and G. fuscipes). We used previously described ACPs in Drosophila melanogaster and Anopheles gambiae as reference sequences. We identified 36, 27, 31, 29 and 33 diverse ACP orthologous genes in G. austeni, G. brevipalpis, G. fuscipes, G. pallidipes and G. morsitans genomes respectively, which we classified into 21 functional classes. Our findings provide genetic evidence of MAG proteins in five recently sequenced Glossina genomes. It provides new avenues for molecular studies that evaluate potential field control strategies of these important vectors of human and animal disease.
6
Abry, Muna F., Kelvin M. Kimenyi, Daniel K. Masiga, and Benard W. Kulohoma. "Comparative genomics identifies male accessory gland proteins in five Glossina species." Wellcome Open Research 2 (November 22, 2017): 73. http://dx.doi.org/10.12688/wellcomeopenres.12445.2.
Full textAbstract:
Accessory gland proteins (ACPs) are important reproductive proteins produced by the male accessory glands (MAGs) of most insect species. These proteins are essential for male insect fertility, and are transferred alongside semen to females during copulation. ACPs are poorly characterized in Glossina species (tsetse fly), the principal vector of the parasite that causes life-threatening Human African Trypanosomiasis and Animal trypanosomiasis in endemic regions in Africa. The tsetse fly has a peculiar reproductive cycle because of the absence of oviposition. Females mate once and store sperm in a spermathecal, and produce a single fully developed larva at a time that pupates within minutes of exiting their uterus. This slow reproductive cycle, compared to other insects, significantly restricts reproduction to only 3 to 6 larvae per female lifespan. This unique reproductive cycle is an attractive vector control strategy entry point. We exploit comparative genomics approaches to explore the diversity of ACPs in the recently available whole genome sequence data from five tsetse fly species ( Glossina morsitans, G. austeni, G. brevipalpis, G. pallidipes and G. fuscipes). We used previously described ACPs in Drosophila melanogaster and Anopheles gambiae as reference sequences. We identified 36, 27, 31, 29 and 33 diverse ACP orthologous genes in G. austeni, G. brevipalpis, G. fuscipes, G. pallidipes and G. morsitans genomes respectively, which we classified into 21 functional classes. Our findings provide genetic evidence of MAG proteins in five recently sequenced Glossina genomes. It highlights new avenues for molecular studies that evaluate potential field control strategies of these important vectors of human and animal disease.
7
Michel-Todó, Lucas, Pascal Bigey, Pedro A. Reche, María-Jesus Pinazo, Joaquim Gascón, and Julio Alonso-Padilla. "Design of an Epitope-Based Vaccine Ensemble for Animal Trypanosomiasis by Computational Methods." Vaccines 8, no. 1 (March 16, 2020): 130. http://dx.doi.org/10.3390/vaccines8010130.
Full textAbstract:
African animal trypanosomiasis is caused by vector-transmitted parasites of the genus Trypanosoma. T. congolense and T. brucei brucei are predominant in Africa; T. evansi and T. vivax in America and Asia. They have in common an extracellular lifestyle and livestock tropism, which provokes huge economic losses in regions where vectors are endemic. There are licensed drugs to treat the infections, but adherence to treatment is poor and appearance of resistances common. Therefore, the availability of a prophylactic vaccine would represent a major breakthrough towards the management and control of the disease. Selection of the most appropriate antigens for its development is a bottleneck step, especially considering the limited resources allocated. Herein we propose a vaccine strategy based on multiple epitopes from multiple antigens to counteract the parasites´ biological complexity. Epitopes were identified by computer-assisted genome-wide screenings, considering sequence conservation criteria, antigens annotation and sub-cellular localization, high binding affinity to antigen presenting molecules, and lack of cross-reactivity to proteins in cattle and other breeding species. We ultimately provide 31 B-cell, 8 CD4 T-cell, and 15 CD8 T-cell epitope sequences from 30 distinct antigens for the prospective design of a genetic ensemble vaccine against the four trypanosome species responsible for African animal trypanosomiasis.
8
Andreassend, Sarah K., Stephen J. Bentley, Gregory L. Blatch, Aileen Boshoff, and Robert A. Keyzers. "Screening for Small Molecule Modulators of Trypanosoma brucei Hsp70 Chaperone Activity Based upon Alcyonarian Coral-Derived Natural Products." Marine Drugs 18, no. 2 (January 27, 2020): 81. http://dx.doi.org/10.3390/md18020081.
Full textAbstract:
The Trypanosoma brucei Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure–activity relationship for the malonganenone-class of alkaloids is proposed based upon these results.
9
Yang, Zhiyuan, Mingqiang Wang, Xi Zeng, Angel Tsz-Yau Wan, and Stephen Kwok-Wing Tsui. "In silico analysis of proteins and microRNAs related to human African trypanosomiasis in tsetse fly." Computational Biology and Chemistry 88 (October 2020): 107347. http://dx.doi.org/10.1016/j.compbiolchem.2020.107347.
Full text
10
Koumandou, V. Lila, Cordula Boehm, Katy A. Horder, and Mark C. Field. "Evidence for Recycling of Invariant Surface Transmembrane Domain Proteins in African Trypanosomes." Eukaryotic Cell 12, no. 2 (December 21, 2012): 330–42. http://dx.doi.org/10.1128/ec.00273-12.
Full textAbstract:
ABSTRACT Intracellular trafficking is a vital component of both virulence mechanisms and drug interactions in Trypanosoma brucei , the causative agent of human African trypanosomiasis and n'agana of cattle. Both maintaining the surface proteome composition within a life stage and remodeling the composition when progressing between life stages are important features of immune evasion and development for trypanosomes. Our recent work implicates the abundant transmembrane invariant surface glycoproteins (ISGs) in the uptake of first-line therapeutic suramin, suggesting a potential therapeutic route into the cell. RME-8 is a mediator of recycling pathways in higher eukaryotes and is one of a small cohort of intracellular transport gene products upregulated in mammal-infective trypanosomes, suggesting a role in controlling the copy number of surface proteins in trypanosomes. Here we investigate RME-8 function and its contribution to intracellular trafficking and stability of ISGs. RME-8 is a highly conserved protein and is broadly distributed across multiple endocytic compartments. By knockdown we find that RME-8 is essential and mediates delivery of endocytic probes to late endosomal compartments. Further, we find ISG accumulation within endosomes, but that RME-8 knockdown also increases ISG turnover; combined with previous data, this suggests that it is most probable that ISGs are recycled, and that RME-8 is required to support recycling.
11
POINSIGNON, ANNE, ANDRE GARCIA, PASCAL GRÉBAUT, FRANCK REMOUE, FRANCOIS SIMONDON, DAVID COURTIN, and SYLVIE CORNELIE. "HUMAN/VECTOR RELATIONSHIPS DURING HUMAN AFRICAN TRYPANOSOMIASIS: INITIAL SCREENING OF IMMUNOGENIC SALIVARY PROTEINS OF GLOSSINA SPECIES." American Journal of Tropical Medicine and Hygiene 76, no. 2 (February 1, 2007): 327–33. http://dx.doi.org/10.4269/ajtmh.2007.76.327.
Full text
12
Tripodi, Karina E. J., Simón M. Menendez Bravo, and Julia A. Cricco. "Role of Heme and Heme-Proteins in Trypanosomatid Essential Metabolic Pathways." Enzyme Research 2011 (April 10, 2011): 1–12. http://dx.doi.org/10.4061/2011/873230.
Full textAbstract:
Around the world, trypanosomatids are known for being etiological agents of several highly disabling and often fatal diseases like Chagas disease (Trypanosoma cruzi), leishmaniasis (Leishmania spp.), and African trypanosomiasis (Trypanosoma brucei). Throughout their life cycle, they must cope with diverse environmental conditions, and the mechanisms involved in these processes are crucial for their survival. In this review, we describe the role of heme in several essential metabolic pathways of these protozoans. Notwithstanding trypanosomatids lack of the complete heme biosynthetic pathway, we focus our discussion in the metabolic role played for important heme-proteins, like cytochromes. Although several genes for different types of cytochromes, involved in mitochondrial respiration, polyunsaturated fatty acid metabolism, and sterol biosynthesis, are annotated at the Tritryp Genome Project, the encoded proteins have not yet been deeply studied. We pointed our attention into relevant aspects of these protein functions that are amenable to be considered for rational design of trypanocidal agents.
