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1
Lundkvist, Gabriella B., Krister Kristensson, and Marina Bentivoglio. "Why Trypanosomes Cause Sleeping Sickness." Physiology 19, no. 4 (August 2004): 198–206. http://dx.doi.org/10.1152/physiol.00006.2004.
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African trypanosomiasis or sleeping sickness is hallmarked by sleep and wakefulness disturbances. In contrast to other infections, there is no hypersomnia, but the sleep pattern is fragmented. This overview discusses that the causative agents, the parasites Trypanosoma brucei, target circumventricular organs in the brain, causing inflammatory responses in hypothalamic structures that may lead to dysfunctions in the circadian-timing and sleep-regulatory systems.
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Bakshi, Rahul P., Dongpei Sang, Andrew Morrell, Mark Cushman, and Theresa A. Shapiro. "Activity of Indenoisoquinolines against African Trypanosomes." Antimicrobial Agents and Chemotherapy 53, no. 1 (September 29, 2008): 123–28. http://dx.doi.org/10.1128/aac.00650-07.
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ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.
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HUTCHINSON, RACHEL, and JAMIE R. STEVENS. "Barcoding in trypanosomes." Parasitology 145, no. 5 (November 23, 2017): 563–73. http://dx.doi.org/10.1017/s0031182017002049.
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SUMMARYTrypanosomes (genus Trypanosoma) are parasites of humans, and wild and domestic mammals, in which they cause several economically and socially important diseases, including sleeping sickness in Africa and Chagas disease in the Americas. Despite the development of numerous molecular diagnostics and increasing awareness of the importance of these neglected parasites, there is currently no universal genetic barcoding marker available for trypanosomes. In this review we provide an overview of the methods used for trypanosome detection and identification, discuss the potential application of different barcoding techniques and examine the requirements of the ‘ideal’ trypanosome genetic barcode. In addition, we explore potential alternative genetic markers for barcoding Trypanosoma species, including an analysis of phylogenetically informative nucleotide changes along the length of the 18S rRNA gene.
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Matovu, Enock, Claire Mack Mugasa, Peter Waiswa, Annah Kitibwa, Alex Boobo, and Joseph Mathu Ndung’u. "Haemoparasitic Infections in Cattle from a Trypanosoma brucei Rhodesiense Sleeping Sickness Endemic District of Eastern Uganda." Tropical Medicine and Infectious Disease 5, no. 1 (February 7, 2020): 24. http://dx.doi.org/10.3390/tropicalmed5010024.
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We carried out a baseline survey of cattle in Kaberamaido district, in the context of controlling the domestic animal reservoir of Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) towards elimination. Cattle blood was subjected to capillary tube centrifugation followed by measurement of the packed cell volume (PCV) and examination of the buffy coat area for motile trypanosomes. Trypanosomes were detected in 561 (21.4%) out of 2621 cattle screened by microscopy. These 561 in addition to 724 apparently trypanosome negative samples with low PCVs (≤25%) were transported to the laboratory and tested by PCR targeting the trypanosomal Internal Transcribed Spacer (ITS-1) as well as suspect Tick-Borne Diseases (TBDs) including Anaplasmamosis, Babesiosis, and Theileriosis. PCR for Anaplasma sp yielded the highest number of positive animals (45.2%), followed by Trypanosoma sp (44%), Theileria sp (42.4%) and Babesia (26.3%); multiple infections were a common occurrence. Interestingly, 373 (29%) of these cattle with low PCVs were negative by PCR, pointing to other possible causes of aneamia, such as helminthiasis. Among the trypanosome infections classified as T. brucei by ITS-PCR, 5.5% were positive by SRA PCR, and were, therefore, confirmed as T. b. rhodesiense. Efforts against HAT should therefore consider packages that address a range of conditions. This may enhance acceptability and participation of livestock keepers in programs to eliminate this important but neglected tropical disease. In addition, we demonstrated that cattle remain an eminent reservoir for T. b. rhodesiense in eastern Uganda, which must be addressed to sustain HAT elimination.
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Griffin, Gabriel K. "Trypping up antigenic variation in sleeping sickness." Science Immunology 3, no. 29 (November 2, 2018): eaav7758. http://dx.doi.org/10.1126/sciimmunol.aav7758.
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Kanté Tagueu, Sartrien, Oumarou Farikou, Flobert Njiokou, and Gustave Simo. "Prevalence of Sodalis glossinidius and different trypanosome species in Glossina palpalis palpalis caught in the Fontem sleeping sickness focus of the southern Cameroon." Parasite 25 (2018): 44. http://dx.doi.org/10.1051/parasite/2018044.
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Tsetse flies are the cyclical vector of human and animal African trypanosomiasis. To improve vector control in order to achieve the elimination of human African trypanosomiasis (HAT) and boost the control of animal diseases, investigations have been undertaken on the tripartite association between tsetse, trypanosome, and symbionts. It is in this light that Sodalis glossinidius and different trypanosomes were identified in Glossina palpalis palpalis caught in Fontem in southern Cameroon. For this study, DNA was extracted from whole flies, and S. glossinidius and different trypanosome species were identified by polymerase chain reaction (PCR). Statistical analyses were performed to compare the trypanosome and S. glossinidius infection rates and to look for an association between these microorganisms. Of the 274 G. p. palpalis caught, 3.3% (9/274) were teneral. About 35% (96/274) of these flies harbored S. glossinidius. Of the 265 non-teneral flies, 37.7% were infected by trypanosomes. The infection rates of Trypanosoma congolense “forest type” and Trypanosoma vivax were 26.04% and 18.11%, respectively. About 6.41% of tsetse harbored mixed infections of T. congolense and T. vivax. Of the 69 tsetse with T. congolense infections, 33.33% (23/69) harbored S. glossinidius while 71.86% (69/96) of flies harboring S. glossinidius were not infected by trypanosomes. No association was observed between S. glossinidius and trypanosome infections. Some wild tsetse harbor S. glossinidius and trypanosomes, while others have no infection or are infected by only one of these microorganisms. We conclude that the presence of S. glossinidius does not favor trypanosome infections in G. p. palpalis of the Fontem focus.
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Nagamune, Kisaburo, Alvaro Acosta-Serrano, Haruki Uemura, Reto Brun, Christina Kunz-Renggli, Yusuke Maeda, Michael A. J. Ferguson, and Taroh Kinoshita. "Surface Sialic Acids Taken from the Host Allow Trypanosome Survival in Tsetse Fly Vectors." Journal of Experimental Medicine 199, no. 10 (May 10, 2004): 1445–50. http://dx.doi.org/10.1084/jem.20030635.
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The African trypanosome Trypanosoma brucei, which causes sleeping sickness in humans and Nagana disease in livestock, is spread via blood-sucking Tsetse flies. In the fly's intestine, the trypanosomes survive digestive and trypanocidal environments, proliferate, and translocate into the salivary gland, where they become infectious to the next mammalian host. Here, we show that for successful survival in Tsetse flies, the trypanosomes use trans-sialidase to transfer sialic acids that they cannot synthesize from host's glycoconjugates to the glycosylphosphatidylinositols (GPIs), which are abundantly expressed on their surface. Trypanosomes lacking sialic acids due to a defective generation of GPI-anchored trans-sialidase could not survive in the intestine, but regained the ability to survive when sialylated by means of soluble trans-sialidase. Thus, surface sialic acids appear to protect the parasites from the digestive and trypanocidal environments in the midgut of Tsetse flies.
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MacLEOD, E. T., I. MAUDLIN, A. C. DARBY, and S. C. WELBURN. "Antioxidants promote establishment of trypanosome infections in tsetse." Parasitology 134, no. 6 (February 19, 2007): 827–31. http://dx.doi.org/10.1017/s0031182007002247.
