Journal articles: 'African trypanosomiasis. Dynein. Trypanosoma brucei'

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Dai, Jennifer. "Resolving Trypanosoma brucei Flagellar Structure by Cryo-Electron Tomography." E3S Web of Conferences 131 (2019): 01012. http://dx.doi.org/10.1051/e3sconf/201913101012.

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Trypanosoma brucei is a unicellular eukaryote that can cause human African trypanosomiasis, which has continued to evolve and spread. The key feature of these parasites is that they have a flagellum consists of a typical 9 + 2 axoneme and a lattice-like paraflagellar rod (PFR). It attached to the cell body and is responsible for cell motility, cytokinesis, and morphogenesis. The present study demonstrates the detailed structure and defines the length of the axoneme and three domains of the paraflagellar rod (PFR) using cryo-electron tomography of Trypanosoma brucei flagella. The performed analysis revealed the double-headed structure of the outer-arm dynein, the internal structure of PFR and identified repeating structure in the flagella. Since these structures are critical to the pathogenicity of Trypanosoma brucei, and understanding their organization would help in finding treatments against African trypanosomiasis.

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Kubata, Bruno Kilunga, Michael Duszenko, Zakayi Kabututu, Marc Rawer, Alexander Szallies, Ko Fujimori, Takashi Inui, et al. "Identification of a Novel Prostaglandin F2α Synthase in Trypanosoma brucei." Journal of Experimental Medicine 192, no. 9 (November 6, 2000): 1327–38. http://dx.doi.org/10.1084/jem.192.9.1327.

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Members of the genus Trypanosoma cause African trypanosomiasis in humans and animals in Africa. Infection of mammals by African trypanosomes is characterized by an upregulation of prostaglandin (PG) production in the plasma and cerebrospinal fluid. These metabolites of arachidonic acid (AA) may, in part, be responsible for symptoms such as fever, headache, immunosuppression, deep muscle hyperaesthesia, miscarriage, ovarian dysfunction, sleepiness, and other symptoms observed in patients with chronic African trypanosomiasis. Here, we show that the protozoan parasite T. brucei is involved in PG production and that it produces PGs enzymatically from AA and its metabolite, PGH2. Among all PGs synthesized, PGF2α was the major prostanoid produced by trypanosome lysates. We have purified a novel T. brucei PGF2α synthase (TbPGFS) and cloned its cDNA. Phylogenetic analysis and molecular properties revealed that TbPGFS is completely distinct from mammalian PGF synthases. We also found that TbPGFS mRNA expression and TbPGFS activity were high in the early logarithmic growth phase and low during the stationary phase. The characterization of TbPGFS and its gene in T. brucei provides a basis for the molecular analysis of the role of parasite-derived PGF2α in the physiology of the parasite and the pathogenesis of African trypanosomiasis.

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Dias-Guerreiro, Tatiana, Joana Palma-Marques, Patrícia Mourata-Gonçalves, Graça Alexandre-Pires, Ana Valério-Bolas, Áurea Gabriel, Telmo Nunes, et al. "African Trypanosomiasis: Extracellular Vesicles Shed by Trypanosoma brucei brucei Manipulate Host Mononuclear Cells." Biomedicines 9, no. 8 (August 20, 2021): 1056. http://dx.doi.org/10.3390/biomedicines9081056.

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African trypanosomiasis or sleeping sickness is a zoonotic disease caused by Trypanosoma brucei, a protozoan parasite transmitted by Glossina spp. (tsetse fly). Parasite introduction into mammal hosts triggers a succession of events, involving both innate and adaptive immunity. Macrophages (MΦ) have a key role in innate defence since they are antigen-presenting cells and have a microbicidal function essential for trypanosome clearance. Adaptive immune defence is carried out by lymphocytes, especially by T cells that promote an integrated immune response. Like mammal cells, T. b. brucei parasites release extracellular vesicles (TbEVs), which carry macromolecules that can be transferred to host cells, transmitting biological information able to manipulate cell immune response. However, the exact role of TbEVs in host immune response remains poorly understood. Thus, the current study examined the effect elicited by TbEVs on MΦ and T lymphocytes. A combined approach of microscopy, nanoparticle tracking analysis, multiparametric flow cytometry, colourimetric assays and detailed statistical analyses were used to evaluate the influence of TbEVs in mouse mononuclear cells. It was shown that TbEVs can establish direct communication with cells of innate and adaptative immunity. TbEVs induce the differentiation of both M1- and M2-MΦ and elicit the expansion of MHCI+, MHCII+ and MHCI+MHCII+ MΦ subpopulations. In T lymphocytes, TbEVs drive the overexpression of cell-surface CD3 and the nuclear factor FoxP3, which lead to the differentiation of regulatory CD4+ and CD8+ T cells. Moreover, this study indicates that T. b. brucei and TbEVs seem to display opposite but complementary effects in the host, establishing a balance between parasite growth and controlled immune response, at least during the early phase of infection.

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Pereira, Glaécia AN, Lucianna H. Santos, Steven C. Wang, Luan C. Martins, Filipe S. Villela, Weiting Liao, Marco A. Dessoy, et al. "Benzimidazole inhibitors of the major cysteine protease of Trypanosoma brucei." Future Medicinal Chemistry 11, no. 13 (July 2019): 1537–51. http://dx.doi.org/10.4155/fmc-2018-0523.