13
Müller, N., A. Hemphill, M. Imboden, G. Duvallet, R. H. Dwinger, and T. Seebeck. "Identification and characterization of two repetitive non-variable antigens from African trypanosomes which are recognized early during infection." Parasitology 104, no. 1 (February 1992): 111–20. http://dx.doi.org/10.1017/s0031182000060856.
Full textAbstract:
SUMMARYThe present paper describes two repetitive proteins representing common antigens of African trypanosomes which are non-variant and which are recognized early in infection by the host immune system. These antigens were identified by their ability to immunoreact with bovine serum taken during the early phase of a cyclic trypanosomal infection. Screening of a cDNA library fromT. b. gambiensewith such early infection serum identified a protein which contains a repetitive motif consisting of 68 amino acid repeat units (GM6). Immunofluorescence and immunogold electron microscopy revealed that GM6 is located on fibres which connect the microtubules of the membrane skeleton with the flagellum. A second repetitive antigen detected by this serum is MARP1 (microtubule-associated repetitive protein 1), a protein previously characterized in this laboratory as a high-molecular weight component of the membrane skeleton, which consists of more than 50 tandemly repeated, near-identical 38 amino acid repeat units. Beta-galactosidase fusion products of both proteins demonstrated a strong immunoreactivity with sera fromT. b. bruceiandT. congolense-infected cattle. The result from this preliminary immunological evaluation indicates a high immunodiagnostic sensititivy (90%) of the two recombinant antigens which make them interesting candidates for immunodiagnosis of trypanosomiasis in cattle.
14
Barker, Robert H., Hanlan Liu, Bradford Hirth, Cassandra A. Celatka, Richard Fitzpatrick, Yibin Xiang, Erin K. Willert, et al. "Novel S-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis." Antimicrobial Agents and Chemotherapy 53, no. 5 (March 16, 2009): 2052–58. http://dx.doi.org/10.1128/aac.01674-08.
Full textAbstract:
ABSTRACT Trypanosomiasis remains a significant disease across the sub-Saharan African continent, with 50,000 to 70,000 individuals infected. The utility of current therapies is limited by issues of toxicity and the need to administer compounds intravenously. We have begun a program to pursue lead optimization around MDL 73811, an irreversible inhibitor of S-adenosylmethionine decarboxylase (AdoMetDC). This compound is potent but in previous studies cleared rapidly from the blood of rats (T. L. Byers, T. L. Bush, P. P. McCann, and A. J. Bitonti, Biochem. J. 274:527-533). One of the analogs synthesized (Genz-644131) was shown to be highly active against Trypanosoma brucei rhodesiense in vitro (50% inhibitory concentration, 400 pg/ml). Enzyme kinetic studies showed Genz-644131 to be approximately fivefold more potent than MDL 73811 against the T. brucei brucei AdoMetDC-prozyme complex. This compound was stable in vitro in rat and human liver microsomal and hepatocyte assays, was stable in rat whole-blood assays, did not significantly inhibit human cytochrome P450 enzymes, had no measurable efflux in CaCo-2 cells, and was only 41% bound by serum proteins. Pharmacokinetic studies of mice following intraperitoneal dosing showed that the half-life of Genz-644131 was threefold greater than that of MDL 73811 (7.4 h versus 2.5 h). Furthermore, brain penetration of Genz-644131 was 4.3-fold higher than that of MDL 73811. Finally, in vivo efficacy studies of T. b. brucei strain STIB 795-infected mice showed that Genz-644131 significantly extended survival (from 6.75 days for controls to >30 days for treated animals) and cured animals infected with T. b. brucei strain LAB 110 EATRO. Taken together, the data strengthen validation of AdoMetDC as an important parasite target, and these studies have shown that analogs of MDL 73811 can be synthesized with improved potency and brain penetration.
15
Tinti, Michele, Maria Lucia S. Güther, Thomas W. M. Crozier, Angus I. Lamond, and Michael A. J. Ferguson. "Proteome turnover in the bloodstream and procyclic forms of Trypanosoma brucei measured by quantitative proteomics." Wellcome Open Research 4 (October 9, 2019): 152. http://dx.doi.org/10.12688/wellcomeopenres.15421.1.
Full textAbstract:
Background: Cellular proteins vary significantly in both abundance and turnover rates. These parameters depend upon their rates of synthesis and degradation and it is useful to have access to data on protein turnover rates when, for example, designing genetic knock-down experiments or assessing the potential usefulness of covalent enzyme inhibitors. Little is known about the nature and regulation of protein turnover in Trypanosoma brucei, the etiological agent of human and animal African trypanosomiasis. Methods: To establish baseline data on T. brucei proteome turnover, a Stable Isotope Labelling with Amino acids in Cell culture (SILAC)-based mass spectrometry analysis was performed to reveal the synthesis and degradation profiles for thousands of proteins in the bloodstream and procyclic forms of this parasite. Results: This analysis revealed a slower average turnover rate of the procyclic form proteome relative to the bloodstream proteome. As expected, many of the proteins with the fastest turnover rates have functions in the cell cycle and in the regulation of cytokinesis in both bloodstream and procyclic forms. Moreover, the cellular localization of T. brucei proteins correlates with their turnover, with mitochondrial and glycosomal proteins exhibiting slower than average turnover rates. Conclusions: The intention of this study is to provide the trypanosome research community with a resource for protein turnover data for any protein or group of proteins. To this end, bioinformatic analyses of these data are made available via an open-access web resource with data visualization functions.
16
Li, Bibo, and Yanxiang Zhao. "Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities." Pathogens 10, no. 8 (July 30, 2021): 967. http://dx.doi.org/10.3390/pathogens10080967.
Full textAbstract:
Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, Variant Surface Glycoprotein (VSG), to evade the host immune response. Such antigenic variation is a key pathogenesis mechanism that enables T. brucei to establish long-term infections. VSG is expressed exclusively from subtelomere loci in a strictly monoallelic manner, and DNA recombination is an important VSG switching pathway. The integrity of telomere and subtelomere structure, maintained by multiple telomere proteins, is essential for T. brucei viability and for regulating the monoallelic VSG expression and VSG switching. Here we will focus on T. brucei TRF and RAP1, two telomere proteins with unique nucleic acid binding activities, and summarize their functions in telomere integrity and stability, VSG switching, and monoallelic VSG expression. Targeting the unique features of TbTRF and TbRAP1′s nucleic acid binding activities to perturb the integrity of telomere structure and disrupt VSG monoallelic expression may serve as potential therapeutic strategy against T. brucei.
17
Patham, Bhargavi, Josh Duffy, Ariel Lane, Richard C. Davis, Peter Wipf, Sheara W. Fewell, Jeffrey L. Brodsky, and Kojo Mensa-Wilmot. "Post-translational import of protein into the endoplasmic reticulum of a trypanosome: an in vitro system for discovery of anti-trypanosomal chemical entities." Biochemical Journal 419, no. 2 (March 27, 2009): 507–17. http://dx.doi.org/10.1042/bj20081787.
Full textAbstract:
HAT (human African trypanosomiasis), caused by the protozoan parasite Trypanosoma brucei, is an emerging disease for which new drugs are needed. Expression of plasma membrane proteins [e.g. VSG (variant surface glycoprotein)] is crucial for the establishment and maintenance of an infection by T. brucei. Transport of a majority of proteins to the plasma membrane involves their translocation into the ER (endoplasmic reticulum). Thus inhibition of protein import into the ER of T. brucei would be a logical target for discovery of lead compounds against trypanosomes. We have developed a TbRM (T. brucei microsome) system that imports VSG_117 post-translationally. Using this system, MAL3-101, equisetin and CJ-21,058 were discovered to be small molecule inhibitors of VSG_117 translocation into the ER. These agents also killed bloodstream T. brucei in vitro; the concentrations at which 50% of parasites were killed (IC50) were 1.5 μM (MAL3-101), 3.3 μM (equisetin) and 7 μM (CJ-21,058). Thus VSG_117 import into TbRMs is a rapid and novel assay to identify ‘new chemical entities’ (e.g. MAL3-101, equisetin and CJ-21,058) for anti-trypanosome drug development.
18
ALSFORD, SAM, JOHN M. KELLY, NICOLA BAKER, and DAVID HORN. "Genetic dissection of drug resistance in trypanosomes." Parasitology 140, no. 12 (April 3, 2013): 1478–91. http://dx.doi.org/10.1017/s003118201300022x.
