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1
Rossi, B. C. "Macrophage function in African trypanosomiasis." Thesis, Brunel University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373784.
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Milligan, Paul. "Population dynamics of African trypanosomiasis." Thesis, University of Salford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306017.
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Smuts, Celia Margaretha. "Development of tools to improve the detection of Trypanoma evansi in Australia /." Murdoch University Digital Theses Program, 2009. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20090709.113425.
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Bailey, Wendi. "The diagnosis of human African trypanosomiasis." Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260319.
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Tchamo, Cesaltina da Conceicao Lopes Menete. "Evaluation of the pathogenicity in goats of Trypanosoma congolense from Matutuine, Mozambique." Pretoria : [s.n.], 2007. http://upetd.up.ac.za/thesis/available/etd-04212008-143822/.
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Ibrahim, Hasan Mohamed Saleh. "New therapeutic strategies against trypanosomiasis and leishmaniasis." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1158/.
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Leishmaniasis and African Trypanosomiasis are diseases caused by the Kinetoplastida parasites of Leishmania sp. and Trypanosoma sp. respectively. Control and management of these diseases, which affect a significant number of people in the tropics and subtropical areas of the world, is beset with numerous problems such as drug toxicity, affordability and the emergence and spread of parasites resistance to most of the routinely used drugs. This situation calls for an urgent search for new drugs that would address these concerns. Based on report of excellent antimicrobial activities against other parasites and the possession of other known good values, analogues of choline and curcumin were thoroughly assessed in this study for their potential as antitrypanosomal and antileishmanial drugs. Standard methods such as the Alamar Blue, propidium iodide and direct microscopy methods were used to determine the susceptibility of the parasites to the different analogues. Toxicity tests were performed to determine the effect of these compounds on Human Embryonic Kidney (HEK) cells. The presence of mediated transport of these compounds across the parasite plasma membrane was investigated using the classical uptake technique. In order to investigate the possible mechanism of antiparasitic action of the compounds, this study employed flow cytometry to assess the mitochondrial membrane potential Ym, as well as parameters such as production of reactive oxygen species (ROS), the permeability of the plasma membrane and any effects of the test copounds on the parasite’s cell cycle. Five out of 7 choline compounds tested in this study had EC50 values of 0.13-1.8 µM against T. brucei, 0.14-6.9 µM against L. major, L. mexicana promastigotes and 1.69-12.9 µM against L. mexicana amastigotes. With regard to the curcuminoid compounds, 35 out of 98 tested were observed to exhibit trypanocidal activity better than the original curcumin with EC50 values between 0.05 and 1 µM. Against Leishmania, most of the compounds displayed higher antiparasitic activity than curcumin but lower than observed against trypanosomes. The activity of choline analogues was very similar against L. mexicana and L. major promastigotes (P>0.05), and much higher than against L. mexicana amastigotes. Interestingly, some of the compounds displayed EC50 values below that of pentamidine, the routinely used drug. Assessment of parasite growth pattern in the presence of choline analogues showed that two of the compounds, T1 and MS1, are fast acting, killing the population of BSF T. b. brucei within 8 h with the onset of cell death at 2-4 hours of treatment. In contrast, the other three choline compounds observed to have antiparasitic activities acted more slowly, completely killing the trypanosome population after more than 30 hours of incubation. However, all the choline compounds appeared to rapidly inhibit trypanosome proliferation. The choline compounds exhibited low toxic effects against HEK cell line T29, with the selectivity index (S.I.) being high for some of the compounds. The curcumin compounds, too, were observed to have generally similar or lower toxicity against the human cells than the parent curcumin compound (AS-HK001), which in itself is not considered toxic and routinely used in food. Investigations on the toxicological and pharmacological effects of the curcumin compounds on the survival and the glutathione and protein content of primary murine hepatocytes showed no significant difference between hepatocyte cells treated with curcuminoid compounds AS-HK001, AS-HK009, and AS-HK014 compared with controls. We also investigated how choline and its analogues enter the trypanmosome. Evidence gathered in this study strongly suggests that unlike in Leishmania species and Plasmodium, choline transporters are not expressed in the bloodstream form of T. b. brucei. It was also conclusively shown that the P2, high affinity pentamidine transporter (HAPT) and low affinity pentamidine transporter (LAPT) do not play any significant role in the uptake of this compound. Lacking radiolabeled forms