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Aim: Limitations in available therapies for trypanosomiases indicate the need for improved medicines. Cysteine proteases cruzain and rhodesain are validated targets for treatment of Chagas disease and human African trypanosomiasis. Previous studies reported a benzimidazole series as potent cruzain inhibitors. Results & methodology: Considering the high similarity between these proteases, we evaluated 40 benzimidazoles against rhodesain. We describe their structure-activity relationships (SAR), revealing trends similar to those observed for cruzain and features that lead to enzyme selectivity. This series comprises noncovalent competitive inhibitors (best Ki = 0.21 μM against rhodesain) and micromolar activity against Trypanosoma brucei brucei. A cheminformatics analysis confirms scaffold novelty, and the inhibitors described have favorable predicted physicochemical properties. Conclusion: Our results support this series as a starting point for new human African trypanosomiasis medicines.

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Braakman, Hilde M. H., Fred J. J. M. van de Molengraft, Wim W. A. Hubert, and Dolf H. Boerman. "Lethal African trypanosomiasis in a traveler: MRI and neuropathology." Neurology 66, no. 7 (April 10, 2006): 1094–96. http://dx.doi.org/10.1212/01.wnl.0000209306.41647.13.

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The authors report a case of human African trypanosomiasis with CNS involvement caused by Trypanosoma brucei rhodesiense in a 52-year-old woman, which relapsed after melarsoprol treatment. After a second regimen, she developed a severe toxic polyneuropathy, progressing to coma and eventually death. MRI revealed rapidly progressive multiple white matter lesions as well as damage of the central gray matter and cortex. The autopsy results confirmed the diagnosis of human African trypanosomiasis.

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Katabazi, Aziz, Adamu Almustapha Aliero, Sarah Gift Witto, Martin Odoki, and Simon Peter Musinguzi. "Prevalence of Trypanosoma congolense and Trypanosoma vivax in Lira District, Uganda." BioMed Research International 2021 (June 14, 2021): 1–7. http://dx.doi.org/10.1155/2021/7284042.

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Trypanosomes are the causative agents of animal African trypanosomiasis (AAT) and human African trypanosomiasis (HAT), the former affecting domestic animals prevalent in Sub-Saharan Africa. The main species causing AAT in cattle are T. congolense, T. vivax, and T. b. brucei. Northern Uganda has been politically unstable with no form of vector control in place. The return of displaced inhabitants led to the restocking of cattle from AAT endemic areas. It was thus important to estimate the burden of trypanosomiasis in the region. This study was designed to compare the prevalence of animal African trypanosomes in cattle in Lira District using microscopy and polymerase chain reaction amplification (PCR) methods. In this cross-sectional study, a total of 254 cattle from the three villages of Acanakwo A, Barropok, and Acungkena in Lira District, Uganda, were selected by simple random sampling technique and screened for trypanosomiasis using microscopy and PCR methods. The prevalence of trypanosomiasis according to microscopic results was 5/254 (2.0%) as compared to 11/254 (4.3%) trypanosomiasis prevalence according to PCR analysis. The prevalence of trypanosomiasis infection in the animal studied is 11/254 (4.3%). Trypanosoma congolense was the most dominant trypanosome species with a proportion of 9/11 (81.8%), followed by T. vivax 1/11 (9.1%) and mixed infection of T. congolense/T. vivax1/11 (9.1%). Barropok village had the highest prevalence of trypanosomiasis with 6/11 (54.5%). There is a statistically significant relationship ( OR = 6.041 ; 95% CI: 1.634-22.331; p < 0.05 ) between abnormal PCV and trypanosome infection. Polymerase reaction amplification was the most reliable diagnostic method due to its high sensitivity and specificity as compared to the conventional microscopic method. Polymerase reaction amplification appears to have adequate accuracy to substitute the use of a microscope where facilities allow. This study, therefore, underscores the urgent need for local surveillance schemes more especially at the grassroots in Uganda to provide data for reference guideline development needed for the control of trypanosomiasis in Uganda.

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Graça, Nuno A. G., Luis Gaspar, David M. Costa, Inês Loureiro, Paul Kong Thoo-Lin, Isbaal Ramos, Meritxell Roura, et al. "Activity of Bisnaphthalimidopropyl Derivatives against Trypanosoma brucei." Antimicrobial Agents and Chemotherapy 60, no. 4 (January 19, 2016): 2532–36. http://dx.doi.org/10.1128/aac.02490-15.

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ABSTRACTCurrent treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives againstTrypanosoma brucei. BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showedin vitroinhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed. However, cure was not achieved. BNIPDabut constitutes a new scaffold for antitrypanosomal drugs that deserves further consideration.

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Faria, Joana, Carolina B. Moraes, Rita Song, Bruno S. Pascoalino, Nakyung Lee, Jair L. Siqueira-Neto, Deu John M. Cruz, et al. "Drug Discovery for Human African Trypanosomiasis." Journal of Biomolecular Screening 20, no. 1 (October 23, 2014): 70–81. http://dx.doi.org/10.1177/1087057114556236.

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Human African trypanosomiasis (HAT) is a vector-transmitted tropical disease caused by the protozoan parasite Trypanosoma brucei. High-throughput screening (HTS) of small-molecule libraries in whole-cell assays is one of the most frequently used approaches in drug discovery for infectious diseases. To aid in drug discovery efforts for HAT, the SYBR Green assay was developed for T. brucei in a 384-well format. This semi-automated assay is cost- and time-effective, robust, and reproducible. The SYBR Green assay was compared to the resazurin assay by screening a library of 4000 putative kinase inhibitors, revealing a superior performance in terms of assay time, sensitivity, simplicity, and reproducibility, and resulting in a higher hit confirmation rate. Although the resazurin assay allows for comparatively improved detection of slow-killing compounds, it also has higher false-positive rates that are likely to arise from the assay experimental conditions. The compounds with the most potent antitrypanosomal activity were selected in both screens and grouped into 13 structural clusters, with 11 new scaffolds as antitrypanosomal agents. Several of the identified compounds had IC50 <1 µM coupled with high selectivity toward the parasite. The core structures of the scaffolds are shown, providing promising new starting points for drug discovery for HAT.