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SUMMARYEfficient, cyclical transmission of trypanosomes through tsetse flies is central to maintenance of human sleeping sickness and nagana across sub-Saharan Africa. Infection rates in tsetse are normally very low as most parasites ingested with the fly bloodmeal die in the fly gut, displaying the characteristics of apoptotic cells. Here we show that a range of antioxidants (glutathione, cysteine, N-acetyl-cysteine, ascorbic acid and uric acid), when added to the insect bloodmeal, can dramatically inhibit cell death of Trypanosoma brucei brucei in tsetse. Both L- and D-cysteine invoked similar effects suggesting that inhibition of trypanosome death is not dependent on protein synthesis. The present work suggests that antioxidants reduce the midgut environment protecting trypanosomes from cell death induced by reactive oxygen species.
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Magez, Stefan, Joar Esteban Pinto Torres, Seoyeon Oh, and Magdalena Radwanska. "Salivarian Trypanosomes Have Adopted Intricate Host-Pathogen Interaction Mechanisms That Ensure Survival in Plain Sight of the Adaptive Immune System." Pathogens 10, no. 6 (May 31, 2021): 679. http://dx.doi.org/10.3390/pathogens10060679.
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Salivarian trypanosomes are extracellular parasites affecting humans, livestock and game animals. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are human infective sub-species of T. brucei causing human African trypanosomiasis (HAT—sleeping sickness). The related T. b. brucei parasite lacks the resistance to survive in human serum, and only inflicts animal infections. Animal trypanosomiasis (AT) is not restricted to Africa, but is present on all continents. T. congolense and T. vivax are the most widespread pathogenic trypanosomes in sub-Saharan Africa. Through mechanical transmission, T. vivax has also been introduced into South America. T. evansi is a unique animal trypanosome that is found in vast territories around the world and can cause atypical human trypanosomiasis (aHT). All salivarian trypanosomes are well adapted to survival inside the host’s immune system. This is not a hostile environment for these parasites, but the place where they thrive. Here we provide an overview of the latest insights into the host-parasite interaction and the unique survival strategies that allow trypanosomes to outsmart the immune system. In addition, we review new developments in treatment and diagnosis as well as the issues that have hampered the development of field-applicable anti-trypanosome vaccines for the implementation of sustainable disease control.
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Mogk, Stefan, Hartwig Wolburg, Claudia Frey, Bruno Kubata, and Michael Duszenko. "Brain infection by African trypanosomes during sleeping sickness." Neurology, Psychiatry and Brain Research 18, no. 2 (March 2012): 49–51. http://dx.doi.org/10.1016/j.npbr.2012.02.012.
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Calderano, Simone Guedes, Patricia Diogo de Melo Godoy, Julia Pinheiro Chagas da Cunha, and Maria Carolina Elias. "Trypanosome Prereplication Machinery: A Potential New Target for an Old Problem." Enzyme Research 2011 (May 25, 2011): 1–8. http://dx.doi.org/10.4061/2011/518258.
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Approximately ten million people suffer from Chagas disease worldwide, caused by Trypanosoma cruzi, with the disease burden predominately focused in Latin America. Sleeping sickness is another serious health problem, caused by Trypanosoma brucei, especially in sub-Saharan countries. Unfortunately, the drugs currently available to treat these diseases have toxic effects and are not effective against all disease phases or parasite strains. Therefore, there is a clear need for the development of novel drugs and drug targets to treat these diseases. We propose the trypanosome prereplication machinery component, Orc1/Cdc6, as a potential target for drug development. In trypanosomes, Orc1/Cdc6 is involved in nuclear DNA replication, and, despite its involvement in such a conserved process, Orc1/Cdc6 is distinct from mammalian Orc1 and Cdc6 proteins. Moreover, RNAi-mediated silencing of trypanosome Orc1/Cdc6 expression in T. brucei decreased cell survival, indicating that Orc1/Cdc6 is critical for trypanosome survival.
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JAMONNEAU, V., S. RAVEL, M. KOFFI, D. KABA, D. G. ZEZE, L. NDRI, B. SANE, B. COULIBALY, G. CUNY, and P. SOLANO. "Mixed infections of trypanosomes in tsetse and pigs and their epidemiological significance in a sleeping sickness focus of Côte d'Ivoire." Parasitology 129, no. 6 (November 18, 2004): 693–702. http://dx.doi.org/10.1017/s0031182004005876.
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In a sleeping sickness focus of Côte d'Ivoire, trypanosomes were characterized in humans, pigs and tsetse using various techniques. Out of 74 patients, all the 43 stocks isolated by KIVI (Kit for In Vitro Isolation) appeared to belong to only one zymodeme of Trypanosoma brucei gambiense group 1 (the major zymodeme Z3). The only stock isolated on rodents belonged to a different, new, zymodeme (Z50), of T. b. gambiense group 1. From 18 pigs sampled in the same locations as the patients, PCR showed a high proportion of mixed infections of T. brucei s. l. and T. congolense riverine-forest. Zymodemes of T. brucei s. l. from these pigs were different from those found in humans. From a total of 16260 captured tsetse (Glossina palpalis palpalis), 1701 were dissected and 28% were found to be infected by trypanosomes. The most prevalent trypanosome was T. congolense riverine-forest type, followed by T. vivax, T. brucei s. l. and T. congolense savannah type, this latter being associated to the forest type of T. congolense in most cases. Mixed infections by 2 or 3 of these trypanosomes were also found. Use of a microsatellite marker allowed us to distinguish T. b. gambiense group 1 in some of the mature infections in tsetse. Differences in infection rates and in trypanosome genotypes according to the host might indicate that the pig may not be an active animal reservoir for humans in this focus.
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Matovu, Enock, Mhairi L. Stewart, Federico Geiser, Reto Brun, Pascal Mäser, Lynsey J. M. Wallace, Richard J. Burchmore, et al. "Mechanisms of Arsenical and Diamidine Uptake and Resistance in Trypanosoma brucei." Eukaryotic Cell 2, no. 5 (October 2003): 1003–8. http://dx.doi.org/10.1128/ec.2.5.1003-1008.2003.
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ABSTRACT Sleeping sickness, caused by Trypanosoma brucei spp., has become resurgent in sub-Saharan Africa. Moreover, there is an alarming increase in treatment failures with melarsoprol, the principal agent used against late-stage sleeping sickness. In T. brucei, the uptake of melarsoprol as well as diamidines is thought to be mediated by the P2 aminopurine transporter, and loss of P2 function has been implicated in resistance to these agents. The trypanosomal gene TbAT1 has been found to encode a P2-type transporter when expressed in yeast. Here we investigate the role of TbAT1 in drug uptake and drug resistance in T. brucei by genetic knockout of TbAT1. Tbat1-null trypanosomes were deficient in P2-type adenosine transport and lacked adenosine-sensitive transport of pentamidine and melaminophenyl arsenicals. However, the null mutants were only slightly resistant to melaminophenyl arsenicals and pentamidine, while resistance to other diamidines such as diminazene was more pronounced. Nevertheless, the reduction in drug sensitivity might be of clinical significance, since mice infected with tbat1-null trypanosomes could not be cured with 2 mg of melarsoprol/kg of body weight for four consecutive days, whereas mice infected with the parental line were all cured by using this protocol. Two additional pentamidine transporters, HAPT1 and LAPT1, were still present in the null mutant, and evidence is presented that HAPT1 may be responsible for the residual uptake of melaminophenyl arsenicals. High-level arsenical resistance therefore appears to involve the loss of more than one transporter.
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Boulanger, Nathalie, Rebecca J. L. Munks, Joanne V. Hamilton, Françoise Vovelle, Reto Brun, Mike J. Lehane, and Philippe Bulet. "Epithelial Innate Immunity." Journal of Biological Chemistry 277, no. 51 (October 7, 2002): 49921–26. http://dx.doi.org/10.1074/jbc.m206296200.