of the choline analogues, this study could not identify a definitive route of uptake of this class of compounds into the parasite. Analysis of cell cycle progression, by flow cytometry, showed trypanosomes in the G1, S, and G2/M stages. Curcuminoids do not appear to cause any important changes in the proportion of cells in G1, S or G2/M phase of the cell cycle. Cells exposed to various concentrations of some curcumin compounds, such as AS-HK014 and AS-HK096, showed a rapid increase in cell permeability, reaching between 80% and 90% in 4 hours. The permeability was observed to increase with increasing drug concentration and/or the incubation time. Investigations of cell membrane permeability also showed that choline analogues caused plasma membrane defects which could probably lead to cell death. With regard to the effect of the compound on mitochondrial membrane potential Ym the dicationic choline compounds, including M38, G25, T4 and MS1, were observed to have pronounced effects on Ym with an onset as early as 8 h of contact and we believe the mitochondria could be the main target of these compounds rather than indicating the induction of apoptosis, as the action of the test compounds was not associated with the production of reactive oxygen species. Indeed, both choline and curcumin analogues reduced the production of reactive oxygen species in T. b. brucei cultures. Furthermore, there were no major defects in choline phospholipid metabolism upon treatment with the choline compounds, suggesting that phospholipid metabolism is not the target of the anti-trypanocidal activity of these compounds. Preliminary results with infected ICR mice infected with T. b. brucei did not reveal significant in vivo activity of the three curcumin compounds on blood parasitemia when they were injected intra-peritoneally with two doses of 50 mg/kg body weight. With reference to evidence obtained in this study, it can firmly be concluded that analogues of choline and curcumin display highly promising antiparasitic activities and are generally non-toxic to human cells. Information provided in this thesis could therefore assist in the further development of these classes of compounds as lead compounds against kinetoplastid diseases. We strongly recommend that further investigation be carried out to understand the full mechanism of action of these compounds in order to facilitate this strategy.
7
Nyasulu, Yohane. "The study of human trypanosomiasis in Malawi." Thesis, University of Salford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304724.
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Isobe, Hiroyuki. "Medizin und Kolonialgesellschaft : die Bekämpfung der Schlafkrankheit in den deutschen "Schutzgebieten" vor dem Ersten Weltkrieg /." Berlin : Lit, 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?u20=9783825816032.
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9
Matemba, Lucas E. "Epidemiology of human African trypanosomiasis in western Tanzania." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/24915.
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This thesis started by reviewing the existing sleeping sickness historical records in Tanzania with the aim of exploring the evidence for the existence of Trypanosoma brucei gambiense in Tanzania. Findings from the available historical data did not provide sufficient evidence for the existence of T. b. gambiense sleeping sickness in Tanzania.The thesis further estimated under-reporting of T. b. rhodesiense in endemic areas of Tanzania using an established model. Using data from a 2000-2004 outbreak of T. b. rhodesiense in Urambo, the model predicts 46% underreporting. All unreported cases were assumed to be undetected deaths as sleeping sickness is invariable fatal if left untreated. These underreporting findings were then used to recalibrate the burden of T. b. rhodesiense (using Disability-Adjusted Life Years – DALYs), as a metric. The burden imposed to rural communities by rhodesiense sleeping sickness is high. The costs of hospitalization are very high considering the long duration of hospital stay (26 days mean hospital stay) for sleeping sickness patients. Finally the thesis investigated spatial and behavioural risk factors for T. b. rhodesiense sleeping sickness in Urambo district, through a matched case control study both at the village and within village scales. Statistically significant cluster was observed at the village level (P = 0.001). However there was no significant spatial association in an individual village’s analysis. There was an increased risk of sleeping sickness in homesteads with a previous history of the disease (P < 0.001). Presence of wild animals in the villages (P<0.001) and forest visits (P = 0.001) were also significantly associated with sleeping sickness in the district.
10
Stebeck, Caroline Elizabeth. "The identification and characterization of two unique membrane-associated molecules of African trypanosomes." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq21950.pdf.
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Mhlanga, Jama Donewell Mayixeke. "Antigenic variation in Trypanosoma brucei, a relationship with poly ADP-ribose polymerase." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240553.
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Majekodunmi, Ayodele. "Pastoral livelihoods and the epidemiology of emergent trypanosomiasis on the Jos Plateau, Nigeria." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/7834.