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Rao, Srinivasa P. S., Suresh B. Lakshminarayana, Jan Jiricek, Marcel Kaiser, Ryan Ritchie, Elmarie Myburgh, Frantisek Supek, et al. "Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis." Tropical Medicine and Infectious Disease 5, no. 1 (February 17, 2020): 28. http://dx.doi.org/10.3390/tropicalmed5010028.

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Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and ‘easy to use’ oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in T. brucei. These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis.

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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.

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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.

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Keck, Devin, Callie Stuart, Josie Duncan, Emily Gullette, and Rodrigo Martinez-Duarte. "Highly Localized Enrichment of Trypanosoma brucei Parasites Using Dielectrophoresis." Micromachines 11, no. 6 (June 26, 2020): 625. http://dx.doi.org/10.3390/mi11060625.

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Human African trypanosomiasis (HAT), also known as sleeping sickness, is a vector-borne neglected tropical disease endemic to rural sub-Saharan Africa. Current methods of early detection in the affected rural communities generally begin with general screening using the card agglutination test for trypanosomiasis (CATT), a serological test. However, the gold standard for confirmation of trypanosomiasis remains the direct observation of the causative parasite, Trypanosoma brucei. Here, we present the use of dielectrophoresis (DEP) to enrich T. brucei parasites in specific locations to facilitate their identification in a future diagnostic assay. DEP refers to physical movement that can be selectively induced on the parasites when exposing them to electric field gradients of specific magnitude, phase and frequency. The long-term goal of our work is to use DEP to selectively trap and enrich T. brucei in specific locations while eluting all other cells in a sample. This would allow for a diagnostic test that enables the user to characterize the presence of parasites in specific locations determined a priori instead of relying on scanning a sample. In the work presented here, we report the characterization of the conditions that lead to high enrichment, 780% in 50 s, of the parasite in specific locations using an array of titanium microelectrodes.

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Parwan, Deepika, Ranjan Kumar, and Sumit Aggrawal. "African Trypanosomiasis in Young Female in North India - A Rare Case Report." Annals of Pathology and Laboratory Medicine 8, no. 4 (May 10, 2021): C71–73. http://dx.doi.org/10.21276/apalm.2997.

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Human African trypanosomiasis, also known as sleeping sickness, is a vector-borne parasitic disease. It is caused by infection with protozoan parasites belonging to the genus Trypanosoma. They are transmitted to humans by tsetse fly (Glossina genus) bites which have acquired their infection from human beings or from animals harboring human pathogenic parasites. Tsetse flies are found just in sub-Saharan Africa though only certain species transmit the disease. We report a case of human African trypanosomiasis in a 28-year-old Indian female who had a travel history to sub–Saharan Africa, Uganda and she presented with a history of fever, body ache, headache, decreased oral intake, pain lower abdomen, swelling and discharge from forearm chancre since last 4-5 days. Peripheral smear showed heavy parasitemia by flagellated forms of Trypanosoma and the diagnosis of Trypanosoma brucei was given on Peripheral smear report. Serological testing was also done and a diagnosis of West-African trypanosomiasis was confirmed. The patient was successfully treated and made a good recovery. So West-African trypanosomiasis should be considered in the differential diagnosis with presentation of fever with chancre in every person with recent history of travel to African countries as it is universally fatal without treatment.

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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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Bacchi, C. J., K. Sanabria, A. J. Spiess, M. Vargas, C. J. Marasco, L. M. Jimenez, B. Goldberg, and J. R. Sufrin. "In vivo efficacies of 5'-methylthioadenosine analogs as trypanocides." Antimicrobial Agents and Chemotherapy 41, no. 10 (October 1997): 2108–12. http://dx.doi.org/10.1128/aac.41.10.2108.

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5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.

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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.

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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.

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MacLean, Lorna M., Martin Odiit, John E. Chisi, Peter G. E. Kennedy, and Jeremy M. Sternberg. "Focus–Specific Clinical Profiles in Human African Trypanosomiasis Caused by Trypanosoma brucei rhodesiense." PLoS Neglected Tropical Diseases 4, no. 12 (December 7, 2010): e906. http://dx.doi.org/10.1371/journal.pntd.0000906.

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Garcia, A., V. Jamonneau, B. Sane, F. Fournet, P. N'Guessan, L. N'Dri, R. Sanon, D. Kaba, and C. Laveissiere. "Host age and time of exposure in Trypanosoma brucei gambiense Human African Trypanosomiasis." Tropical Medicine and International Health 7, no. 5 (May 2002): 429–34. http://dx.doi.org/10.1046/j.1365-3156.2002.00878.x.

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Truc, P., and M. Tibayrenc. "Population genetics of Trypanosoma brucei in Central Africa: taxonomic and epidemiological significance." Parasitology 106, no. 2 (February 1993): 137–49. http://dx.doi.org/10.1017/s003118200007493x.