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The gut epithelium is an essential interface in insects that transmit parasites. We investigated the role that local innate immunity might have on vector competence, takingStomoxys calcitransas a model.S. calcitransis sympatric with tsetse flies, feeds on many of the same vertebrate hosts, and is thus regularly exposed to the trypanosomes that cause African sleeping sickness and nagana. Despite this,S. calcitransis not a cyclical vector of these trypanosomes. Trypanosomes develop exclusively in the lumen of digestive organs, and so epithelial immune mechanisms, and in particular antimicrobial peptides (AMPs), may be the prime determinants of the fate of an infection. To investigate whyS. calcitransis not a cyclical vector of trypanosomes, we have looked in its midgut for AMPs with trypanolytic activity. We have identified a new AMP of 42 amino acids, which we named stomoxyn, constitutively expressed and secreted exclusively in the anterior midgut ofS. calcitrans. It displays an amphipathic helical structure and exhibits a broad activity spectrum affecting the growth of microorganisms. Interestingly, this AMP exhibits trypanolytic activity toTrypanosoma brucei rhodesiense. We argue that stomoxyn may help to explain whyS. calcitransis not a vector of trypanosomes causing African sleeping sickness and nagana.
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Banerjee, Hiren, Barbara Knoblach, and Richard A. Rachubinski. "The early-acting glycosome biogenic protein Pex3 is essential for trypanosome viability." Life Science Alliance 2, no. 4 (July 24, 2019): e201900421. http://dx.doi.org/10.26508/lsa.201900421.
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Trypanosomatid parasites are infectious agents for diseases such as African sleeping sickness, Chagas disease, and leishmaniasis that threaten millions of people, mostly in the emerging world. Trypanosomes compartmentalize glycolytic enzymes to an organelle called the glycosome, a specialized peroxisome. Functionally intact glycosomes are essential for trypanosomatid viability, making glycosomal proteins as potential drug targets against trypanosomatid diseases. Peroxins (Pex), of which Pex3 is the master regulator, control glycosome biogenesis. Although Pex3 has been found throughout the eukaryota, its identity has remained stubbornly elusive in trypanosomes. We used bioinformatics predictive of protein secondary structure to identify trypanosomal Pex3. Microscopic and biochemical analyses showed trypanosomal Pex3 to be glycosomal. Interaction of Pex3 with the peroxisomal membrane protein receptor Pex19 observed for other eukaryotes is replicated by trypanosomal Pex3 and Pex19. Depletion of Pex3 leads to mislocalization of glycosomal proteins to the cytosol, reduced glycosome numbers, and trypanosomatid death. Our findings are consistent with Pex3 being an essential gene in trypanosomes.
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Caljon, Guy, Jan Van Den Abbeele, Benoît Stijlemans, Marc Coosemans, Patrick De Baetselier, and Stefan Magez. "Tsetse Fly Saliva Accelerates the Onset of Trypanosoma brucei Infection in a Mouse Model Associated with a Reduced Host Inflammatory Response." Infection and Immunity 74, no. 11 (September 5, 2006): 6324–30. http://dx.doi.org/10.1128/iai.01046-06.
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ABSTRACT Tsetse flies (Glossina sp.) are the vectors that transmit African trypanosomes, protozoan parasites that cause human sleeping sickness and veterinary infections in the African continent. These blood-feeding dipteran insects deposit saliva at the feeding site that enables the blood-feeding process. Here we demonstrate that tsetse fly saliva also accelerates the onset of a Trypanosoma brucei infection. This effect was associated with a reduced inflammatory reaction at the site of infection initiation (reflected by a decrease of interleukin-6 [IL-6] and IL-12 mRNA) as well as lower serum concentrations of the trypanocidal cytokine tumor necrosis factor. Variant-specific surface glycoprotein-specific antibody isotypes immunoglobulin M (IgM) and IgG2a, implicated in trypanosome clearance, were not suppressed. We propose that tsetse fly saliva accelerates the onset of trypanosome infection by inhibiting local and systemic inflammatory responses involved in parasite control.
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Solomon Ngutor, Karshima, Lawal A. Idris, and Okubanjo Oluseyi Oluyinka. "Silent HumanTrypanosoma brucei gambienseInfections around the Old Gboko Sleeping Sickness Focus in Nigeria." Journal of Parasitology Research 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/2656121.
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Trypanosoma brucei gambiensecauses Gambian trypanosomosis, a disease ravaging affected rural parts of Sub-Saharan Africa. We screened 1200 human blood samples forT. b. gambienseusing the card agglutination test for trypanosomosis, characterized trypanosome isolates withTrypanosoma gambienseserum glycoprotein-PCR (TgsGP-PCR), and analyzed our data using Chi square and odds ratio at 95% confidence interval for statistical association. Of the 1200 samples, the CATT revealed an overall infection rate of 1.8% which ranged between 0.0% and 3.5% across study sites. Age and sex based infection rates ranged between 1.2% and 2.3%. We isolated 7 (33.3%) trypanosomes from the 21 seropositive samples using immunosuppressed mice which were identified asT. b. gambiensegroup 1 by TgsGP-PCR. Based on study sites, PCR revealed an overall infection rate of 0.6% which ranged between 0.0% and 1.5%. Females and males revealed PCR based infection rates of 0.3% and 0.8%, respectively. Infection rates in adults (1.3%) and children (0.1%) varied significantly (p<0.05). We observed silentT. b. gambienseinfections among residents of this focus. Risks of disease development into the second fatal stage in these patients who may also serve as reservoirs of infection in the focus exist.
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Lorger, Mihaela, Markus Engstler, Matthias Homann, and H. Ulrich Göringer. "Targeting the Variable Surface of African Trypanosomes with Variant Surface Glycoprotein-Specific, Serum-Stable RNA Aptamers." Eukaryotic Cell 2, no. 1 (February 2003): 84–94. http://dx.doi.org/10.1128/ec.2.1.84-94.2003.
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ABSTRACT African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.
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Rudenko, Gloria. "African trypanosomes: the genome and adaptations for immune evasion." Essays in Biochemistry 51 (October 24, 2011): 47–62. http://dx.doi.org/10.1042/bse0510047.
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The African trypanosome Trypanosoma brucei is a flagellated unicellular parasite transmitted by tsetse flies that causes African sleeping sickness in sub-Saharan Africa. Trypanosomes are highly adapted for life in the hostile environment of the mammalian bloodstream, and have various adaptations to their cell biology that facilitate immune evasion. These include a specialized morphology, with most nutrient uptake occurring in the privileged location of the flagellar pocket. In addition, trypanosomes show extremely high rates of recycling of a protective VSG (variant surface glycoprotein) coat, whereby host antibodies are stripped off of the VSG before it is re-used. VSG recycling therefore functions as a mechanism for cleaning the VSG coat, allowing trypanosomes to survive in low titres of anti-VSG antibodies. Lastly, T. brucei has developed an extremely sophisticated strategy of antigenic variation of its VSG coat allowing it to evade host antibodies. A single trypanosome has more than 1500 VSG genes, most of which are located in extensive silent arrays. Strikingly, most of these silent VSGs are pseudogenes, and we are still in the process of trying to understand how non-intact VSGs are recombined to produce genes encoding functional coats. Only one VSG is expressed at a time from one of approximately 15 telomeric VSG ES (expression site) transcription units. It is becoming increasingly clear that chromatin remodelling must play a critical role in ES control. Hopefully, a better understanding of these unique trypanosome adaptations will eventually allow us to disrupt their ability to multiply in the mammalian bloodstream.
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Vourchakbé, Joël, Zebaze Arnol Auvaker Tiofack, Tagueu Sartrien Kante, Mbida Mpoame, and Gustave Simo. "Molecular identification of Trypanosoma brucei gambiense in naturally infected pigs, dogs and small ruminants confirms domestic animals as potential reservoirs for sleeping sickness in Chad." Parasite 27 (2020): 63. http://dx.doi.org/10.1051/parasite/2020061.