Full textAbstract:
SUMMARYThe trypanosomes cause two neglected tropical diseases, Chagas disease in the Americas and African trypanosomiasis in sub-Saharan Africa. Over recent years a raft of molecular tools have been developed enabling the genetic dissection of many aspects of trypanosome biology, including the mechanisms underlying resistance to some of the current clinical and veterinary drugs. This has led to the identification and characterization of key resistance determinants, including transporters for the anti-Trypanosoma bruceidrugs, melarsoprol, pentamidine and eflornithine, and the activator of nifurtimox-benznidazole, the anti-Trypanosoma cruzidrugs. More recently, advances in sequencing technology, combined with the development of RNA interference libraries in the clinically relevant bloodstream form ofT. bruceihave led to an exponential increase in the number of proteins known to interact either directly or indirectly with the anti-trypanosomal drugs. In this review, we discuss these findings and the technological developments that are set to further revolutionise our understanding of drug-trypanosome interactions. The new knowledge gained should inform the development of novel interventions against the devastating diseases caused by these parasites.
19
Zoltner, Martin, Gustavo D. Campagnaro, Gergana Taleva, Alana Burrell, Michela Cerone, Ka-Fai Leung, Fiona Achcar, et al. "Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes." Journal of Biological Chemistry 295, no. 24 (April 30, 2020): 8331–47. http://dx.doi.org/10.1074/jbc.ra120.012355.
Full textAbstract:
Introduced about a century ago, suramin remains a frontline drug for the management of early-stage East African trypanosomiasis (sleeping sickness). Cellular entry into the causative agent, the protozoan parasite Trypanosoma brucei, occurs through receptor-mediated endocytosis involving the parasite's invariant surface glycoprotein 75 (ISG75), followed by transport into the cytosol via a lysosomal transporter. The molecular basis of the trypanocidal activity of suramin remains unclear, but some evidence suggests broad, but specific, impacts on trypanosome metabolism (i.e. polypharmacology). Here we observed that suramin is rapidly accumulated in trypanosome cells proportionally to ISG75 abundance. Although we found little evidence that suramin disrupts glycolytic or glycosomal pathways, we noted increased mitochondrial ATP production, but a net decrease in cellular ATP levels. Metabolomics highlighted additional impacts on mitochondrial metabolism, including partial Krebs' cycle activation and significant accumulation of pyruvate, corroborated by increased expression of mitochondrial enzymes and transporters. Significantly, the vast majority of suramin-induced proteins were normally more abundant in the insect forms compared with the blood stage of the parasite, including several proteins associated with differentiation. We conclude that suramin has multiple and complex effects on trypanosomes, but unexpectedly partially activates mitochondrial ATP-generating activity. We propose that despite apparent compensatory mechanisms in drug-challenged cells, the suramin-induced collapse of cellular ATP ultimately leads to trypanosome cell death.
20
Burger, Adélle, Michael H. Ludewig, and Aileen Boshoff. "Investigating the Chaperone Properties of a Novel Heat Shock Protein, Hsp70.c, fromTrypanosoma brucei." Journal of Parasitology Research 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/172582.
Full textAbstract:
The neglected tropical disease, African Trypanosomiasis, is fatal and has a crippling impact on economic development. Heat shock protein 70 (Hsp70) is an important molecular chaperone that is expressed in response to stress and Hsp40 acts as its co-chaperone. These proteins play a wide range of roles in the cell and they are required to assist the parasite as it moves from a cold blooded insect vector to a warm blooded mammalian host. A novel cytosolic Hsp70, fromTrypanosoma brucei, TbHsp70.c, contains an acidic substrate binding domain and lacks the C-terminal EEVD motif. The ability of a cytosolic Hsp40 fromTrypanosoma bruceiJ protein 2, Tbj2, to function as a co-chaperone of TbHsp70.c was investigated. The main objective was to functionally characterize TbHsp70.c to further expand our knowledge of parasite biology. TbHsp70.c and Tbj2 were heterologously expressed and purified and both proteins displayed the ability to suppress aggregation of thermolabile MDH and chemically denatured rhodanese. ATPase assays revealed a 2.8-fold stimulation of the ATPase activity of TbHsp70.c by Tbj2. TbHsp70.c and Tbj2 both demonstrated chaperone activity and Tbj2 functions as a co-chaperone of TbHsp70.c.In vivoheat stress experiments indicated upregulation of the expression levels of TbHsp70.c.
21
Weems, Ebony, Ujjal K. Singha, VaNae Hamilton, Joseph T. Smith, Karin Waegemann, Dejana Mokranjac, and Minu Chaudhuri. "Functional Complementation Analyses Reveal that the Single PRAT Family Protein of Trypanosoma brucei Is a Divergent Homolog of Tim17 in Saccharomyces cerevisiae." Eukaryotic Cell 14, no. 3 (January 9, 2015): 286–96. http://dx.doi.org/10.1128/ec.00203-14.
Full textAbstract:
ABSTRACT Trypanosoma brucei , a parasitic protozoan that causes African trypanosomiasis, possesses a single member of the presequence and amino acid transporter (PRAT) protein family, which is referred to as TbTim17. In contrast, three homologous proteins, ScTim23, ScTim17, and ScTim22, are found in Saccharomyces cerevisiae and higher eukaryotes. Here, we show that TbTim17 cannot rescue Tim17, Tim23, or Tim22 mutants of S. cerevisiae . We expressed S. cerevisiae Tim23, Tim17, and Tim22 in T. brucei . These heterologous proteins were properly imported into mitochondria in the parasite. Further analysis revealed that although ScTim23 and ScTim17 were integrated into the mitochondrial inner membrane and assembled into a protein complex similar in size to TbTim17, only ScTim17 was stably associated with TbTim17. In contrast, ScTim22 existed as a protease-sensitive soluble protein in the T. brucei mitochondrion. In addition, the growth defect caused by TbTim17 knockdown in T. brucei was partially restored by the expression of ScTim17 but not by the expression of either ScTim23 or ScTim22, whereas the expression of TbTim17 fully complemented the growth defect caused by TbTim17 knockdown, as anticipated. Similar to the findings for cell growth, the defect in the import of mitochondrial proteins due to depletion of TbTim17 was in part restored by the expression of ScTim17 but was not complemented by the expression of either ScTim23 or ScTim22. Together, these results suggest that TbTim17 is divergent compared to ScTim23 but that its function is closer to that of ScTim17. In addition, ScTim22 could not be sorted properly in the T. brucei mitochondrion and thus failed to complement the function of TbTim17.
22
Bruhn, David F., Mark P. Sammartino, and Michele M. Klingbeil. "Three Mitochondrial DNA Polymerases Are Essential for Kinetoplast DNA Replication and Survival of Bloodstream Form Trypanosoma brucei." Eukaryotic Cell 10, no. 6 (April 29, 2011): 734–43. http://dx.doi.org/10.1128/ec.05008-11.
Full textAbstract:
ABSTRACT Trypanosoma brucei , the causative agent of human African trypanosomiasis, has a complex life cycle that includes multiple life cycle stages and metabolic changes as the parasite switches between insect vector and mammalian host. The parasite's single mitochondrion contains a unique catenated mitochondrial DNA network called kinetoplast DNA (kDNA) that is composed of minicircles and maxicircles. Long-standing uncertainty about the requirement of kDNA in bloodstream form (BF) T. brucei has recently eroded, with reports of posttranscriptional editing and subsequent translation of kDNA-encoded transcripts as essential processes for BF parasites. These studies suggest that kDNA and its faithful replication are indispensable for this life cycle stage. Here we demonstrate that three kDNA replication proteins (mitochondrial DNA polymerases IB, IC, and ID) are required for BF parasite viability. Silencing of each polymerase was lethal, resulting in kDNA loss, persistence of prereplication DNA monomers, and collapse of the mitochondrial membrane potential. These data demonstrate that kDNA replication is indeed crucial for BF T. brucei . The contributions of mitochondrial DNA polymerases IB, IC, and ID to BF parasite viability suggest that these and other kDNA replication proteins warrant further investigation as a new class of targets for the development of antitrypanosomal drugs.
23
Moreno, Cláudia Jassica Gonçalves, Taffarel Torres, and Marcelo Sousa Silva. "Variable Surface Glycoprotein from Trypanosoma brucei Undergoes Cleavage by Matrix Metalloproteinases: An in silico Approach." Pathogens 8, no. 4 (October 8, 2019): 178. http://dx.doi.org/10.3390/pathogens8040178.