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African trypanosomiasis is a widespread disease of livestock which is a major constraint to livestock production, mixed farming and the rural economy. The Jos Plateau in Nigeria was historically free of tsetse flies and trypanosomiasis and this lack of disease attracted large numbers of cattle keeping pastoralists. The area now plays an important role in the national/regional cattle industry, holding 300,000 pastoralists and over a million cattle, ~ 7% of the national herd. However, over the past twenty years tsetse flies have (re)invaded the Jos plateau and trypanosomiasis is now a significant problem. Little is known about the distribution and overall prevalence of the disease across the Jos plateau or about the habits and customs that could affect the epidemiology of the disease in this area. This knowledge is essential if successful interventions to reduce its impact are to be put in place. To bridge this gap, a longitudinal two stage cluster survey was carried out in 2008 to determine the prevalence of bovine trypanosomiasis. The study showed that the prevalence of trypanosomiasis across the Jos plateau was 46.8% (39.0 – 54.5%) with no significant seasonal variation. T. b. brucei was present at a prevalence of 3.3% (1% – 5.5%); T. congolense savannah at a prevalence of 27.7% (21.8% - 33.6%); T. vivax at a prevalence of 26.7% (18.2% - 35.3%). Although there was no significant seasonal variation in prevalence across the Jos plateau, seasonal variations were observed at village level to create 3 distinct groups. Group 1 villages (50.0%) which followed the expected pattern of low prevalence in the dry season and high prevalence in the wet season; Group 2 villages (16.7%) where there was no seasonal variation; Group 3 villages (33.3%) where paradoxically the prevalence was higher in the dry season and lower in the wet season. This reversed epidemiological pattern is attributed to the harsh climatic conditions of the dry season which reduce resistance to infection in cattle and increase vector – host contact. Migration was shown to be a significant risk factor for trypanosomiasis infection and the dry season was shown to significantly increase the effect of all risk factors. Participatory rural assessment was also conducted to investigate socio – economic factors and knowledge, attitudes and practices concerning tsetse and trypanosomiasis. The results of the participatory rural assessment exercise show that trypanosomiasis is well recognised by farmers on the Jos plateau. They are aware of the animal health and production disadvantages associated with it and make considerable efforts to control it, along with other livestock diseases. However, they lack the adequate knowledge to effectively control these diseases themselves and there are gaps in veterinary service provision. Wealth ranking showed that the majority of pastoralists in the study were either in the ‘middle’ or ‘better – off’ groups. Only 6.1% were classed as poor. Anaemia as an indicator for trypanosomiasis was investigated and FAMACHA charts were evaluated as a potential penside test for anaemia. Results show that anaemia in cattle on the Jos Plateau is not strongly related to trypanosomiasis and that the FAMACHA chart is a poor test for anaemia in cattle.
13
au, ngiles@anhb uwa edu, and Natalie Giles. "Exploitation of the Protein Tubulin For Controlling African Trypanosomiasis." Murdoch University, 2005. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20060315.191003.
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This thesis presents the results of an investigation into the structural protein, tubulin, as a potential target for anti-trypanosomatid drug discovery and vaccine development. Recombinant alpha- and beta- tubulin proteins from Trypanosoma brucei rhodesiense were expressed as soluble fusion proteins in an E. coli expression system. The recombinant alpha- and beta- tubulins were used to determine the nature of binding of novel trifluralin analogues EPL-AJ 1003, 1007, 1008, 1016 and 1017. Native tubulin from rats was used to determine the extent of binding to mammalian tubulin. The results of this study clearly demonstrate two important aspects of the binding of trifluralins to tubulin. Firstly, they have specific affinity for trypanosomal tubulin compared with mammalian regardless of the chemical composition of the trifluralin analogue tested. Secondly, they have a demonstrably stronger affinity for alpha-tubulin compared with beta-tubulin. In addition, compounds 1007, 1008, 1016 and 1017 have strong binding affinities for alpha-tubulin, with limited binding affinity for mammalian tubulin, which indicates that these compounds selectively bind to trypanosomal tubulin.