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SUMMARYIn order to estimate the value of population genetics for both the taxonomy of trypanosomes belonging to the species Trypanosoma brucei and a better understanding of Human African Trypanosomiasis (HAT), we undertook a cellulose acetate electrophoresis isoenzyme study involving 55 stocks isolated from man and animals in Congo, Zaire and Cameroun. Out of the 24 loci surveyed, 15 exhibited variability, which made it possible to delimit 23 zymodemes, divided into 2 groups. The first group equated to the classical subspecies Trypanosoma brucei gambiense, while the second corresponded to the classical subspecies Trypanosoma brucei brucei. These results broadly agree with the current taxonomy, and are corroborated by RFLP analysis of kDNA. Statistical analysis indicates a basically clonal reproduction system of the trypanosomes in the area studied; the zymodemes are equivalent to natural clones (or a family of closely related clones), stable in space and time. Epidemiological hypotheses are proposed according to the geographic distribution of the clones in this area.

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Waema, Maxwell W., Naomi W. Maina, Maina Ngotho, Simon M. Karanja, Beatrice M. Gachie, Dawn N. Maranga, and John M. Kagira. "IgM, lgG and IL-6 profiles in the Trypanosoma brucei brucei monkey model of human African trypanosomiasis." Acta Tropica 168 (April 2017): 45–49. http://dx.doi.org/10.1016/j.actatropica.2017.01.012.

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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.

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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.

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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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Dofuor, Aboagye Kwarteng, Temitayo Samson Ademolue, Cynthia Mmalebna Amisigo, Kwaku Kyeremeh, and Theresa Manful Gwira. "Chemical Derivatization and Characterization of Novel Antitrypanosomals for African Trypanosomiasis." Molecules 26, no. 15 (July 25, 2021): 4488. http://dx.doi.org/10.3390/molecules26154488.

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The search for novel antitrypanosomals and the investigation into their mode of action remain crucial due to the toxicity and resistance of commercially available antitrypanosomal drugs. In this study, two novel antitrypanosomals, tortodofuordioxamide (compound 2) and tortodofuorpyramide (compound 3), were chemically derived from the natural N-alkylamide tortozanthoxylamide (compound 1) through structural modification. The chemical structures of these compounds were confirmed through spectrometric and spectroscopic analysis, and their in vitro efficacy and possible mechanisms of action were, subsequently, investigated in Trypanosoma brucei (T. brucei), one of the causative species of African trypanosomiasis (AT). The novel compounds 2 and 3 displayed significant antitrypanosomal potencies in terms of half-maximal effective concentrations (EC50) and selectivity indices (SI) (compound 1, EC50 = 7.3 μM, SI = 29.5; compound 2, EC50 = 3.2 μM, SI = 91.3; compound 3, EC50 = 4.5 μM, SI = 69.9). Microscopic analysis indicated that at the EC50 values, the compounds resulted in the coiling and clumping of parasite subpopulations without significantly affecting the normal ratio of nuclei to kinetoplasts. In contrast to the animal antitrypanosomal drug diminazene, compounds 1, 2 and 3 exhibited antioxidant absorbance properties comparable to the standard antioxidant Trolox (Trolox, 0.11 A; diminazene, 0.50 A; compound 1, 0.10 A; compound 2, 0.09 A; compound 3, 0.11 A). The analysis of growth kinetics suggested that the compounds exhibited a relatively gradual but consistent growth inhibition of T. brucei at different concentrations. The results suggest that further pharmacological optimization of compounds 2 and 3 may facilitate their development into novel AT chemotherapy.

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Moreno, Cláudia, Adriana Temporão, Taffarel Torres, and Marcelo Sousa Silva. "Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis." International Journal of Molecular Sciences 20, no. 6 (March 25, 2019): 1484. http://dx.doi.org/10.3390/ijms20061484.

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The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.

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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.

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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.

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Cockram, Peter E., Emily A. Dickie, Michael P. Barrett, and Terry K. Smith. "Halogenated tryptophan derivatives disrupt essential transamination mechanisms in bloodstream form Trypanosoma brucei." PLOS Neglected Tropical Diseases 14, no. 12 (December 4, 2020): e0008928. http://dx.doi.org/10.1371/journal.pntd.0008928.

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Amino acid metabolism within Trypanosoma brucei, the causative agent of human African trypanosomiasis, is critical for parasite survival and virulence. Of these metabolic processes, the transamination of aromatic amino acids is one of the most important. In this study, a series of halogenated tryptophan analogues were investigated for their anti-parasitic potency. Several of these analogues showed significant trypanocidal activity. Metabolomics analysis of compound-treated parasites revealed key differences occurring within aromatic amino acid metabolism, particularly within the widely reported and essential transamination processes of this parasite.

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Boukobza, Monique, Sylvie Lariven, Sandrine Houzé, and Jean-Pierre Laissy. "Unusual MRI Findings in African Trypanosoma brucei gambiense Trypanosomiasis: Dentate Nuclei and Hypothalamic Lesions." American Journal of Tropical Medicine and Hygiene 102, no. 1 (January 8, 2020): 5–6. http://dx.doi.org/10.4269/ajtmh.19-0204.

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Jackson, Andrew P., Mandy Sanders, Andrew Berry, Jacqueline McQuillan, Martin A. Aslett, Michael A. Quail, Bridget Chukualim, et al. "The Genome Sequence of Trypanosoma brucei gambiense, Causative Agent of Chronic Human African Trypanosomiasis." PLoS Neglected Tropical Diseases 4, no. 4 (April 13, 2010): e658. http://dx.doi.org/10.1371/journal.pntd.0000658.