Full textAbstract:
In order to survive as extracellular parasites in the mammalian host environment, Trypanosoma brucei has developed efficient mechanisms of immune system evasion, which include the abundant expression of a variable surface glycoprotein (VSG) coat. VSGs are anchored in the parasite membrane by covalent C-terminal binding to glycosylphosphatidylinositol and may be periodically removed by a phospholipase C (PLC) and a major surface protein (TbMSP). VSG molecules show extraordinary antigenic diversity and a comparative analysis of protein sequences suggests that conserved elements may be a suitable target against African trypanosomiasis. However, the cleavage mechanisms of these molecules remain unclear. Moreover, in protozoan infections, including those caused by Trypanosoma brucei, it is possible to observe an increased expression of the matrix metalloproteinases (MMPs). To address the cleavage mechanism of VSGs, the PROSPER server was used for the identification of VSG sequence cleavage sites. After data compilation, it was observed that 64 VSG consensus sequences showed a high conservation of hydrophobic residues, such as valine (V), methionine (M), leucine (L) and isoleucine (I) in the fifth position—the exact location of the cleavage site. In addition, the PROSPER server identified conserved cleavage site portions of VSG proteins recognized by three matrix metalloproteases (gelatinases: MMP-2, MMP-3 and MMP-9). However, further biological studies are needed in order to analyze and confirm this prediction.
24
Garzón, Edwin, Philippe Holzmuller, Rachel Bras-Gonçalves, Philippe Vincendeau, Gérard Cuny, Jean Loup Lemesre, and Anne Geiger. "The Trypanosoma brucei gambiense Secretome Impairs Lipopolysaccharide-Induced Maturation, Cytokine Production, and Allostimulatory Capacity of Dendritic Cells." Infection and Immunity 81, no. 9 (June 24, 2013): 3300–3308. http://dx.doi.org/10.1128/iai.00125-13.
Full textAbstract:
ABSTRACTTrypanosoma brucei gambiense, a parasitic protozoan belonging to kinetoplastids, is the main etiological agent of human African trypanosomiasis (HAT), or sleeping sickness. One major characteristic of this disease is the dysregulation of the host immune system. The present study demonstrates that the secretome (excreted-secreted proteins) ofT. b. gambienseimpairs the lipopolysaccharide (LPS)-induced maturation of murine dendritic cells (DCs). The upregulation of major histocompatibility complex class II, CD40, CD80, and CD86 molecules, as well as the secretion of cytokines such as tumor necrosis factor alpha, interleukin-10 (IL-10), and IL-6, which are normally released at high levels by LPS-stimulated DCs, is significantly reduced when these cells are cultured in the presence of theT. b. gambiensesecretome. Moreover, the inhibition of DC maturation results in the loss of their allostimulatory capacity, leading to a dramatic decrease in Th1/Th2 cytokine production by cocultured lymphocytes. These results provide new insights into a novel efficient immunosuppressive mechanism directly involving the alteration of DC function which might be used byT. b. gambienseto interfere with the host immune responses in HAT and promote the infectious process.
25
Yang, Sihyung, Tanja Wenzler, Patrik N. Miller, Huali Wu, David W. Boykin, Reto Brun, and Michael Zhuo Wang. "Pharmacokinetic Comparison To Determine the Mechanisms Underlying the Differential Efficacies of Cationic Diamidines against First- and Second-Stage Human African Trypanosomiasis." Antimicrobial Agents and Chemotherapy 58, no. 7 (May 5, 2014): 4064–74. http://dx.doi.org/10.1128/aac.02605-14.
Full textAbstract:
ABSTRACTHuman African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first-stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second-stage (meningoencephalitic, or central nervous system [CNS]) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first-stage HAT. However, only DB829 cured animals with second-stage infection. In this study, we aimed to determine the mechanisms underlying the differential efficacies of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. The results showed that DB829, an azadiamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 had the lowest. None of these diamidines was a P-gp substrate, and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacies of these diamidines in mice with second-stage infection. In conclusion, pharmacokinetics and CNS penetration influenced thein vivoefficacies of cationic diamidines against first- and second-stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines.
26
Shamshad, Hina, Abdul Hafiz, Ismail I. Althagafi, Maria Saeed, and Agha Zeeshan Mirza. "Characterization of the Trypanosoma brucei Pteridine Reductase Active- Site using Computational Docking and Virtual Screening Techniques." Current Computer-Aided Drug Design 16, no. 5 (November 9, 2020): 583–98. http://dx.doi.org/10.2174/1573409915666190827163327.
Full textAbstract:
Background: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei. Methods: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred. Results: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites. Conclusion: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn’t enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.
27
Saha, Arpita, Amit Kumar Gaurav, Unnati M. Pandya, Marjia Afrin, Ranjodh Sandhu, Vishal Nanavaty, Brittny Schnur, and Bibo Li. "TbTRF suppresses the TERRA level and regulates the cell cycle-dependent TERRA foci number with a TERRA binding activity in its C-terminal Myb domain." Nucleic Acids Research 49, no. 10 (May 28, 2021): 5637–53. http://dx.doi.org/10.1093/nar/gkab401.
Full textAbstract:
Abstract Telomere repeat-containing RNA (TERRA) has been identified in multiple organisms including Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis. T. brucei regularly switches its major surface antigen, VSG, to evade the host immune response. VSG is expressed exclusively from subtelomeric expression sites, and we have shown that telomere proteins play important roles in the regulation of VSG silencing and switching. In this study, we identify several unique features of TERRA and telomere biology in T. brucei. First, the number of TERRA foci is cell cycle-regulated and influenced by TbTRF, the duplex telomere DNA binding factor in T. brucei. Second, TERRA is transcribed by RNA polymerase I mainly from a single telomere downstream of the active VSG. Third, TbTRF binds TERRA through its C-terminal Myb domain, which also has the duplex DNA binding activity, in a sequence-specific manner and suppresses the TERRA level without affecting its half-life. Finally, levels of the telomeric R-loop and telomere DNA damage were increased upon TbTRF depletion. Overexpression of an ectopic allele of RNase H1 that resolves the R-loop structure in TbTRF RNAi cells can partially suppress these phenotypes, revealing an underlying mechanism of how TbTRF helps maintain telomere integrity.
28
Zhang, Xueying, Fadi Li, Fang Qin, Wanhong Li, and Xiangpeng Yue. "Exploration of ovine milk whey proteome during postnatal development using an iTRAQ approach." PeerJ 8 (October 8, 2020): e10105. http://dx.doi.org/10.7717/peerj.10105.
Full textAbstract:
Background Ovine milk is a rich source of bioactive proteins that supports the early growth and development of the newborn lambs. A large number of researches had targeted to the identification of ovine milk fat globule membrane proteins (MFGMPs), caseins (CNs), mastitis milk proteins in past years, but the dynamic change tendency of milk whey proteins during postnatal development has received limited attention. This research aimed to investigate the dynamic changes of ovine milk whey proteins after delivery, and explore the functions of whey proteins on early development of the newborns. Methods In this research, Hu sheep milk samples were collected from six individuals by manual milking manner, at 0 d, 3 d, 7 d, 14 d, 28 d and 56 d after delivery, respectively. The milk whey proteins were identified and quantified by the isobaric tag for relative and absolute quantification (iTRAQ) coupled with liquid chromatography (LC)-electrospray ionization (ESI) tandem MS (MS/MS) methods. In addition, biological functions of differentially expressed proteins (DEPs) were annotated by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results A total of 310 proteins were identified , of which 121 were differentially expressed. In detail, 30 (10 up-regulated and 20 down-regulated), 22 (11 up-regulated and 11 down-regulated), 11 (four up-regulated and seven down-regulated), 11 (eight up-regulated and three down-regulated), 10 (six up-regulated and four down-regulated) DEPs were identified in 3 d vs. 0 d, 7 d vs. 3 d, 14 d vs. 7 d, 28 d vs. 14 d, 56 d vs. 28 d comparison groups, respectively. The GO annotation analysis revealed that biological process principally involved metabolic and biological regulation, the major cellular location were organelle, cell and extracellular region, and the mainly molecular function were binding and catalytic activity. Circadian rhythm, fatty acid biosynthesis and African trypanosomiasis were enriched by KEGG annotation analysis. Conclusion The study reveals a comprehensive understanding of Hu sheep milk proteome, suggesting whey proteins change dramatically in early development of newborn lambs, which provide a potential guidance for early weaning of lambs.