The morphology of bloodstream forms of T. b. rhodesiense exposed to trifluralin analogues was studied using electron microscopy and immunofluorescence to determine the ultrastructural changes these compounds induce as a result of binding to tubulin. All compounds tested induced severe irreparable damage in T. b. rhodesiense, including perturbation of subpellicular microtubules, extensive cytoplasmic swellings, axoneme and paraflagellar rod malformation, disconfiguration around the flagellar pocket and membrane disintegration. These results suggest that the mechanism of action of these trifluralin analogues is through the disruption of polymerization of tubulin into microtubules as a result of binding to alpha-tubulin.
The potential for recombinant trypanosomal tubulins to be used as vaccine candidates was assessed by monitoring parasitaemia and length of survival of mice immunised with the proteins and challenged with a lethal infection of T. b. rhodesiense. Although all the mice vaccinated with recombinant tubulin developed a patent parasitaemia and did not survive, they were partially protected because their patency period and length of survival were significantly greater than the control groups. Furthermore, plasma collected from mice immunised with recombinant trypanosomal tubulin contained antibodies that recognized tubulin in a soluble extraction from T. b. rhodesiense. The results of this thesis confirm the potential for the structural protein, tubulin, to be used as a target for anti-trypanosomatid drug discovery and vaccine development.
14
Eltayeb, Ragaa Abdelkhalig. "Immunopathology and signalling molecules involved during experimental African trypanosomiasis /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4382-6/.
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Giles, Natalie Lydia. "Exploitation of the protein tubulin for controlling African trypanosomiasis /." Access via Murdoch University Digital Theses Project, 2005. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20060315.191003.
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Brownlow, Andrew C. "Evaluation of a novel method for controlling bovine trypanosomiasis." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/4930.
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The problem of controlling tsetse flies in Africa is an old one. The tsetse fly transmits the trypanosome parasites which cause sleeping sickness in humans and disease in cattle. Because cattle are a favoured food source for tsetse much work has been done looking at the use of insecticide treated cattle as a control strategy for the tsetse fly. Such treatment methods possess many advantages; they are safe and relatively environmentally benign, they can be applied by individual farmers without the need for logistically demanding and costly traditional control programmes and, in addition to tsetse flies the insecticides are effective against a wide range of other harmful cattle parasites. The cost of the insecticide is however a significant constraint to the number of livestock keepers who can afford to employ the technique and as a result many cattle remain untreated. Following the discovery that tsetse had a significant predilection for feeding on the legs and belly of cattle, it was hypothesised that restricting the insecticide to only those areas could offer comparable protection to treating the whole animal. Such an approach would use up to 80% less drug and thus make the treatment per animal much cheaper. In addition, preferentially targeting areas favoured by tsetse, and leaving the rest of the animal untreated, preserves some important ecological balances between cattle and their parasites which traditional treatment methods destabilise. This thesis describes the design, implementation and analysis of a longitudinal study run over 8 months in south east Uganda that sought to compare the effect of applying insecticide to cattle only on the regions favoured by tsetse flies. Cattle were recruited to the study and assigned one of four treatment groups; a whole body application of deltamethrin insecticide pour-on; a restricted application of deltamethrin spray, applied to the front legs, ears and belly; a prophylactic trypanocide injection of isometamidium chloride, and a control group, that received no further treatments. All animals in the study were however cleared using twin doses of a trypanocide diminazene aceturate at the start of the study.
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Acup, Christine Amongi. "Epidemiology and control of human African trypanosomiasis in Uganda." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/16246.