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Human African trypanosomiasis (HAT) has been targeted for zero transmission to humans by 2030. Animal reservoirs of gambiense-HAT could jeopardize these elimination goals. This study was undertaken to identify potential host reservoirs for Trypanosoma brucei gambiense by detecting its natural infections in domestic animals of Chadian HAT foci. Blood samples were collected from 267 goats, 181 sheep, 154 dogs, and 67 pigs. Rapid diagnostic test (RDT) and capillary tube centrifugation (CTC) were performed to search for trypanosomes. DNA was extracted from the buffy coat, and trypanosomes of the subgenus Trypanozoon as well as T. b. gambiense were identified by PCR. Of 669 blood samples, 19.4% were positive by RDT and 9.0% by CTC. PCR revealed 150 animals (22.4%) with trypanosomes belonging to Trypanozoon, including 18 (12%) T. b. gambiense. This trypanosome was found in all investigated animal species and all HAT foci. Between animal species or villages, no significant differences were observed in the number of animals harboring T. b. gambiense DNA. Pigs, dogs, sheep and goats appeared to be potential reservoir hosts for T. b. gambiense in Chad. The identification of T. b. gambiense in all animal species of all HAT foci suggests that these animals should be considered when designing new control strategies for sustainable elimination of HAT. Investigations aiming to decrypt their specific role in each epidemiological setting are important to achieve zero transmission of HAT.
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MORLAIS, I., P. GREBAUT, J. M. BODO, S. DJOHA, and G. CUNY. "Characterization of trypanosome infections by polymerase chain reaction (PCR) amplification in wild tsetse flies in Cameroon." Parasitology 116, no. 6 (June 1998): 547–54. http://dx.doi.org/10.1017/s0031182098002625.
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The polymerase chain reaction (PCR) method was used to characterize trypanosome infections in tsetse flies from 3 sleeping sickness foci in Cameroon. The predominant tsetse species found was Glossina palpalis palpalis. An average infection rate of 12·1% was revealed by microscopical examination of 888 non-teneral tsetse flies. PCR amplification analyses for trypanosome identification were carried out on 467 flies, with primer sets specific for Trypanosoma (Trypanozoon) brucei s.l., T. (Duttonella) vivax, T. (Nannomonas) simiae and forest type T. (Nannomonas) congolense. Of 467 flies 93 were positive by microscopical analysis while PCR succeeded in identifying 89 positive flies. Of the PCR-positive flies 34 (38·2%) were negative by microscopical examination. PCR amplification, when compared to the parasitological technique, gave a higher estimate of infection rate of trypanosomes in natural tsetse populations. The PCR technique did, however, fail to identify 40·9% (38/93) of the parasitologically positive flies. The reasons for this failure are discussed. The overall prevalence of mixed infections, assessed by PCR, was 37·1%; the majority (72·7%) involved T. brucei and forest type T. congolense.
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Carrington, Mark. "Slippery customers: How African trypanosomes evade mammalian defences." Biochemist 31, no. 4 (August 1, 2009): 8–11. http://dx.doi.org/10.1042/bio03104008.
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African trypanosomes are excellent parasites and can maintain an infection of a large mammalian host for months or years. In endemic areas, Human African Trypanosomiasis, also called sleeping sickness, has been largely unaffected by the advent of modern medicine, and trypanosomiasis of domestic livestock is a major restraint on productivity in endemic areas and is arguably the major contributor to the institutionalized poverty in much of rural sub-Saharan Africa1,2. A simple way of visualizing the effect of the livestock disease is to compare maps showing the distribution of livestock (www.ilri.org/InfoServ/Webpub/Fulldocs/Mappoverty/index.htm) and tsetse flies, the insect vector (www.fao.org/ag/AGAinfo/programmes/en/paat/maps.html): the lack of overlap is remarkable. Tsetse flies are only present in sub-Saharan Africa, and this probably restricted the spread of African trypanosomiasis until historical times. Livestock infections are now present in much of South Asia and South America, a product of long distance trade and adaptation of the trypanosomes to mechanical transmission3. The majority of research is on Trypanosoma brucei as this includes the human infective subspecies. This article provides a description of progress in the understanding the molecular details of how the trypanosome interacts with the mammalian immune system and how these studies have extended beyond this to fundamental aspects of eukaryotic cell biology.
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Kagbadouno, Moise Saa, Mamadou Camara, Jeremi Rouamba, Jean-Baptiste Rayaisse, Ibrahima Sory Traoré, Oumou Camara, Mory Fassou Onikoyamou, et al. "Epidemiology of Sleeping Sickness in Boffa (Guinea): Where Are the Trypanosomes?" PLoS Neglected Tropical Diseases 6, no. 12 (December 13, 2012): e1949. http://dx.doi.org/10.1371/journal.pntd.0001949.
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Field, Mark C. "Drug screening by crossing membranes: a novel approach to identification of trypanocides." Biochemical Journal 419, no. 2 (March 27, 2009): e1-e3. http://dx.doi.org/10.1042/bj20090283.
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Trypanosomes are a group of protozoan parasites that inflict huge health and economic burdens across the globe. The African trypanosome, Trypanosoma brucei, the causative agent of sleeping sickness, has a highly sophisticated mechanism of antigenic variation that facilitates chronic survival in the mammalian host, and also all but eliminates any realistic hope for vaccination-based control. However, trypanosomes are also highly divergent organisms, with many biochemical processes setting them apart from their hosts, and there remains great optimism that these features may be exploited for development of new drugs. Unfortunately, the compounds that are in use at present are decades old and resistance has emerged. The article in this issue of the Biochemical Journal by Patham et al., a joint team from the universities of Pittsburgh and Georgia, represents one approach to exploiting this divergence. The authors of the study have exploited novel aspects of the biochemistry within the system for translocation of nascent polypeptides across the endoplasmic reticulum membrane to identify three compounds that are able to inhibit the process. They then demonstrate that these same compounds are both trypanocidal, but well tolerated by human tissue culture cells. These observations may present interesting new leads in the fight against trypanosomiasis, and potentially identify a new target that can be explored for therapeutic potential.
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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.
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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.
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Rudenko, Gloria. "Epigenetics and transcriptional control in African trypanosomes." Essays in Biochemistry 48 (September 20, 2010): 201–19. http://dx.doi.org/10.1042/bse0480201.
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The African trypanosome Trypanosoma brucei is a unicellular parasite which causes African sleeping sickness. Transcription in African trypanosomes displays some unusual features, as most of the trypanosome genome is transcribed as extensive polycistronic RNA Pol II (polymerase II) transcription units that are not transcriptionally regulated. In addition, RNA Pol I is used for transcription of a small subset of protein coding genes in addition to the rDNA (ribosomal DNA). These Pol I-transcribed protein coding genes include the VSG (variant surface glycoprotein) genes. Although a single trypanosome has many hundreds of VSG genes, the active VSG is transcribed in a strictly monoalleleic fashion from one of approx. 15 telomeric VSG ESs (expression sites). Originally, it was thought that chromatin was not involved in the transcriptional control of ESs; however, this view is now being re-evaluated. It has since been shown that the active ES is depleted of nucleosomes compared with silent ESs. In addition, a number of proteins involved in chromatin remodelling or histone modification and which play a role in ES silencing {including TbISWI [T. brucei ISWI (imitation-switch protein)] and DOT1B} have recently been identified. Lastly, the telomere-binding protein TbRAP1 (T. brucei RAP1) has been shown to establish a repressive gradient extending from the ES telomere end up to the ES promoter. We still need to determine which epigenetic factors are involved in ‘marking’ the active ES as part of the counting mechanism of monoallelic exclusion. The challenge will come in determining how these multiple regulatory layers contribute to ES control.
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Ohaeri, Carmelita C., and Mark C. Eluwa. "Parasitism data of Glossina palpalis and G. tachinoides (Diptera: Glossinidae) by trypanosome species in parts of Abia State, Nigeria." Veterinary Science Development 1, no. 1 (December 28, 2011): 17. http://dx.doi.org/10.4081/vsd.2011.3521.