29
Singha, Ujjal K., Shvetank Sharma, and Minu Chaudhuri. "Downregulation of Mitochondrial Porin Inhibits Cell Growth and Alters Respiratory Phenotype in Trypanosoma brucei." Eukaryotic Cell 8, no. 9 (July 17, 2009): 1418–28. http://dx.doi.org/10.1128/ec.00132-09.
Full textAbstract:
ABSTRACT Porin is the most abundant outer membrane (OM) protein of mitochondria. It forms the aqueous channel on the mitochondrial OM and mediates major metabolite flux between mitochondria and cytosol. Mitochondrial porin in Trypanosoma brucei, a unicellular parasitic protozoan and the causative agent of African trypanosomiasis, possesses a β-barrel structure similar to the bacterial OM porin OmpA. T. brucei porin (TbPorin) is present as a monomer as well as an oligomer on the mitochondrial OM, and its expression is developmentally regulated. In spite of its distinct structure, the TbPorin function is similar to those of other eukaryotic porins. TbPorin RNA interference (RNAi) reduced cell growth in both procyclic and bloodstream forms. The depletion of TbPorin decreased ATP production by inhibiting metabolite flux through the OM. Additionally, the level of trypanosome alternative oxidase (TAO) decreased, whereas the levels of cytochrome-dependent respiratory complexes III and IV increased in TbPorin-depleted mitochondria. Furthermore, the depletion of TbPorin reduced cellular respiration via TAO, which is not coupled with oxidative phosphorylation, but increased the capacity for cyanide-sensitive respiration. Together, these data reveal that TbPorin knockdown reduced the mitochondrial ATP level, which in turn increased the capacity of the cytochrome-dependent respiratory pathway (CP), in an attempt to compensate for the mitochondrial energy crisis. However, a simultaneous decrease in the substrate-level phosphorylation due to TbPorin RNAi caused growth inhibition in the procyclic form. We also found that the expressions of TAO and CP proteins are coordinately regulated in T. brucei according to mitochondrial energy demand.
30
Li, Bibo. "DNA Double-Strand Breaks and Telomeres Play Important Roles in Trypanosoma brucei Antigenic Variation." Eukaryotic Cell 14, no. 3 (January 9, 2015): 196–205. http://dx.doi.org/10.1128/ec.00207-14.
Full textAbstract:
ABSTRACTHuman-infecting microbial pathogens all face a serious problem of elimination by the host immune response. Antigenic variation is an effective immune evasion mechanism where the pathogen regularly switches its major surface antigen. In many cases, the major surface antigen is encoded by genes from the same gene family, and its expression is strictly monoallelic. Among pathogens that undergo antigenic variation,Trypanosoma brucei(a kinetoplastid), which causes human African trypanosomiasis,Plasmodium falciparum(an apicomplexan), which causes malaria,Pneumocystis jirovecii(a fungus), which causes pneumonia, andBorrelia burgdorferi(a bacterium), which causes Lyme disease, also express their major surface antigens from loci next to the telomere. Except forPlasmodium, DNA recombination-mediated gene conversion is a major pathway for surface antigen switching in these pathogens. In the last decade, more sophisticated molecular and genetic tools have been developed inT. brucei, and our knowledge of functions of DNA recombination in antigenic variation has been greatly advanced. VSG is the major surface antigen inT. brucei. In subtelomeric VSG expression sites (ESs),VSGgenes invariably are flanked by a long stretch of upstream 70-bp repeats. Recent studies have shown that DNA double-strand breaks (DSBs), particularly those in 70-bp repeats in the active ES, are a natural potent trigger for antigenic variation inT. brucei. In addition, telomere proteins can influence VSG switching by reducing the DSB amount at subtelomeric regions. These findings will be summarized and their implications will be discussed in this review.
31
Dubois, Melissa E., Karen P. Demick, and John M. Mansfield. "Trypanosomes Expressing a Mosaic Variant Surface Glycoprotein Coat Escape Early Detection by the Immune System." Infection and Immunity 73, no. 5 (May 2005): 2690–97. http://dx.doi.org/10.1128/iai.73.5.2690-2697.2005.
Full textAbstract:
ABSTRACT Host resistance to African trypanosomiasis is partially dependent on an early and strong T-independent B-cell response against the variant surface glycoprotein (VSG) coat expressed by trypanosomes. The repetitive array of surface epitopes displayed by a monotypic surface coat, in which identical VSG molecules are closely packed together in a uniform architectural display, cross-links cognate B-cell receptors and initiates T-independent B-cell activation events. However, this repetitive array of identical VSG epitopes is altered during the process of antigenic variation, when former and nascent VSG proteins are transiently expressed together in a mosaic surface coat. Thus, T-independent B-cell recognition of the trypanosome surface coat may be disrupted by the introduction of heterologous VSG molecules into the coat structure. To address this hypothesis, we transformed Trypanosoma brucei rhodesiense LouTat 1 with the 117 VSG gene from Trypanosoma brucei brucei MiTat 1.4 in order to produce VSG double expressers; coexpression of the exogenous 117 gene along with the endogenous LouTat 1 VSG gene resulted in the display of a mosaic VSG coat. Results presented here demonstrate that the host's ability to produce VSG-specific antibodies and activate B cells during early infection with VSG double expressers is compromised relative to that during infection with the parental strain, which displays a monotypic coat. These findings suggest a previously unrecognized mechanism of immune response evasion in which coat-switching trypanosomes fail to directly activate B cells until coat VSG homogeneity is achieved. This process affords an immunological advantage to trypanosomes during the process of antigenic variation.
32
Lenz, Krauth-Siegel, and Schmidt. "Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase." Molecules 24, no. 20 (October 16, 2019): 3737. http://dx.doi.org/10.3390/molecules24203737.
Full textAbstract:
In the course of our investigations on the antitrypanosomal potential of sesquiterpene lactones (STL), we have recently reported on the exceptionally strong activity of 4,15-iso-Atriplicolide tiglate, which demonstrated an IC50 value of 15 nM against Trypanosoma brucei rhodesiense, the etiologic agent responsible for East African human trypanosomiasis (HAT). Since STLs are known to often interact with their biological targets (e.g., in anti-inflammatory and anti-tumor activity) by means of the covalent modification of biological nucleophiles—most prominently free cysteine thiol groups in proteins—it was a straightforward assumption that such compounds might interfere with the trypanothione-associated detoxification system of trypanosomes. This system heavily relies on thiol groups in the form of the dithiol trypanothione (T(SH)2) and in the active centers of enzymes involved in trypanothione metabolism and homeostasis. Indeed, we found in the present study that 4,15-iso-atriplicolide tiglate, as well as its structural homologues, the corresponding methacrylate and isobutyrate, are inhibitors of trypanothione reductase (TR), the enzyme serving the parasites to keep T(SH)2 in the dithiol state. The TR inhibitory activity was demonstrated to be time-dependent and irreversible. Quite interestingly, of the several further STLs with different core structures that were also tested, none inhibited TR at a significant level. Thus, the TR inhibitory effect by the 4,15-iso-atriplicolide esters appears to be specific for this particular type of furanoheliangolide-type STL. Some structure–activity relationships can already be deduced on the basis of the data reported here, which may serve as the starting point for searching further, possibly more potent, TR inhibitors.
33
HOLMES, P. H., E. KATUNGUKA-RWAKISHAYA, J. J. BENNISON, G. J. WASSINK, and J. J. PARKINS. "Impact of nutrition on the pathophysiology of bovine trypanosomiasis." Parasitology 120, no. 7 (May 2000): 73–85. http://dx.doi.org/10.1017/s0031182099005806.
Full textAbstract:
Trypanosomiasis is a major veterinary problem over much of sub-Saharan Africa and is frequently associated with undernutrition. There is growing evidence that nutrition can have a profound effect on the pathophysiological features of animal trypanosomiasis. These features include anaemia, pyrexia, body weight changes, reduced feed intake and diminished productivity including reduced draught work output, milk yield and reproductive capacity. Anaemia is a principal characteristic of trypanosomiasis and the rate at which it develops is influenced by both protein and energy intakes. Pyrexia is associated with increased energy demands for maintenance which is ultimately manifested by reductions in voluntary activity levels and productivity. Weight changes in trypanosomiasis are markedly influenced by the levels of protein intake. High intakes allow infected animals to grow at the same rate as uninfected controls providing energy intake is adequate whilst low energy levels can exacerbate the adverse effects of trypanosomiasis on body weight. Reductions in feed intake are less apparent in animals which are provided with high protein diets and where intake is limited by the disease animals will often exhibit preferential selection of higher quality browse. Further studies are required to evaluate the minimum levels of protein and energy supplementation required to ameliorate the adverse effect of trypanosomiasis, the nature and quality of protein supplement to achieve these benefits and the influence these have on digestive physiology.