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Chen, Nian, Ke Jin, Jingjing Xu, Jianfu Zhang, and Yali Weng. "Human African trypanosomiasis caused by Trypanosoma brucei gambiense: The first case report in China." International Journal of Infectious Diseases 79 (February 2019): 34–36. http://dx.doi.org/10.1016/j.ijid.2018.11.004.

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Morty, Rory E., Patrick Bulau, Roger Pellé, Sherwin Wilk, and Koji Abe. "Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts." Biochemical Journal 394, no. 3 (February 24, 2006): 635–45. http://dx.doi.org/10.1042/bj20051593.

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Peptidases of parasitic protozoans are emerging as novel virulence factors and therapeutic targets in parasitic infections. A trypanosome-derived aminopeptidase that exclusively hydrolysed substrates with Glp (pyroglutamic acid) in P1 was purified 9248-fold from the plasma of rats infected with Trypanosoma brucei brucei. The enzyme responsible was cloned from a T. brucei brucei genomic DNA library and identified as type I PGP (pyroglutamyl peptidase), belonging to the C15 family of cysteine peptidases. We showed that PGP is expressed in all life cycle stages of T. brucei brucei and is expressed in four other blood-stream-form African trypanosomes. Trypanosome PGP was optimally active and stable at bloodstream pH, and was insensitive to host plasma cysteine peptidase inhibitors. Native purified and recombinant hyper-expressed trypanosome PGP removed the N-terminal Glp blocking groups from TRH (thyrotrophin-releasing hormone) and GnRH (gonadotropin-releasing hormone) with a kcat/Km value of 0.5 and 0.1 s−1·μM−1 respectively. The half-life of TRH and GnRH was dramatically reduced in the plasma of trypanosome-infected rats, both in vitro and in vivo. Employing an activity-neutralizing anti-trypanosome PGP antibody, and pyroglutamyl diazomethyl ketone, a specific inhibitor of type I PGP, we demonstrated that trypanosome PGP is entirely responsible for the reduced plasma half-life of TRH, and partially responsible for the reduced plasma half-life of GnRH in a rodent model of African trypanosomiasis. The abnormal degradation of TRH and GnRH, and perhaps other neuropeptides N-terminally blocked with a pyroglutamyl moiety, by trypanosome PGP, may contribute to some of the endocrine lesions observed in African trypanosomiasis.

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Dickie, Emily A., Simon A. Young, and Terry K. Smith. "Substrate specificity of the neutral sphingomyelinase from Trypanosoma brucei." Parasitology 146, no. 5 (November 5, 2018): 604–16. http://dx.doi.org/10.1017/s0031182018001853.

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AbstractThe kinetoplastid parasite Trypanosoma brucei causes African trypanosomiasis in both humans and animals. Infections place a significant health and economic burden on developing nations in sub-Saharan Africa, but few effective anti-parasitic treatments are currently available. Hence, there is an urgent need to identify new leads for drug development. The T. brucei neutral sphingomyelinase (TbnSMase) was previously established as essential to parasite survival, consequently being identified as a potential drug target. This enzyme may catalyse the single route to sphingolipid catabolism outside the T. brucei lysosome. To obtain new insight into parasite sphingolipid catabolism, the substrate specificity of TbnSMase was investigated using electrospray ionization tandem mass spectrometry (ESI-MS/MS). Recombinant TbnSMase was shown to degrade sphingomyelin, inositol-phosphoceramide and ethanolamine-phosphoceramide sphingolipid substrates, consistent with the sphingolipid complement of the parasites. TbnSMase also catabolized ceramide-1-phosphate, but was inactive towards sphingosine-1-phosphate. The broad-range specificity of this enzyme towards sphingolipid species is a unique feature of TbnSMase. Additionally, ESI-MS/MS analysis revealed previously uncharacterized activity towards lyso-phosphatidylcholine despite the enzyme's inability to degrade phosphatidylcholine. Collectively, these data underline the enzyme's importance in choline homoeostasis and the turnover of sphingolipids in T. brucei.

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Oluwafemi, Awotunde J., Emmanuel O. Okanla, Pelayo Camps, Diego Muñoz-Torrero, Zachary B. Mackey, Peter K. Chiang, Scott Seville, and Colin W. Wright. "Evaluation of Cryptolepine and Huperzine Derivatives as Lead Compounds towards New Agents for the Treatment of Human African Trypanosomiasis." Natural Product Communications 4, no. 2 (February 2009): 1934578X0900400. http://dx.doi.org/10.1177/1934578x0900400205.

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The alkaloid cryptolepine (1) and eight synthetic analogues (2-8) were assessed for in vitro activities against Trypanosoma brucei. Four of the analogues were found to be highly potent with IC50 values of less than 3 nM and three of these were assessed against T. brucei brucei infection in rats. The most effective compound was 2, 7-dibromocryptolepine (7); a single oral dose of 20 mg/kg suppressed parasitaemia and increased the mean survival time to 13.6 days compared with 8.4 days for untreated controls. In addition, four huperzine derivatives (9-12) were shown to have in vitro antitrypanosomal activities with IC50 values ranging from 303-377 nM.

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Buckner, Buchynskyy, Nagendar, Patrick, Gillespie, Herbst, Tidwell, and Gelb. "Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach." Tropical Medicine and Infectious Disease 5, no. 1 (February 5, 2020): 23. http://dx.doi.org/10.3390/tropicalmed5010023.

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The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases.

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Cestari, Igor, and Kenneth Stuart. "Inhibition of Isoleucyl-tRNA Synthetase as a Potential Treatment for Human African Trypanosomiasis." Journal of Biological Chemistry 288, no. 20 (April 2, 2013): 14256–63. http://dx.doi.org/10.1074/jbc.m112.447441.