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<em>Glossina</em> species are important medical and agricultural vectors transmitting the African animal trypanosomes and also the agent of sleeping sickness in human. Parasitism data of <em>Glossina</em> species by trypanosomes were carried out over a period of one year, from April 2003 to March 2004 using bioconical traps to catch tsetse at some selected Local Government Areas of Abia State, Nigeria. Four hundred and twenty seven (427) flies were dissected and examined microscopically for the presence of trypanosome infection. The survey found <em>Glossina palpalis</em> as the predominant tsetse species in the area. Out of the 427 flies dissected, 17 (3.9%) were infected with trypanosome. The highest infection was recorded among <em>G. palpalis</em> (3.7%) and this was significantly higher (P<0.001) when compared with those of <em>G. tachinoides</em> (0.2%). Female flies had higher infection than males (2.3% as against 1.6%, respectively). Majority of the infected flies were caught during rainy season (2.8%) and few were caught in dry season (1.1%). Twelve (2.8%) of all the parasites were located in the proboscis indicating <em>Trypanosoma vivax </em>infection, while 5 (1.1%) were from mid-gut of the flies indicating <em>T. congolense</em> infection. No parasite was observed in all the <em>Glossina</em> species caught at Ikwuano and Umuahia South areas, while trypanosome parasitism was highest in <em>Glossina</em> species caught at Isuikwuato, 2.5% of the flies in this area were parasitized. The low parasitic infection rate observed here indicates a marginal effect on the vector population of trypanosomes in Abia State, Nigeria.
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Kozak, Radoslaw P., Karina Mondragon-Shem, Christopher Williams, Clair Rose, Samirah Perally, Guy Caljon, Jan Van Den Abbeele, et al. "Tsetse salivary glycoproteins are modified with paucimannosidic N-glycans, are recognised by C-type lectins and bind to trypanosomes." PLOS Neglected Tropical Diseases 15, no. 2 (February 2, 2021): e0009071. http://dx.doi.org/10.1371/journal.pntd.0009071.
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African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional downregulation of tsetse genes encoding for salivary proteins, which reduces its anti-hemostatic and anti-clotting properties. To better understand trypanosome transmission and the possible role of glycans in insect bloodfeeding, we characterized the N-glycome of tsetse saliva glycoproteins. Tsetse salivary N-glycans were enzymatically released, tagged with either 2-aminobenzamide (2-AB) or procainamide, and analyzed by HILIC-UHPLC-FLR coupled online with positive-ion ESI-LC-MS/MS. We found that the N-glycan profiles of T. brucei-infected and naïve tsetse salivary glycoproteins are almost identical, consisting mainly (>50%) of highly processed Man3GlcNAc2 in addition to several other paucimannose, high mannose, and few hybrid-type N-glycans. In overlay assays, these sugars were differentially recognized by the mannose receptor and DC-SIGN C-type lectins. We also show that salivary glycoproteins bind strongly to the surface of transmissible metacyclic trypanosomes. We suggest that although the repertoire of tsetse salivary N-glycans does not change during a trypanosome infection, the interactions with mannosylated glycoproteins may influence parasite transmission into the vertebrate host.
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Subota, Ines, Brice Rotureau, Thierry Blisnick, Sandra Ngwabyt, Mickaël Durand-Dubief, Markus Engstler, and Philippe Bastin. "ALBA proteins are stage regulated during trypanosome development in the tsetse fly and participate in differentiation." Molecular Biology of the Cell 22, no. 22 (November 15, 2011): 4205–19. http://dx.doi.org/10.1091/mbc.e11-06-0511.
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The protozoan parasite Trypanosoma brucei is responsible for sleeping sickness and alternates between mammal and tsetse fly hosts, where it has to adapt to different environments. We investigated the role of two members of the ALBA family, which encodes hypothetical RNA-binding proteins conserved in most eukaryotes. We show that ALBA3/4 proteins colocalize with the DHH1 RNA-binding protein and with a subset of poly(A+) RNA in stress granules upon starvation. Depletion of ALBA3/4 proteins by RNA interference in the cultured procyclic stage produces cell modifications mimicking several morphogenetic aspects of trypanosome differentiation that usually take place in the fly midgut. A combination of immunofluorescence data and videomicroscopy analysis of live trypanosomes expressing endogenously ALBA fused with fluorescent proteins revealed that ALBA3/4 are present throughout the development of the parasite in the tsetse fly, with the striking exception of the transition stages found in the proventriculus region. This involves migration of the nucleus toward the posterior end of the cell, a phenomenon that is perturbed upon forced expression of ALBA3 during the differentiation process, showing for the first time the involvement of an RNA-binding protein in trypanosome development in vivo.
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Wenzler, Tanja, David W. Boykin, Mohamed A. Ismail, James Edwin Hall, Richard R. Tidwell, and Reto Brun. "New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289." Antimicrobial Agents and Chemotherapy 53, no. 10 (July 20, 2009): 4185–92. http://dx.doi.org/10.1128/aac.00225-09.
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ABSTRACT African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.
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Faulkner, Sara D., Monika W. Oli, Rudo Kieft, Laura Cotlin, Justin Widener, April Shiflett, Michael J. Cipriano, et al. "In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei." Eukaryotic Cell 5, no. 8 (August 2006): 1276–86. http://dx.doi.org/10.1128/ec.00116-06.
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ABSTRACT The host range of African trypanosomes is influenced by innate protective molecules in the blood of primates. A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to Trypanosoma brucei brucei but not the human sleeping sickness parasite Trypanosoma brucei rhodesiense. It is thought that T. b. rhodesiense evolved from a T. b. brucei-like ancestor and expresses a defense protein that ablates the antitrypanosomal activity of human HDL. To directly investigate this possibility, we developed an in vitro selection to generate human HDL-resistant T. b. brucei. Here we show that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs. Complete transcriptome analysis of the HDL-susceptible and -resistant trypanosomes confirmed that VSG switching had occurred but failed to reveal the expression of other genes specifically associated with human HDL resistance, including the serum resistance-associated gene (SRA) of T. b. rhodesiense. In addition, we found that while the original active expression site was still utilized, expression of three expression site-associated genes (ESAG) was altered in the HDL-resistant trypanosomes. These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei.
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van Hellemond, J. J., F. R. Opperdoes, and A. G. M. Tielens. "The extraordinary mitochondrion and unusual citric acid cycle in Trypanosoma brucei." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 967–71. http://dx.doi.org/10.1042/bst0330967.
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African trypanosomes are parasitic protozoa that cause sleeping sickness and nagana. Trypanosomes are not only of scientific interest because of their clinical importance, but also because these protozoa contain several very unusual biological features, such as their specially adapted mitochondrion and the compartmentalization of glycolytic enzymes in glycosomes. The energy metabolism of Trypanosoma brucei differs significantly from that of their hosts and changes drastically during the life cycle. Despite the presence of all citric acid cycle enzymes in procyclic insect-stage T. brucei, citric acid cycle activity is not used for energy generation. Recent investigations on the influence of substrate availability on the type of energy metabolism showed that absence of glycolytic substrates did not induce a shift from a fermentative metabolism to complete oxidation of substrates. Apparently, insect-stage T. brucei use parts of the citric acid cycle for other purposes than for complete degradation of mitochondrial substrates. Parts of the cycle are suggested to be used for (i) transport of acetyl-CoA units from the mitochondrion to the cytosol for the biosynthesis of fatty acids, (ii) degradation of proline and glutamate to succinate, (iii) generation of malate, which can then be used for gluconeogenesis. Therefore the citric acid cycle in trypanosomes does not function as a cycle.
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Vaidya, Tushar, Moiz Bakhiet, Kent L. Hill, Tomas Olsson, Krister Kristensson, and John E. Donelson. "The Gene for a T Lymphocyte Triggering Factor from African Trypanosomes." Journal of Experimental Medicine 186, no. 3 (August 4, 1997): 433–38. http://dx.doi.org/10.1084/jem.186.3.433.