34
Kwofie, Kofi D., Nguyen Huu Tung, Mitsuko Suzuki-Ohashi, Michael Amoa-Bosompem, Richard Adegle, Maxwell M. Sakyiamah, Frederick Ayertey, et al. "Antitrypanosomal Activities and Mechanisms of Action of Novel Tetracyclic Iridoids from Morinda lucida Benth." Antimicrobial Agents and Chemotherapy 60, no. 6 (March 7, 2016): 3283–90. http://dx.doi.org/10.1128/aac.01916-15.
Full textAbstract:
Trypanosoma bruceiparasites are kinetoplastid protozoa that devastate the health and economic well-being of millions of people in Africa through the disease human African trypanosomiasis (HAT). New chemotherapy has been eagerly awaited due to severe side effects and the drug resistance issues plaguing current drugs. Recently, there has been an emphasis on the use of medicinal plants worldwide.Morinda lucidaBenth. is a popular medicinal plant widely distributed in Africa, and several research groups have reported on the antiprotozoal activities of this plant. In this study, we identified three novel tetracyclic iridoids, molucidin, ML-2-3, and ML-F52, from the CHCl3fraction ofM. lucidaleaves, which possess activity against the GUTat 3.1 strain ofT. brucei brucei. The 50% inhibitory concentrations (IC50) of molucidin, ML-2-3, and ML-F52 were 1.27 μM, 3.75 μM, and 0.43 μM, respectively. ML-2-3 and ML-F52 suppressed the expression of paraflagellum rod protein subunit 2, PFR-2, and caused cell cycle alteration, which preceded apoptosis induction in the bloodstream form ofTrypanosomaparasites. Novel tetracyclic iridoids may be promising lead compounds for the development of new chemotherapies for African trypanosomal infections in humans and animals.
35
Boniface, Pone Kamdem, and Ferreira Igne Elizabeth. "Flavonoid-derived Privileged Scaffolds in anti-Trypanosoma brucei Drug Discovery." Current Drug Targets 20, no. 12 (August 22, 2019): 1295–314. http://dx.doi.org/10.2174/1389450120666190618114857.
Full textAbstract:
Objective: Human African Trypanosomiasis (HAT), also known as sleeping sickness is one of the 20 neglected tropical diseases listed by the World Health Organization, which lead to death if left untreated. This disease is caused by Trypanosoma brucei gambiense, which is the chronic form of the disease present in western and central Africa, and by T. brucei rhodesiense, which is the acute form of the disease located in eastern and southern Africa. Many reports have highlighted the effectiveness of flavonoid-based compounds against T. brucei. Methods: A literature search was conducted for naturally occurring and synthetic anti-T brucei flavonoids by referencing textbooks and scientific databases (SciFinder, PubMed, Science Direct, Wiley, ACS, SciELO, Google Scholar, Springer, among others) from their inception until February 2019. Results: The present review summarizes the current standings and perspectives for the use of flavonoids as lead compounds for the potential treatment of HAT. Conclusion: Flavonoids isolated from different parts of plants and species were reported to exhibit moderate to high in vitro antitrypanosomal activity against T. brucei. In addition, synthetic flavonoids revealed anti-T. brucei activity. Molecular interactions of bioactive flavonoids with T. brucei protein targets showed promising results.
36
Shibata, Sayaka, J. Robert Gillespie, Angela M. Kelley, Alberto J. Napuli, Zhongsheng Zhang, Kuzma V. Kovzun, Ranae M. Pefley, et al. "Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice." Antimicrobial Agents and Chemotherapy 55, no. 5 (January 31, 2011): 1982–89. http://dx.doi.org/10.1128/aac.01796-10.
Full textAbstract:
ABSTRACTHuman African trypanosomiasis continues to be an important public health threat in extensive regions of sub-Saharan Africa. Treatment options for infected patients are unsatisfactory due to toxicity, difficult administration regimes, and poor efficacy of available drugs. The aminoacyl-tRNA synthetases were selected as attractive drug targets due to their essential roles in protein synthesis and cell survival. Comparative sequence analysis disclosed differences between the trypanosome and mammalian methionyl-tRNA synthetases (MetRSs) that suggested opportunities for selective inhibition using drug-like molecules. Experiments using RNA interference on the single MetRS ofTrypanosoma bruceidemonstrated that this gene product was essential for normal cell growth. Small molecules (diaryl diamines) similar to those shown to have potent activity on prokaryotic MetRS enzymes were synthesized and observed to have inhibitory activity on theT. bruceiMetRS (50% inhibitory concentration, <50 nM) and on bloodstream forms ofT. bruceicultures (50% effective concentration, as low as 4 nM). Twenty-one compounds had a close correlation between enzyme binding/inhibition andT. bruceigrowth inhibition, indicating that they were likely to be acting on the intended target. The compounds had minimal effects on mammalian cell growth at 20 μM, demonstrating a wide therapeutic index. The most potent compound was tested in the murine model of trypanosomiasis and demonstrated profound parasite suppression and delayed mortality. A homology model of theT. bruceiMetRS based on other MetRS structures was used to model binding of the lead diaryl diamine compounds. Future studies will focus on improving the pharmacological properties of the MetRS inhibitors.
37
Lu, Jun, Suman K. Vodnala, Anna-Lena Gustavsson, Tomas N. Gustafsson, Birger Sjöberg, Henrik A. Johansson, Sangit Kumar, et al. "Ebsulfur Is a Benzisothiazolone Cytocidal Inhibitor Targeting the Trypanothione Reductase of Trypanosoma brucei." Journal of Biological Chemistry 288, no. 38 (July 29, 2013): 27456–68. http://dx.doi.org/10.1074/jbc.m113.495101.
Full textAbstract:
Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.
38
MENZIES, STEFANIE K., LINDSAY B. TULLOCH, GORDON J. FLORENCE, and TERRY K. SMITH. "The trypanosome alternative oxidase: a potential drug target?" Parasitology 145, no. 2 (November 29, 2016): 175–83. http://dx.doi.org/10.1017/s0031182016002109.
Full textAbstract:
SUMMARYNew drugs against Trypanosoma brucei, the causative agent of Human African Trypanosomiasis, are urgently needed to replace the highly toxic and largely ineffective therapies currently used. The trypanosome alternative oxidase (TAO) is an essential and unique mitochondrial protein in these parasites and is absent from mammalian mitochondria, making it an attractive drug target. The structure and function of the protein are now well characterized, with several inhibitors reported in the literature, which show potential as clinical drug candidates. In this review, we provide an update on the functional activity and structural aspects of TAO. We then discuss TAO inhibitors reported to date, problems encountered with in vivo testing of these compounds, and discuss the future of TAO as a therapeutic target.
39
Arnston, Phillip M., and William N. Setzer. "Macromolecular Targets of Antiparasitic Germacranolide Sesquiterpenoids: An In Silico Investigation." Combinatorial Chemistry & High Throughput Screening 23, no. 6 (October 5, 2020): 477–503. http://dx.doi.org/10.2174/1386207323666200218114759.
Full textAbstract:
Background: The parasitic protozoal infections leishmaniasis, human African trypanosomiasis, and Chagas disease are neglected tropical diseases that pose serious health risks for much of the world’s population. Current treatment options suffer from limitations, but plantderived natural products may provide economically advantageous therapeutic alternatives. Several germacranolide sesquiterpenoids have shown promising antiparasitic activities, but the mechanisms of activity have not been clearly established. Objective: The objective is to use in silico screening of known antiparasitic germacranolides against recognized protozoal protein targets in order to provide insight into the molecular mechanisms of activity of these natural products. Methods: Conformational analyses of the germacranolides were carried out using density functional theory, followed by molecular docking. A total of 88 Leishmania protein structures, 86 T. brucei protein structures, and 50 T. cruzi protein structures were screened against 27 antiparasitic germacranolides. Results: The in-silico screening has revealed which of the protein targets of Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are preferred by the sesquiterpenoid ligands.