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Trypanosoma brucei sp. causes human African trypanosomiasis (HAT; African sleeping sickness). The parasites initially proliferate in the hemolymphatic system and then invade the central nervous system, which is lethal if not treated. New drugs are needed for HAT because the approved drugs are few, toxic, and difficult to administer, and drug resistance is spreading. We showed by RNAi knockdown that T. brucei isoleucyl-tRNA synthetase is essential for the parasites in vitro and in vivo in a mouse model of infection. By structure prediction and experimental analysis, we also identified small molecules that inhibit recombinant isoleucyl-tRNA synthetase and that are lethal to the parasites in vitro and highly selective compared with mammalian cells. One of these molecules acts as a competitive inhibitor of the enzyme and cures mice of the infection. Because members of this class of molecules are known to cross the blood-brain barrier in humans and to be tolerated, they may be attractive as leading candidates for drug development for HAT.

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Marsela, Megasari, Kyoko Hayashida, Ryo Nakao, Elisha Chatanga, Alex Kiarie Gaithuma, Kawai Naoko, Janelisa Musaya, Chihiro Sugimoto, and Junya Yamagishi. "Molecular identification of trypanosomes in cattle in Malawi using PCR methods and nanopore sequencing: epidemiological implications for the control of human and animal trypanosomiases." Parasite 27 (2020): 46. http://dx.doi.org/10.1051/parasite/2020043.

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This study aimed to identify trypanosomes infecting cattle in Malawi in order to understand the importance of cattle in the transmission dynamics of Human African Trypanosomiasis (HAT) and Animal African Trypanosomosis (AAT). A total of 446 DNA samples from cattle blood from three regions of Malawi were screened for African trypanosomes by ITS1 PCR. The obtained amplicons were sequenced using a portable next-generation sequencer, MinION, for validation. Comparison of the results from ITS1 PCR and MinION sequencing showed that combining the two methods provided more accurate species identification than ITS1 PCR alone. Further PCR screening targeting the serum resistance-associated (SRA) gene was conducted to detect Trypanosoma brucei rhodesiense. Trypanosoma congolense was the most prevalent Trypanosoma sp., which was found in Nkhotakota (10.8%; 20 of 185), followed by Kasungu (2.5%; 5 of 199). Of note, the prevalence of T. b. rhodesiense detected by SRA PCR was high in Kasungu and Nkhotakota showing 9.5% (19 of 199) and 2.7% (5 of 185), respectively. We report the presence of animal African trypanosomes and T. b. rhodesiense from cattle at the human–livestock–wildlife interface for the first time in Malawi. Our results confirmed that animal trypanosomes are important causes of anemia in cattle and that cattle are potential reservoirs for human African trypanosomiasis in Malawi.

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Steketee, Pieter C., Emily A. Dickie, James Iremonger, Kathryn Crouch, Edith Paxton, Siddharth Jayaraman, Omar A. Alfituri, et al. "Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition." PLOS Pathogens 17, no. 7 (July 26, 2021): e1009734. http://dx.doi.org/10.1371/journal.ppat.1009734.

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Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. Stable-isotope labelling of glucose enabled the comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.

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Dofuor, Aboagye Kwarteng, Georgina Isabella Djameh, Frederick Ayertey, Peter Bolah, Michael Amoa-Bosompem, Kwaku Kyeremeh, Laud Kenneth Okine, Theresa Manful Gwira, and Mitsuko Ohashi. "Antitrypanosomal Effects of Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler Extracts on African Trypanosomes." Evidence-Based Complementary and Alternative Medicine 2019 (July 4, 2019): 1–14. http://dx.doi.org/10.1155/2019/1730452.

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African trypanosomiasis is a disease caused by the parasitic protozoa of the Trypanosoma genus. Despite several efforts at chemotherapeutic interventions, the disease poses serious health and economic concerns to humans and livestock of many sub-Saharan African countries. Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler (Z. zanthoxyloides LZT) is a plant species of important phytochemical and pharmacological relevance in the subtropical zones of the African continent. However, the mechanisms of its antitrypanosomal effects in African trypanosomes remain to be elucidated. The aim of the study was to determine the in vitro effects and mechanisms of action of Z. zanthoxyloides LZT (root) fractions against Trypanosoma brucei. T. brucei (GUTat 3.1 strain), L. donovani (D10 strain), P. falciparum (3D 7 strain), Jurkat cells, and Chang liver cells were cultivated in vitro to the log phase in their respective media at 37°C. Crude extracts and fractions were prepared from air-dried pulverized plant material of Z. zanthoxyloides LZT (root) using the modified Kupchan method of solvent partitioning. Half-maximal inhibitory concentrations (IC50) were determined through the alamar blue cell viability assay. Effects of fractions on cell death and cell cycle of T. brucei were determined using flow cytometry. Fluorescence microscopy was used to investigate the effects of fractions on the morphology and distribution of T. brucei. Antitrypanosomal compounds of fractions were characterized using high-performance liquid chromatography (HPLC) and attenuated total reflectance infrared (ATR-IR) spectroscopy. Methanol, butanol, and dichloromethane fractions were selectively active against T. brucei with respective IC50 values of 3.89, 4.02, and 5.70 μg/ml. Moreover, methanol, butanol, and dichloromethane fractions significantly induced apoptosis-like cell death with remarkable alteration in the cell cycle of T. brucei. Furthermore, dichloromethane and methanol fractions altered the morphology, induced aggregation, and altered the ratio of nuclei to kinetoplasts in the parasite. The HPLC chromatograms and ATR-IR spectra of the active fractions suggested the presence of aromatic hydrocarbons with hydroxyl, carbonyl, amine, or amide functional groups. The results suggest that Z. zanthoxyloides LZT have potential chemotherapeutic effects on African trypanosomes with implications for novel therapeutic interventions in African trypanosomiasis.