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An early and essential event in the protective immune response against most viruses and protozoa is the production of interferon-γ (IFN-γ). In contrast, during infection with African trypanosomes, protozoan parasites that cause human sleeping sickness, the increased levels of IFN-γ do not correlate with a protective response. We showed previously that African trypanosomes express a protein called T lymphocyte triggering factor (TLTF), which triggers CD8+ T lymphocytes to proliferate and to secrete IFN-γ. Here, we isolate the gene for TLTF and demonstrate that the recombinant version of TLTF specifically induces CD8+, but not CD4+, T cells to secrete IFN-γ. Studies with TLTF fused to the green fluorescent protein show that TLTF is localized to small vesicles that are found primarily at or near the flagellar pocket, the site of secretion in trypanosomes. TLTF is likely to be only the first example of a class of proteins that we designate as trypanokines, i.e., factors secreted by trypanosomes that modulate the cytokine network of the host immune system for the benefit of the parasite.
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Lillico, Simon, Mark C. Field, Pat Blundell, Graham H. Coombs, and Jeremy C. Mottram. "Essential Roles for GPI-anchored Proteins in African Trypanosomes Revealed Using Mutants Deficient in GPI8." Molecular Biology of the Cell 14, no. 3 (March 2003): 1182–94. http://dx.doi.org/10.1091/mbc.e02-03-0167.
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The survival of Trypanosoma brucei, the causative agent of Sleeping Sickness and Nagana, is facilitated by the expression of a dense surface coat of glycosylphosphatidylinositol (GPI)-anchored proteins in both its mammalian and tsetse fly hosts. We have characterized T. brucei GPI8, the gene encoding the catalytic subunit of the GPI:protein transamidase complex that adds preformed GPI anchors onto nascent polypeptides. Deletion ofGPI8 (to give Δgpi8) resulted in the absence of GPI-anchored proteins from the cell surface of procyclic form trypanosomes and accumulation of a pool of non–protein-linked GPI molecules, some of which are surface located. Procyclic Δgpi8, while viable in culture, were unable to establish infections in the tsetse midgut, confirming that GPI-anchored proteins are essential for insect-parasite interactions. Applying specific inducible GPI8 RNAi with bloodstream form parasites resulted in accumulation of unanchored variant surface glycoprotein and cell death with a defined multinuclear, multikinetoplast, and multiflagellar phenotype indicative of a block in cytokinesis. These data show that GPI-anchored proteins are essential for the viability of bloodstream form trypanosomes even in the absence of immune challenge and imply that GPI8 is important for proper cell cycle progression.
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Mosimann, Marc, Shinobu Goshima, Tanja Wenzler, Alexandra Lüscher, Nobuyuki Uozumi, and Pascal Mäser. "A Trk/HKT-Type K+ Transporter from Trypanosoma brucei." Eukaryotic Cell 9, no. 4 (February 26, 2010): 539–46. http://dx.doi.org/10.1128/ec.00314-09.
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ABSTRACT The molecular mechanisms of K+ homeostasis are only poorly understood for protozoan parasites. Trypanosoma brucei subsp. parasites, the causative agents of human sleeping sickness and nagana, are strictly extracellular and need to actively concentrate K+ from their hosts’ body fluids. The T. brucei genome contains two putative K+ channel genes, yet the trypanosomes are insensitive to K+ antagonists and K+ channel-blocking agents, and they do not spontaneously depolarize in response to high extracellular K+ concentrations. However, the trypanosomes are extremely sensitive to K+ ionophores such as valinomycin. Surprisingly, T. brucei possesses a member of the Trk/HKT superfamily of monovalent cation permeases which so far had only been known from bacteria, archaea, fungi, and plants. The protein was named TbHKT1 and functions as a Na+-independent K+ transporter when expressed in Escherichia coli, Saccharomyces cerevisiae, or Xenopus laevis oocytes. In trypanosomes, TbHKT1 is expressed in both the mammalian bloodstream stage and the Tsetse fly midgut stage; however, RNA interference (RNAi)-mediated silencing of TbHKT1 expression did not produce a growth phenotype in either stage. The presence of HKT genes in trypanosomatids adds a further piece to the enigmatic phylogeny of the Trk/HKT superfamily of K+ transporters. Parsimonial analysis suggests that the transporters were present in the first eukaryotes but subsequently lost in several of the major eukaryotic lineages, in at least four independent events.
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Truc, P., V. Jamonneau, P. N'Guessan, L. N'Dri, and P. B. Diallo. "Pathogenicity of african trypanosomes: A new approach of the epidemiology of gambian sleeping sickness." Parasitology International 47 (August 1998): 33. http://dx.doi.org/10.1016/s1383-5769(98)80036-6.
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CAPEWELL, PAUL, ANNELI COOPER, CAROLINE CLUCAS, WILLIAM WEIR, and ANNETTE MACLEOD. "A co-evolutionary arms race: trypanosomes shaping the human genome, humans shaping the trypanosome genome." Parasitology 142, S1 (June 26, 2014): S108—S119. http://dx.doi.org/10.1017/s0031182014000602.
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SUMMARYTrypanosoma brucei is the causative agent of African sleeping sickness in humans and one of several pathogens that cause the related veterinary disease Nagana. A complex co-evolution has occurred between these parasites and primates that led to the emergence of trypanosome-specific defences and counter-measures. The first line of defence in humans and several other catarrhine primates is the trypanolytic protein apolipoprotein-L1 (APOL1) found within two serum protein complexes, trypanosome lytic factor 1 and 2 (TLF-1 and TLF-2). Two sub-species of T. brucei have evolved specific mechanisms to overcome this innate resistance, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. In T. b. rhodesiense, the presence of the serum resistance associated (SRA) gene, a truncated variable surface glycoprotein (VSG), is sufficient to confer resistance to lysis. The resistance mechanism of T. b. gambiense is more complex, involving multiple components: reduction in binding affinity of a receptor for TLF, increased cysteine protease activity and the presence of the truncated VSG, T. b. gambiense-specific glycoprotein (TgsGP). In a striking example of co-evolution, evidence is emerging that primates are responding to challenge by T. b. gambiense and T. b. rhodesiense, with several populations of humans and primates displaying resistance to infection by these two sub-species.
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Villafraz, Oriana, Marc Biran, Erika Pineda, Nicolas Plazolles, Edern Cahoreau, Rodolpho Ornitz Oliveira Souza, Magali Thonnus, et al. "Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline." PLOS Pathogens 17, no. 3 (March 1, 2021): e1009204. http://dx.doi.org/10.1371/journal.ppat.1009204.
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Trypanosoma brucei, a protist responsible for human African trypanosomiasis (sleeping sickness), is transmitted by the tsetse fly where the procyclic forms of the parasite develop in the proline-rich (1–2 mM) and glucose-depleted digestive tract. Proline is essential for the midgut colonization of the parasite in the insect vector, however other carbon sources could be available and used to feed its central metabolism. Here we show that procyclic trypanosomes can consume and metabolize metabolic intermediates, including those excreted from glucose catabolism (succinate, alanine and pyruvate), with the exception of acetate, which is the ultimate end-product excreted by the parasite. Among the tested metabolites, tricarboxylic acid (TCA) cycle intermediates (succinate, malate and α-ketoglutarate) stimulated growth of the parasite in the presence of 2 mM proline. The pathways used for their metabolism were mapped by proton-NMR metabolic profiling and phenotypic analyses of thirteen RNAi and/or null mutants affecting central carbon metabolism. We showed that (i) malate is converted to succinate by both the reducing and oxidative branches of the TCA cycle, which demonstrates that procyclic trypanosomes can use the full TCA cycle, (ii) the enormous rate of α-ketoglutarate consumption (15-times higher than glucose) is possible thanks to the balanced production and consumption of NADH at the substrate level and (iii) α-ketoglutarate is toxic for trypanosomes if not appropriately metabolized as observed for an α-ketoglutarate dehydrogenase null mutant. In addition, epimastigotes produced from procyclics upon overexpression of RBP6 showed a growth defect in the presence of 2 mM proline, which is rescued by α-ketoglutarate, suggesting that physiological amounts of proline are not sufficient per se for the development of trypanosomes in the fly. In conclusion, these data show that trypanosomes can metabolize multiple metabolites, in addition to proline, which allows them to confront challenging environments in the fly.