40
Schopf, Lisa R., Hanna Filutowicz, Xiao-Juan Bi, and John M. Mansfield. "Interleukin-4-Dependent Immunoglobulin G1 Isotype Switch in the Presence of a Polarized Antigen-Specific Th1-Cell Response to the Trypanosome Variant Surface Glycoprotein." Infection and Immunity 66, no. 2 (February 1, 1998): 451–61. http://dx.doi.org/10.1128/iai.66.2.451-461.1998.
Full textAbstract:
ABSTRACT This study examines B-cell immunoglobulin (Ig) class-switching events in the context of parasite antigen-specific Th-cell responses in experimental African trypanosomiasis. Inbred mice were infected withTrypanosoma brucei rhodesiense, and the coordinate stimulation of Th-cell cytokine responses and B-cell responses to the trypanosome variant surface glycoprotein (VSG) was measured. The cytokines produced by T cells in response to VSG, at both the transcript and protein levels, were gamma interferon and interleukin-2 (IL-2) but not IL-4 or IL-5. Isotype profiles of antibodies specific for VSG showed that IgG1, IgG2a, and IgG3 switch responses predominated; no VSG-specific IgE responses were detected. To determine whether cryptic IL-4 responses played a role in promoting the unexpected IgG1 switch response, IL-4 knockout mice were infected; the cytokine responses and Ig isotype profiles of IL-4 knockout mice were identical to those of the wild-type control mice except for dramatically reduced IgG1 levels in response to VSG. Thus, these results revealed an IL-4-dependent component of the VSG-driven B-cell Cμ-to-Cγ1 switch. We speculate that an IL-4 response is mediated primarily by cells other than T lymphocytes since IL-4-secreting but parasite antigen-unresponsive, “background” cells were detected in all infected mice and since infected nude mice also displayed a detectable IgG1 switch response. Overall, our results suggest that B-cell clonal stimulation, maturation, and Ig class switching in African trypanosomiasis may be partially regulated by unusual mechanisms that do not include antigen-specific Th1 or Th2 cells.
41
Kalidas, Savitha, Igor Cestari, Severine Monnerat, Qiong Li, Sandesh Regmi, Nicholas Hasle, Mehdi Labaied, Marilyn Parsons, Kenneth Stuart, and Margaret A. Phillips. "Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei." Eukaryotic Cell 13, no. 4 (February 21, 2014): 504–16. http://dx.doi.org/10.1128/ec.00017-14.
Full textAbstract:
ABSTRACT Human African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight Trypanosoma brucei aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyl-tRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (α and β) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in T. brucei mammalian stage parasites showed that all were essential for parasite growth and survival in vitro . The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of T. brucei ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for T. brucei survival and are likely to be excellent targets for drug discovery efforts.
42
Ojo, Kayode K., J. Robert Gillespie, Aaron J. Riechers, Alberto J. Napuli, Christophe L. M. J. Verlinde, Frederick S. Buckner, Michael H. Gelb, et al. "Glycogen Synthase Kinase 3 Is a Potential Drug Target for African Trypanosomiasis Therapy." Antimicrobial Agents and Chemotherapy 52, no. 10 (July 21, 2008): 3710–17. http://dx.doi.org/10.1128/aac.00364-08.
Full textAbstract:
ABSTRACT Development of a safe, effective, and inexpensive therapy for African trypanosomiasis is an urgent priority. In this study, we evaluated the validity of Trypanosoma brucei glycogen synthase kinase 3 (GSK-3) as a potential drug target. Interference with the RNA of either of two GSK-3 homologues in bloodstream-form T. brucei parasites led to growth arrest and altered parasite morphology, demonstrating their requirement for cell survival. Since the growth arrest after RNA interference appeared to be more profound for T. brucei GSK-3 “short” (Tb10.161.3140) than for T. brucei GSK-3 “long” (Tb927.7.2420), we focused on T. brucei GSK-3 short for further studies. T. brucei GSK-3 short with an N-terminal maltose-binding protein fusion was cloned, expressed, and purified in a functional form. The potency of a GSK-3-focused inhibitor library against the recombinant enzyme of T. brucei GSK-3 short, as well as bloodstream-form parasites, was evaluated with the aim of determining if compounds that inhibit enzyme activity could also block the parasites' growth and proliferation. Among the compounds active against the cell, there was an excellent correlation between activity inhibiting the T. brucei GSK-3 short enzyme and the inhibition of T. brucei growth. Thus, there is reasonable genetic and chemical validation of GSK-3 short as a drug target for T. brucei. Finally, selective inhibition may be required for therapy targeting the GSK-3 enzyme, and a molecular model of the T. brucei GSK-3 short enzyme suggests that compounds that selectively inhibit T. brucei GSK-3 short over the human GSK-3 enzymes can be found.
43
Lejon, Veerle, Jo Robays, François Xavier N'Siesi, Dieudonné Mumba, Annemie Hoogstoel, Sylvie Bisser, Hansotto Reiber, Marleen Boelaert, and Philippe Büscher. "Treatment Failure Related to Intrathecal Immunoglobulin M (IgM) Synthesis, Cerebrospinal Fluid IgM, and Interleukin-10 in Patients with Hemolymphatic-Stage Sleeping Sickness." Clinical and Vaccine Immunology 14, no. 6 (April 11, 2007): 732–37. http://dx.doi.org/10.1128/cvi.00103-07.
Full textAbstract:
ABSTRACT Human African trypanosomiasis treatment is stage dependent, but the tests used for staging are controversial. Central nervous system involvement and its relationship with suramin treatment failure were assessed in 60 patients with parasitologically confirmed hemolymphatic-stage Trypanosoma brucei gambiense infection (white blood cell count of ≤5/μl and no trypanosomes in the cerebrospinal fluid [CSF]). The prognostic value of CSF interleukin-10, immunoglobulin M (IgM; as determined by nephelometry and the point-of-care LATEX/IgM test), total protein, and trypanosome-specific antibody was assessed. The IgM and interleukin-10 levels in serum were measured; and the presence of neurological signs, intrathecal IgM synthesis, and blood-CSF barrier dysfunction was determined. After suramin treatment, 14 of 60 patients had relapses (23%). Relapses were significantly correlated with intrathecal IgM synthesis (odds ratio [OR], 46; 95% confidence interval [CI], 8 to 260), a CSF IgM concentration of ≥1.9 mg/liter (OR, 11.7; 95% CI, 2.7 to 50), a CSF end titer by the LATEX/IgM assay of ≥2 (OR, 10.4; 95% CI, 2.5 to 44), and a CSF interleukin-10 concentration of >10 pg/ml (OR, 5; 95% CI, 1.3 to 20). The sensitivities of these markers for treatment failure ranged from 43 to 79%, and the specificities ranged from 74 to 93%. The results show that T. brucei gambiense-infected patients who have signs of neuroinflammation in CSF and who are treated with drugs recommended for use at the hemolymphatic stage are at risk of treatment failure. This highlights the need for the development and the evaluation of accurate point-of-care tests for the staging of human African trypanosomiasis.
44
Morty, Rory E., John D. Lonsdale-Eccles, Reinhardt Mentele, Ennes A. Auerswald, and Theresa H. T. Coetzer. "Trypanosome-Derived Oligopeptidase B Is Released into the Plasma of Infected Rodents, Where It Persists and Retains Full Catalytic Activity." Infection and Immunity 69, no. 4 (April 1, 2001): 2757–61. http://dx.doi.org/10.1128/iai.69.4.2757-2761.2001.
Full textAbstract:
ABSTRACT A trypsin-like serine peptidase activity, levels of which correlate with blood parasitemia levels, is present in the plasma of rats acutely infected with Trypanosoma brucei brucei. Antibodies to a trypanosome peptidase with a trypsin-like substrate specificity (oligopeptidase B [OP-Tb]) cross-reacted with a protein in the plasma of trypanosome-infected rats on a Western blot. These antibodies also abolished 80% of the activity in the plasma of trypanosome-infected rats, suggesting that the activity may be attributable to a parasite-derived peptidase. We purified the enzyme responsible for the bulk of this activity from parasite-free T. b. brucei-infected rat plasma and confirmed its identity by protein sequencing. We show that live trypanosomes do not release OP-Tb in vitro and propose that disrupted parasites release it into the host circulation, where it is unregulated and retains full catalytic activity and may thus play a role in the pathogenesis of African trypanosomiasis.
45
Mabille, Dorien, Camila Cardoso Santos, Rik Hendrickx, Mathieu Claes, Peter Takac, Christine Clayton, Sarah Hendrickx, et al. "4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma brucei." Microorganisms 9, no. 4 (April 13, 2021): 826. http://dx.doi.org/10.3390/microorganisms9040826.