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Poverty and disease are bound together in rural communities of sub-Saharan Africa (SSA) exacerbated by weak social services and conflict. The infectious disease burden in SSA combines the neglected tropical diseases (NTDs) and the 'big three' (malaria, HIV/AIDS and tuberculosis), so-called because they attract more global attention and hence funding. NTDs include human African trypanosomiasis (HAT or sleeping sickness), first noticed by the outside world during the slave trade era and later in the 2-th century by widespread epidemics of disease across the tsetse fly belt. HAT describes two diseases: i) Gambian HAT caused by Trypanosoma brucei gambiense is characteristically chronic with an infectious period lasting up to three years and ii) Rhodesian HAT caused by T.b. rhodesiense is an acute disease, killing its victim within weeks of infection. The two diseases are frequently considered together as both are transmitted by tsetse flies, the parasites are morphologically indistinguishable and the associated diseases are both fatal if left untreated. However, the two diseases are clinical, epidemiologically and geographical distinct, each requiring different control strategies. Under field conditions, where microscopy is the basic diagnostic tool, differentiation is simply by geographical location of the patient; the Great Rift Valley separates the Gambian disease present in West and Central Africa, from East and southern Africa's Rhodesian disease. Control strategies are also distinct; while the Belgian and French colonial strategies to control the disease were patient-centred, the British colonial powers in East Africa were motivated by the effect of tsetse borne diseases on animal health. Towards the end of the colonial ear, both types of disease were heading for elimination but during the immediate post-colonial era in the 1960s, political instability compromised the rigid HAT control programs that had been put in place. For zoonotic Rhodesian sleeping sickness, complex tsetse control programmes proved difficult to maintain and to justify economically; for Gambian sleeping sickness the generalised breakdown of medical services allowed the disease to return, sometimes to devastating levels. The millennium development goals (MDGs) set out in 2000, highlighted specific challenges and opportunities for national and global development. HAT impacts national health goals of national development plans and MDGs and impedes rural development of SSA. NTDs were not addressed directly by MDGs but the World Health Organization (WHO) has reaffirmed its commitment not only to control of HAT but also to eliminate it as a public health problem by 2020. Currently there are 25 countries reporting HAT to WHO, and while the overall prevalence of HAT across Africa continues to fall, epidemics have been recorded, particularly from central Africa, South Sudan and Uganda. Uganda is uniquely, the only country affected by both T.b. gambiense and T.b. rhodesiense and until the present study, there was no evidence to suggest that the two parasite species co-existed in Uganda. The development of a new control paradigm for T.b. rhodesiese in South East Uganda has lowered the incidence of human infections and, more importantly, halted the northerly spread of this parasite. However, recurring epidemics in several established and new disease foci in central Uganda highlight the difficulties involved in eliminating this disease. The present study assesses past and present HAT control strategies centred on Dokolo, Kaberamaido and Soroti Districts located at the centre of Uganda. These districts are highly endemic for T.b. rodesiense, they represent the region of concern for overlap with T.b. gambiense foci in central Uganda, and are the current focus of the Stamp out Sleeping sickness control initiative. The point prevalence of T. brucei s.1 in cattle reservoir from villages with (out) reported human disease located at specific distances to Otuboi, Chagwere and Ochero cattle markets, was evaluated before and six months after trypanocidal treatment, to assess the transferrable impact of zoonotic T.b. rhodesiense to the human population. Overall, the proportion of T. brucei s.1 in cattle dropped significantly from 22% at baseline to 9% six months after trypanocide treatment (P < 0.05, Chi-square + 17.92, 95% C.I. + 1.71 to 4.49). All villages located in sub-counties that received at least 80% treatment coverage had a drop in T. brucei s.1 prevalence from 30.4% (95%, C.I + 22.8 to 38.0) before treatment was done, to 12.9% (95%, C.I. + 7.4 to 18.4) six months after treatment. More specifically, impact on human infective T.b. rhodesiense was also halved. In fact only three cattle were detected with the parasite six months after treatment compared with six from those sampled as baseline. This study also utilises documented cases between 2009 and 2012 to assess the current HAT reporting system for monitoring and evaluating transmission dynamics of the disease. Using a questionnaire, capacity and preparedness of healthcare professionals to respond to disease epidemics was assessed. The point prevalence of sleeping sickness in the three districts in 2009 was determined by screening volunteers. Microscopic examinations detected trypanosomes in four volunteers (4/5311 or 0.075 %) while PCR detected significantly more infections (24, p < 0.001). Multiplex PCR showed that ten of the Trypanozoon infections were T.b. rhodesiense while nested PCR identified four infections as T.b. gamiense, indicating that the distribution of the two forms of sleeping sickness overlaps in Uganda. Second phase investigations followed up the PCR positive cases; these people were screened again, together with members of their homestead and the inhabitants of three neighbouring homes. Besides microscopy and PCR, study subjects were examined clinically for sleeping sickness and completed a questionnaire to assess community recognition of the disease. This extended screen revealed no new cases underlining the importance of stringent early screening that PCR techniques can provide. At local healthcare centres, 54% of reported sleeping sickness cases were diagnosed only at the late stage, indicating a weakness in early diagnosis and hence early reporting. Interviews with local health workers also revealed weaknesses in recognition of clinical signs and a gap in diagnostic capacity. While records at treating hospitals remain a useful indicator for targeting active foci of infection, improvement in capacity to diagnose HAT at an early stage should contribute both to rural health and disease control strategies and also towards WHO's 2020 target of elimination of HAT.