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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.

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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.

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Dofuor, Kwain, Osei, Tetevi, Okine, Ohashi, Gwira, and Kyeremeh. "N-(Isobutyl)-3,4-methylenedioxy Cinnamoyl Amide." Molbank 2019, no. 3 (July 5, 2019): M1070. http://dx.doi.org/10.3390/m1070.

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The plant Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler is one of the most important medicinal species of the genus Zanthoxylum on the African continent. It is used in the treatment and management of parasitic diseases in sub-Saharan Africa. These properties have inspired scientists to investigate species within the genus for bioactive compounds. However, a study, which details a spectroscopic, spectrometric and bioactivity guided extraction and isolation of antiparasitic compounds from the genus Zanthoxylum is currently non-existent. Tortozanthoxylamide (1), which is a derivative of the known compound armatamide was isolated from Z. zanthoxyloides and the full structure determined using UV, IR, 1D/2D-NMR and high-resolution liquid chromatography tandem mass spectrometry (HRESI-LC-MS) data. When tested against Trypanosoma brucei subsp. brucei, the parasite responsible for animal African trypanosomiasis in sub-Saharan Africa, 1 (IC50 7.78 µM) was just four times less active than the commercially available drug diminazene aceturate (IC50 1.88 µM). Diminazene aceturate is a potent drug for the treatment of animal African trypanosomiasis. Tortozanthoxylamide (1) exhibits a significant antitrypanosomal activity through remarkable alteration of the cell cycle in T. brucei subsp. brucei, but it is selectively non-toxic to mouse macrophages RAW 264.7 cell lines. This suggests that 1 may be considered as a scaffold for the further development of natural antitrypanosomal compounds.

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HIDE, G., and A. TAIT. "Molecular epidemiology of African sleeping sickness." Parasitology 136, no. 12 (June 26, 2009): 1491–500. http://dx.doi.org/10.1017/s0031182009990333.

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SUMMARYHuman sleeping sickness in Africa, caused by Trypanosoma brucei spp. raises a number of questions. Despite the widespread distribution of the tsetse vectors and animal trypanosomiasis, human disease is only found in discrete foci which periodically give rise to epidemics followed by periods of endemicity A key to unravelling this puzzle is a detailed knowledge of the aetiological agents responsible for different patterns of disease – knowledge that is difficult to achieve using traditional microscopy. The science of molecular epidemiology has developed a range of tools which have enabled us to accurately identify taxonomic groups at all levels (species, subspecies, populations, strains and isolates). Using these tools, we can now investigate the genetic interactions within and between populations of Trypanosoma brucei and gain an understanding of the distinction between human- and nonhuman-infective subspecies. In this review, we discuss the development of these tools, their advantages and disadvantages and describe how they have been used to understand parasite genetic diversity, the origin of epidemics, the role of reservoir hosts and the population structure. Using the specific case of T.b. rhodesiense in Uganda, we illustrate how molecular epidemiology has enabled us to construct a more detailed understanding of the origins, generation and dynamics of sleeping sickness epidemics.

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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.

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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.

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Carvalho, Luis, Marta Martínez-García, Ignacio Pérez-Victoria, José Ignacio Manzano, Vanessa Yardley, Francisco Gamarro, and José M. Pérez-Victoria. "The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei." Antimicrobial Agents and Chemotherapy 59, no. 10 (July 20, 2015): 6151–60. http://dx.doi.org/10.1128/aac.00879-15.

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ABSTRACTThe protozoan parasiteTrypanosoma bruceicauses human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills differentT. bruceispp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca2+, and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significantin vitroactivity againstT. brucei.

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Kourbeli, Violeta, Eleni Chontzopoulou, Kalliopi Moschovou, Dimitrios Pavlos, Thomas Mavromoustakos, and Ioannis P. Papanastasiou. "An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases." Molecules 26, no. 15 (July 30, 2021): 4629. http://dx.doi.org/10.3390/molecules26154629.

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The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled “Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology”.

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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.

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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.

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Chappuis, François, Louis Loutan, Pere Simarro, Veerle Lejon, and Philippe Büscher. "Options for Field Diagnosis of Human African Trypanosomiasis." Clinical Microbiology Reviews 18, no. 1 (January 2005): 133–46. http://dx.doi.org/10.1128/cmr.18.1.133-146.2005.

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SUMMARY Human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense or T. b. rhodesiense remains highly prevalent in several rural areas of sub-Saharan Africa and is lethal if left untreated. Therefore, accurate tools are absolutely required for field diagnosis. For T. b. gambiense HAT, highly sensitive tests are available for serological screening but the sensitivity of parasitological confirmatory tests remains insufficient and needs to be improved. Screening for T. b. rhodesiense infection still relies on clinical features in the absence of serological tests available for field use. Ongoing research is opening perspectives for a new generation of field diagnostics. Also essential for both forms of HAT is accurate determination of the disease stage because of the high toxicity of melarsoprol, the drug most widely used during the neurological stage of the illness. Recent studies have confirmed the high accuracy of raised immunoglobulin M levels in the cerebrospinal fluid for the staging of T. b. gambiense HAT, and a promising simple assay (LATEX/IgM) is being tested in the field. Apart from the urgent need for better tools for the field diagnosis of this neglected disease, improved access to diagnosis and treatment for the population at risk remains the greatest challenge for the coming years.