Full textAbstract:
Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.
46
Subramanya, Sandesh, C. Frank Hardin, Dietmar Steverding, and Kojo Mensa-Wilmot. "Glycosylphosphatidylinositol-specific phospholipase C regulates transferrin endocytosis in the African trypanosome." Biochemical Journal 417, no. 3 (January 16, 2009): 685–94. http://dx.doi.org/10.1042/bj20080167.
Full textAbstract:
GPI-PLC (glycosylphosphatidylinositol-specific phospholipase C) is expressed in bloodstream-form Trypanosoma brucei, a protozoan that causes human African trypanosomiasis. Loss of genes encoding GPI-PLC reduces the virulence of a pleomorphic strain of the parasite, for reasons that are not clear. In the present paper, we report that GPI-PLC stimulates endocytosis of transferrin by 300–500%. Surprisingly, GPI-PLC is not detected at endosomes, suggesting that the enzyme does not interact directly with the endosomal machinery. We therefore hypothesized that a diffusible product of the GPI-PLC enzyme reaction [possibly DAG (diacylglycerol)] mediated the biological effects of the protein. Two sets of data support this assertion. First, a catalytically inactive Q81L mutant of GPI-PLC, expressed in a GPI-PLC-null background, had no effect on endocytosis, indicating that enzyme activity is essential for the protein to stimulate endocytosis. Secondly, the exogenous DAGs OAG (1-oleyl-2-acetyl-sn-glycerol) and DMG (dimyristoylglycerol) independently stimulated endocytosis of transferrin. Furthermore, the DAG mimic PMA, a phorbol ester, also activated endocytosis in T. brucei. DAG-stimulated endocytosis is a novel pathway in the trypanosome. We surmise that (i) GPI-PLC regulates transferrin endocytosis in T. brucei, (ii) GPI-PLC is a signalling enzyme, and (iii) DAG is a second messenger for GPI-PLC. We propose that regulation of endocytosis is a physiological function of GPI-PLC in bloodstream T. brucei.
47
Behera, Ranjan, Sarah M. Thomas, and Kojo Mensa-Wilmot. "New Chemical Scaffolds for Human African Trypanosomiasis Lead Discovery from a Screen of Tyrosine Kinase Inhibitor Drugs." Antimicrobial Agents and Chemotherapy 58, no. 4 (January 27, 2014): 2202–10. http://dx.doi.org/10.1128/aac.01691-13.
Full textAbstract:
ABSTRACTHuman African trypanosomiasis (HAT) is caused by the protozoanTrypanosoma brucei. New drugs are needed to treat HAT because of undesirable side effects and difficulties in the administration of the antiquated drugs that are currently used. In human proliferative diseases, protein tyrosine kinase (PTK) inhibitors (PTKIs) have been developed into drugs (e.g., lapatinib and erlotinib) by optimization of a 4-anilinoquinazoline scaffold. Two sets of facts raise a possibility that drugs targeted against human PTKs could be “hits” for antitrypanosomal lead discoveries. First, trypanosome protein kinases bind some drugs, namely, lapatinib, CI-1033, and AEE788. Second, the pan-PTK inhibitor tyrphostin A47 blocks the endocytosis of transferrin and inhibits trypanosome replication. Following up on these concepts, we performed a focused screen of various PTKI drugs as possible antitrypanosomal hits. Lapatinib, CI-1033, erlotinib, axitinib, sunitinib, PKI-166, and AEE788 inhibited the replication of bloodstreamT. brucei, with a 50% growth inhibitory concentration (GI50) between 1.3 μM and 2.5 μM. Imatinib had no effect (i.e., GI50> 10 μM). To discover leads among the drugs, a mouse model of HAT was used in a proof-of-concept study. Orally administered lapatinib reduced parasitemia, extended the survival of all treated mice, and cured the trypanosomal infection in 25% of the mice. CI-1033 and AEE788 reduced parasitemia and extended the survival of the infected mice. On the strength of these data and noting their oral bioavailabilities, we propose that the 4-anilinoquinazoline and pyrrolopyrimidine scaffolds of lapatinib, CI-1033, and AEE788 are worth optimizing againstT. bruceiin medicinal chemistry campaigns (i.e., scaffold repurposing) to discover new drugs against HAT.
48
Aresta-Branco, Francisco, Margarida Sanches-Vaz, Fabio Bento, João A. Rodrigues, and Luisa M. Figueiredo. "African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system." Proceedings of the National Academy of Sciences 116, no. 41 (September 25, 2019): 20725–35. http://dx.doi.org/10.1073/pnas.1905120116.
Full textAbstract:
Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression, and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed prolonged survival in which nearly 90% of the mice survived a 30-d period of infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reducing disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental to the parasite, even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.
49
Aksoy, Emre, Aurélien Vigneron, XiaoLi Bing, Xin Zhao, Michelle O’Neill, Yi-neng Wu, James D. Bangs, Brian L. Weiss, and Serap Aksoy. "Mammalian African trypanosome VSG coat enhances tsetse’s vector competence." Proceedings of the National Academy of Sciences 113, no. 25 (May 16, 2016): 6961–66. http://dx.doi.org/10.1073/pnas.1600304113.
Full textAbstract:
Tsetse flies are biological vectors of African trypanosomes, the protozoan parasites responsible for causing human and animal trypanosomiases across sub-Saharan Africa. Currently, no vaccines are available for disease prevention due to antigenic variation of the Variant Surface Glycoproteins (VSG) that coat parasites while they reside within mammalian hosts. As a result, interference with parasite development in the tsetse vector is being explored to reduce disease transmission. A major bottleneck to infection occurs as parasites attempt to colonize tsetse’s midgut. One critical factor influencing this bottleneck is the fly’s peritrophic matrix (PM), a semipermeable, chitinous barrier that lines the midgut. The mechanisms that enable trypanosomes to cross this barrier are currently unknown. Here, we determined that as parasites enter the tsetse’s gut, VSG molecules released from trypanosomes are internalized by cells of the cardia—the tissue responsible for producing the PM. VSG internalization results in decreased expression of a tsetse microRNA (mir-275) and interferes with the Wnt-signaling pathway and the Iroquois/IRX transcription factor family. This interference reduces the function of the PM barrier and promotes parasite colonization of the gut early in the infection process. Manipulation of the insect midgut homeostasis by the mammalian parasite coat proteins is a novel function and indicates that VSG serves a dual role in trypanosome biology—that of facilitating transmission through its mammalian host and insect vector. We detail critical steps in the course of trypanosome infection establishment that can serve as novel targets to reduce the tsetse’s vector competence and disease transmission.
50
Tang, Sonya C., and Theresa A. Shapiro. "Newly Identified Antibacterial Compounds Are Topoisomerase Poisons in African Trypanosomes." Antimicrobial Agents and Chemotherapy 54, no. 2 (December 14, 2009): 620–26. http://dx.doi.org/10.1128/aac.01025-09.
Full textAbstract:
ABSTRACT Human African trypanosomiasis, caused by the Trypanosoma brucei protozoan parasite, is fatal when left untreated. Current therapies are antiquated, and there is a need for new pharmacologic agents against T. brucei targets that have no human ortholog. Trypanosomes have a single mitochondrion with a unique mitochondrial DNA, known as kinetoplast DNA (kDNA), a topologically complex network that contains thousands of interlocking circular DNAs, termed minicircles (∼1 kb) and maxicircles (∼23 kb). Replication of kDNA depends on topoisomerases, enzymes that catalyze reactions that change DNA topology. T. brucei has an unusual type IA topoisomerase that is dedicated to kDNA metabolism. This enzyme has no ortholog in humans, and RNA interference (RNAi) studies have shown that it is essential for parasite survival, making it an ideal drug target. In a large chemical library screen, two compounds were recently identified as poisons of bacterial topoisomerase IA. We found that these compounds are trypanocidal in the low micromolar range and that they promote the formation of linearized minicircles covalently bound to protein on the 5′ end, consistent with the poisoning of mitochondrial topoisomerase IA. Surprisingly, however, band depletion studies showed that it is topoisomerase IImt, and not topoisomerase IAmt, that is trapped. Both compounds are planar aromatic polycyclic structures that intercalate into and unwind DNA. These findings reinforce the utility of topoisomerase IImt as a target for development of new drugs for African sleeping sickness.