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Selby, Richard, Kevin Bardosh, Kim Picozzi, Charles Waiswa, and Susan C. Welburn. "Cattle movements and trypanosomes: restocking efforts and the spread of Trypanosoma brucei rhodesiense sleeping sickness in post-conflict Uganda." Parasites & Vectors 6, no. 1 (2013): 281. http://dx.doi.org/10.1186/1756-3305-6-281.
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Stephens, Natalie A., and Stephen L. Hajduk. "Endosomal Localization of the Serum Resistance-Associated Protein in African Trypanosomes Confers Human Infectivity." Eukaryotic Cell 10, no. 8 (June 24, 2011): 1023–33. http://dx.doi.org/10.1128/ec.05112-11.
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ABSTRACT Trypanosoma brucei rhodesiense is the causative agent of human African sleeping sickness. While the closely related subspecies T. brucei brucei is highly susceptible to lysis by a subclass of human high-density lipoproteins (HDL) called trypanosome lytic factor (TLF), T. brucei rhodesiense is resistant and therefore able to establish acute and fatal infections in humans. This resistance is due to expression of the serum resistance-associated (SRA) gene, a member of the variant surface glycoprotein (VSG) gene family. Although much has been done to establish the role of SRA in human serum resistance, the specific molecular mechanism of SRA-mediated resistance remains a mystery. Thus, we report the trafficking and steady-state localization of SRA in order to provide more insight into the mechanism of SRA-mediated resistance. We show that SRA traffics to the flagellar pocket of bloodstream-form T. brucei organisms, where it localizes transiently before being endocytosed to its steady-state localization in endosomes, and we demonstrate that the critical point of colocalization between SRA and TLF occurs intracellularly.
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Friedman, David J., and Martin R. Pollak. "APOL1 and Kidney Disease: From Genetics to Biology." Annual Review of Physiology 82, no. 1 (February 10, 2020): 323–42. http://dx.doi.org/10.1146/annurev-physiol-021119-034345.
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Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic trypanosomes that cause African sleeping sickness. We consider the genetic evidence supporting the association between APOL1 and kidney disease across the range of clinical phenotypes in the APOL1 nephropathy spectrum. We then explore the origins of the APOL1 risk variants and evolutionary struggle between humans and trypanosomes at both the molecular and population genetic level. Finally, we survey the rapidly growing literature investigating APOL1 biology as elucidated from experiments in cell-based systems, cell-free systems, mouse and lower organism models of disease, and through illuminating natural experiments in humans.
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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.
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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.
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Kaba, Dramane, Vincent Djohan, Djakaridja Berté, Bi Tra Dieudonné TA, Richard Selby, Koffi Alain De Marie Kouadio, Bamoro Coulibaly, et al. "Use of vector control to protect people from sleeping sickness in the focus of Bonon (Côte d’Ivoire)." PLOS Neglected Tropical Diseases 15, no. 6 (June 28, 2021): e0009404. http://dx.doi.org/10.1371/journal.pntd.0009404.
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Background Gambian human African trypanosomiasis (gHAT) is a neglected tropical disease caused by Trypanosoma brucei gambiense transmitted by tsetse flies (Glossina). In Côte d’Ivoire, Bonon is the most important focus of gHAT, with 325 cases diagnosed from 2000 to 2015 and efforts against gHAT have relied largely on mass screening and treatment of human cases. We assessed whether the addition of tsetse control by deploying Tiny Targets offers benefit to sole reliance on the screen-and-treat strategy. Methodology and principal findings In 2015, we performed a census of the human population of the Bonon focus, followed by an exhaustive entomological survey at 278 sites. After a public sensitization campaign, ~2000 Tiny Targets were deployed across an area of 130 km2 in February of 2016, deployment was repeated annually in the same month of 2017 and 2018. The intervention’s impact on tsetse was evaluated using a network of 30 traps which were operated for 48 hours at three-month intervals from March 2016 to December 2018. A second comprehensive entomological survey was performed in December 2018 with traps deployed at 274 of the sites used in 2015. Sub-samples of tsetse were dissected and examined microscopically for presence of trypanosomes. The census recorded 26,697 inhabitants residing in 331 settlements. Prior to the deployment of targets, the mean catch of tsetse from the 30 monitoring traps was 12.75 tsetse/trap (5.047–32.203, 95%CI), i.e. 6.4 tsetse/trap/day. Following the deployment of Tiny Targets, mean catches ranged between 0.06 (0.016–0.260, 95%CI) and 0.55 (0.166–1.794, 95%CI) tsetse/trap, i.e. 0.03–0.28 tsetse/trap/day. During the final extensive survey performed in December 2018, 52 tsetse were caught compared to 1,909 in 2015, with 11.6% (5/43) and 23.1% (101/437) infected with Trypanosoma respectively. Conclusions The annual deployment of Tiny Targets in the gHAT focus of Bonon reduced the density of Glossina palpalis palpalis by >95%. Tiny Targets offer a powerful addition to current strategies towards eliminating gHAT from Côte d’Ivoire.
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Vidilaseris, Keni, Nicolas Landrein, Yulia Pivovarova, Johannes Lesigang, Niran Aeksiri, Derrick R. Robinson, Melanie Bonhivers, and Gang Dong. "Crystal structure of the N-terminal domain of the trypanosome flagellar protein BILBO1 reveals a ubiquitin fold with a long structured loop for protein binding." Journal of Biological Chemistry 295, no. 6 (December 27, 2019): 1489–99. http://dx.doi.org/10.1074/jbc.ra119.010768.
Full textAbstract:
Trypanosoma brucei is a protist parasite causing sleeping sickness and nagana in sub-Saharan Africa. T. brucei has a single flagellum whose base contains a bulblike invagination of the plasma membrane called the flagellar pocket (FP). Around the neck of the FP on its cytoplasmic face is a structure called the flagellar pocket collar (FPC), which is essential for FP biogenesis. BILBO1 was the first characterized component of the FPC in trypanosomes. BILBO1's N-terminal domain (NTD) plays an essential role in T. brucei FPC biogenesis and is thus vital for the parasite's survival. Here, we report a 1.6-Å resolution crystal structure of TbBILBO1-NTD, which revealed a conserved horseshoe-like hydrophobic pocket formed by an unusually long loop. Results from mutagenesis experiments suggested that another FPC protein, FPC4, interacts with TbBILBO1 by mainly contacting its three conserved aromatic residues Trp-71, Tyr-87, and Phe-89 at the center of this pocket. Our findings disclose the binding site of TbFPC4 on TbBILBO1-NTD, which may provide a basis for rational drug design targeting BILBO1 to combat T. brucei infections.
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Vaughan, Sue, and Keith Gull. "The structural mechanics of cell division in Trypanosoma brucei." Biochemical Society Transactions 36, no. 3 (May 21, 2008): 421–24. http://dx.doi.org/10.1042/bst0360421.
Full textAbstract:
Undoubtedly, there are fundamental processes driving the structural mechanics of cell division in eukaryotic organisms that have been conserved throughout evolution and are being revealed by studies on organisms such as yeast and mammalian cells. Precision of structural mechanics of cytokinesis is however probably no better illustrated than in the protozoa. A dramatic example of this is the protozoan parasite Trypanosoma brucei, a unicellular flagellated parasite that causes a devastating disease (African sleeping sickness) across Sub-Saharan Africa in both man and animals. As trypanosomes migrate between and within a mammalian host and the tsetse vector, there are periods of cell proliferation and cell differentiation involving at least five morphologically distinct cell types. Much of the existing cytoskeleton remains intact during these processes, necessitating a very precise temporal and spatial duplication and segregation of the many single-copy organelles. This structural precision is aiding progress in understanding these processes as we apply the excellent reverse genetics and post-genomic technologies available in this system. Here we outline our current understanding of some of the structural aspects of cell division in this fascinating organism.