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NYAKUNDI, J. N., B. CRAWLEY, R. A. SMITH, and V. W. PENTREATH. "The relationships between intestinal damage and circulating endotoxins in experimental Trypanosoma brucei brucei infections." Parasitology 124, no. 6 (June 2002): 589–95. http://dx.doi.org/10.1017/s0031182002001701.

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The involvement of intestinal damage in experimental African trypanosomiasis was investigated in rats infected with Trypanosoma brucei brucei by measuring the urinary excretion of the previously administered non-metabolizable sugar probes, D-mannitol and lactulose, and the flux of FITC-dextran across isolated, everted gut segments. There was increased urinary recovery and flux of the sugar probes across the intestine which were significant (P<0·05) and maximum at day 21 of the infection, but subsequently reduced, in the terminal stages of infection (day 33 p.i.). In the case of the everted sac studies the reductions were to less than 25% control values (P<0·001). Levels of circulating endotoxin were increased approximately 3-fold at day 21 p.i., 4-fold at day 33 p.i., compared to controls. At day 21 there was a significant correlation (r = 0·63, P<0·01) between the log endotoxin levels and the increased sugar excretion expressed as the lactulose/mannitol ratios. Histological studies showed damage to the villi, wall thinning and marked cellular infiltrations, which were very prominent in the proximal jejunum and duodenum. These results demonstrate that during trypanosome infections in rats, increased intestinal leakage and increased circulating endotoxins are significant pathological features.

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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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Le, Thanh, Claire Beaufay, Duc Nghiem, Tuan Pham, Marie-Paule Mingeot-Leclercq, and Joëlle Quetin-Leclercq. "Evaluation of the Anti-Trypanosomal Activity of Vietnamese Essential Oils, with Emphasis on Curcuma longa L. and Its Components." Molecules 24, no. 6 (March 23, 2019): 1158. http://dx.doi.org/10.3390/molecules24061158.

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Human African trypanosomiasis (HAT), known as sleeping sickness and caused by Trypanosoma brucei, is threatening low-income populations in sub-Saharan African countries with 61 million people at risk of infection. In order to discover new natural products against HAT, thirty-seven Vietnamese essential oils (EOs) were screened for their activity in vitro on Trypanosoma brucei brucei (Tbb) and cytotoxicity on mammalian cells (WI38, J774). Based on the selectivity indices (SIs), the more active and selective EOs were analyzed by gas chromatography. The anti-trypanosomal activity and cytotoxicity of some major compounds (isolated or commercial) were also determined. Our results showed for the first time the selective anti-trypanosomal effect of four EOs, extracted from three Zingiberaceae species (Curcuma longa, Curcuma zedoaria, and Zingiber officinale) and one Lauraceae species (Litsea cubeba) with IC50 values of 3.17 ± 0.72, 2.51 ± 1.08, 3.10 ± 0.08, and 2.67 ± 1.12 nL/mL respectively and SI > 10. Identified compounds accounted for more than 85% for each of them. Among the five major components of Curcuma longa EO, curlone is the most promising anti-trypanosomal candidate with an IC50 of 1.38 ± 0.45 µg/mL and SIs of 31.7 and 18.2 compared to WI38 and J774 respectively.

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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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Pedró-Rosa, Laura, Frederick S. Buckner, Ranae M. Ranade, Christina Eberhart, Franck Madoux, J. Robert Gillespie, Cho Yeow Koh, et al. "Identification of Potent Inhibitors of the Trypanosoma brucei Methionyl-tRNA Synthetase via High-Throughput Orthogonal Screening." Journal of Biomolecular Screening 20, no. 1 (August 27, 2014): 122–30. http://dx.doi.org/10.1177/1087057114548832.

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Improved therapies for the treatment of Trypanosoma brucei, the etiological agent of the neglected tropical disease human African trypanosomiasis, are urgently needed. We targeted T. brucei methionyl-tRNA synthetase (MetRS), an aminoacyl-tRNA synthase (aaRS), which is considered an important drug target due to its role in protein synthesis, cell survival, and its significant differences in structure from its mammalian ortholog. Previous work using RNA interference of MetRS demonstrated growth inhibition of T. brucei, further validating it as an attractive target. We report the development and implementation of two orthogonal high-throughput screening assays to identify inhibitors of T. brucei MetRS. First, a chemiluminescence assay was implemented in a 1536-well plate format and used to monitor adenosine triphosphate depletion during the aminoacylation reaction. Hit confirmation then used a counterscreen in which adenosine monophosphate production was assessed using fluorescence polarization technology. In addition, a miniaturized cell viability assay was used to triage cytotoxic compounds. Finally, lower throughput assays involving whole parasite growth inhibition of both human and parasite MetRS were used to analyze compound selectivity and efficacy. The outcome of this high-throughput screening campaign has led to the discovery of 19 potent and selective T. brucei MetRS inhibitors.

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Jones, Amy, Jean Rodgers, Barbara Bradley, and Peter Kennedy. "Novel forms of oral melarsoprol cure CNS stage Trypanosoma brucei brucei infection in a murine model of human African trypanosomiasis." BMC Proceedings 2, Suppl 1 (2008): P28. http://dx.doi.org/10.1186/1753-6561-2-s1-p28.

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Journal articles on the topic 'African trypanosomiasis. Dynein. Trypanosoma brucei'

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