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Harmer, Jane, Katie Towers, Max Addison, Sue Vaughan, Michael L. Ginger, and Paul G. McKean. "A centriolar FGR1 oncogene partner-like protein required for paraflagellar rod assembly, but not axoneme assembly in African trypanosomes." Open Biology 8, no. 7 (July 2018): 170218. http://dx.doi.org/10.1098/rsob.170218.
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Proteins of the FGR1 oncogene partner (or FOP) family are found at microtubule organizing centres (MTOCs) including, in flagellate eukaryotes, the centriole or flagellar basal body from which the axoneme extends. We report conservation of FOP family proteins, Tb FOPL and Tb OFD1, in the evolutionarily divergent sleeping sickness parasite Trypanosoma brucei , showing (in contrast with mammalian cells, where FOP is essential for flagellum assembly) depletion of a trypanosome FOP homologue, Tb FOPL, affects neither axoneme nor flagellum elongation. Instead, Tb FOPL depletion causes catastrophic failure in assembly of a lineage-specific, extra-axonemal structure, the paraflagellar rod (PFR). That depletion of centriolar Tb FOPL causes failure in PFR assembly is surprising because PFR nucleation commences approximately 2 µm distal from the basal body. When over-expressed with a C-terminal myc-epitope, Tb FOPL was also observed at mitotic spindle poles. Little is known about bi-polar spindle assembly during closed trypanosome mitosis, but indication of a possible additional MTOC function for Tb FOPL parallels MTOC localization of FOP-like protein TONNEAU1 in acentriolar plants. More generally, our functional analysis of Tb FOPL emphasizes significant differences in evolutionary cell biology trajectories of FOP-family proteins. We discuss how at the molecular level FOP homologues may contribute to flagellum assembly and function in diverse flagellates.
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Page, A. M., and J. R. Lagnado. "Effects of phenothiazine neuroleptic drugs on the microtubular–membrane complex in bloodstream forms of Trypanosoma brucei." Parasitology 111, no. 4 (November 1995): 493–504. http://dx.doi.org/10.1017/s0031182000066002.
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SUMMARYAfrican trypanosomes are parasitic protozoa causing sleeping sickness in humans and related diseases in domestic animals against which no entirely satisfactory forms of chemotherapy are yet available. It was previously shown that related species of trypanosomes, as well as procyclic (insect) forms of Trypanosoma brucei are extremely sensitive to the action of phenothiazine neuroleptic drugs in vitro. In this work, we have carried out a more detailed investigation of the effects of thioridazine, one of the most potent neuroleptic phenothiazine drugs known, on the morphology of the infective bloodstream forms of T. brucei, with particular reference to the parasite's prominent pellicular membrane complex. Our data show that this drug induces rapid changes in cell shape that appear to involve some reorganization of the microtubular membrane skeleton, but does not affect the structural integrity of the microtubular complex. Another early consequence of drug action involved damage to nuclear and cytoplasmic membranes and the appearance of tubular arrays of coated membrane within the flagellar pocket. It was also revealed that the drug induces a rapid release of the variant-specific glycoprotein (VSG) which makes up the surface coat protecting bloodstream forms of the parasite against the host immune system. Our evidence suggests that this release of VSG involves cleavage of the protein's glycosyl-phosphatidylinositol (GPI) membrane anchor by endogenous GPI-specific phospholipase C, probably as a consequence of minor damage to the parasite plasma membrane induced by the drug.
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Ralston, Katherine S., Neville K. Kisalu, and Kent L. Hill. "Structure-Function Analysis of Dynein Light Chain 1 Identifies Viable Motility Mutants in Bloodstream-Form Trypanosoma brucei." Eukaryotic Cell 10, no. 7 (March 4, 2011): 884–94. http://dx.doi.org/10.1128/ec.00298-10.
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ABSTRACT The flagellum of Trypanosoma brucei is an essential and multifunctional organelle that is receiving increasing attention as a potential drug target and as a system for studying flagellum biology. RNA interference (RNAi) knockdown is widely used to test the requirement for a protein in flagellar motility and has suggested that normal flagellar motility is essential for viability in bloodstream-form trypanosomes. However, RNAi knockdown alone provides limited functional information because the consequence is often loss of a multiprotein complex. We therefore developed an inducible system that allows functional analysis of point mutations in flagellar proteins in T. brucei . Using this system, we identified point mutations in the outer dynein light chain 1 (LC1) that allow stable assembly of outer dynein motors but do not support propulsive motility. In procyclic-form trypanosomes, the phenotype of LC1 mutants with point mutations differs from the motility and structural defects of LC1 knockdowns, which lack the outer-arm dynein motor. Thus, our results distinguish LC1-specific functions from broader functions of outer-arm dynein. In bloodstream-form trypanosomes, LC1 knockdown blocks cell division and is lethal. In contrast, LC1 point mutations cause severe motility defects without affecting viability, indicating that the lethal phenotype of LC1 RNAi knockdown is not due to defective motility. Our results demonstrate for the first time that normal motility is not essential in bloodstream-form T. brucei and that the presumed connection between motility and viability is more complex than might be interpreted from knockdown studies alone. These findings open new avenues for dissecting mechanisms of flagellar protein function and provide an important step in efforts to exploit the potential of the flagellum as a therapeutic target in African sleeping sickness.
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Domenicali Pfister, Debora, Gabriela Burkard, Sabine Morand, Christina Kunz Renggli, Isabel Roditi, and Erik Vassella. "A Mitogen-Activated Protein Kinase Controls Differentiation of Bloodstream Forms of Trypanosoma brucei." Eukaryotic Cell 5, no. 7 (July 2006): 1126–35. http://dx.doi.org/10.1128/ec.00094-06.
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ABSTRACT African trypanosomes undergo differentiation in order to adapt to the mammalian host and the tsetse fly vector. To characterize the role of a mitogen-activated protein (MAP) kinase homologue, TbMAPK5, in the differentiation of Trypanosoma brucei, we constructed a knockout in procyclic (insect) forms from a differentiation-competent (pleomorphic) stock. Two independent knockout clones proliferated normally in culture and were not essential for other life cycle stages in the fly. They were also able to infect immunosuppressed mice, but the peak parasitemia was 16-fold lower than that of the wild type. Differentiation of the proliferating long slender to the nonproliferating short stumpy bloodstream form is triggered by an autocrine factor, stumpy induction factor (SIF). The knockout differentiated prematurely in mice and in culture, suggestive of increased sensitivity to SIF. In contrast, a null mutant of a cell line refractory to SIF was able to proliferate normally. The differentiation phenotype was partially rescued by complementation with wild-type TbMAPK5 but exacerbated by introduction of a nonactivatable mutant form. Our results indicate a regulatory function for TbMAPK5 in the differentiation of bloodstream forms of T. brucei that might be exploitable as a target for chemotherapy against human sleeping sickness.
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Bonnet, Julien, Clotilde Boudot, and Bertrand Courtioux. "Overview of the Diagnostic Methods Used in the Field for Human African Trypanosomiasis: What Could Change in the Next Years?" BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/583262.
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Sleeping sickness is a parasitic infection caused by two species of trypanosomes (Trypanosoma brucei gambienseandrhodesiense), transmitted by the tsetse fly. The disease eventually affects the central nervous system, resulting in severe neurological symptoms. Without treatment, death is inevitable. During the first stage of the disease, infected patients are mildly symptomatic and early detection of infection allows safer treatment (administered on an outpatient basis) which can avoid death; routine screening of the exposed population is necessary, especially in areas of high endemicity. The current therapeutic treatment of this disease, especially in stage 2, can cause complications and requires a clinical surveillance for several days. A good stage diagnosis of the disease is the cornerstone for delivering the adequate treatment. The task faced by the medical personnel is further complicated by the lack of support from local health infrastructure, which is at best weak, but often nonexistent. Therefore it is crucial to look for new more efficient technics for the diagnosis of stage which are also best suited to use in the field, in areas not possessing high-level health facilities. This review, after an overview of the disease, summarizes the current diagnosis procedures and presents the advances in the field.