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Giles, Natalie. "Exploitation of the protein tubulin for controlling African trypanosomiasis." Thesis, Giles, Natalie (2005) Exploitation of the protein tubulin for controlling African trypanosomiasis. PhD thesis, Murdoch University, 2005. https://researchrepository.murdoch.edu.au/id/eprint/40/.
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This thesis presents the results of an investigation into the structural protein, tubulin, as a potential target for anti-trypanosomatid drug discovery and vaccine development. Recombinant alpha- and beta- tubulin proteins from Trypanosoma brucei rhodesiense were expressed as soluble fusion proteins in an E. coli expression system. The recombinant alpha- and beta- tubulins were used to determine the nature of binding of novel trifluralin analogues EPL-AJ 1003, 1007, 1008, 1016 and 1017. Native tubulin from rats was used to determine the extent of binding to mammalian tubulin. The results of this study clearly demonstrate two important aspects of the binding of trifluralins to tubulin. Firstly, they have specific affinity for trypanosomal tubulin compared with mammalian regardless of the chemical composition of the trifluralin analogue tested. Secondly, they have a demonstrably stronger affinity for alpha-tubulin compared with beta-tubulin. In addition, compounds 1007, 1008, 1016 and 1017 have strong binding affinities for alpha-tubulin, with limited binding affinity for mammalian tubulin, which indicates that these compounds selectively bind to trypanosomal tubulin.
The morphology of bloodstream forms of T. b. rhodesiense exposed to trifluralin analogues was studied using electron microscopy and immunofluorescence to determine the ultrastructural changes these compounds induce as a result of binding to tubulin. All compounds tested induced severe irreparable damage in T. b. rhodesiense, including perturbation of subpellicular microtubules, extensive cytoplasmic swellings, axoneme and paraflagellar rod malformation, disconfiguration around the flagellar pocket and membrane disintegration. These results suggest that the mechanism of action of these trifluralin analogues is through the disruption of polymerization of tubulin into microtubules as a result of binding to alpha-tubulin.
The potential for recombinant trypanosomal tubulins to be used as vaccine candidates was assessed by monitoring parasitaemia and length of survival of mice immunised with the proteins and challenged with a lethal infection of T. b. rhodesiense. Although all the mice vaccinated with recombinant tubulin developed a patent parasitaemia and did not survive, they were partially protected because their patency period and length of survival were significantly greater than the control groups. Furthermore, plasma collected from mice immunised with recombinant trypanosomal tubulin contained antibodies that recognized tubulin in a soluble extraction from T. b. rhodesiense. The results of this thesis confirm the potential for the structural protein, tubulin, to be used as a target for anti-trypanosomatid drug discovery and vaccine development.
19
Giles, Natalie. "Exploitation of the protein tubulin for controlling African trypanosomiasis." Giles, Natalie (2005) Exploitation of the protein tubulin for controlling African trypanosomiasis. PhD thesis, Murdoch University, 2005. http://researchrepository.murdoch.edu.au/40/.
Full textAbstract:
This thesis presents the results of an investigation into the structural protein, tubulin, as a potential target for anti-trypanosomatid drug discovery and vaccine development. Recombinant alpha- and beta- tubulin proteins from Trypanosoma brucei rhodesiense were expressed as soluble fusion proteins in an E. coli expression system. The recombinant alpha- and beta- tubulins were used to determine the nature of binding of novel trifluralin analogues EPL-AJ 1003, 1007, 1008, 1016 and 1017. Native tubulin from rats was used to determine the extent of binding to mammalian tubulin. The results of this study clearly demonstrate two important aspects of the binding of trifluralins to tubulin. Firstly, they have specific affinity for trypanosomal tubulin compared with mammalian regardless of the chemical composition of the trifluralin analogue tested. Secondly, they have a demonstrably stronger affinity for alpha-tubulin compared with beta-tubulin. In addition, compounds 1007, 1008, 1016 and 1017 have strong binding affinities for alpha-tubulin, with limited binding affinity for mammalian tubulin, which indicates that these compounds selectively bind to trypanosomal tubulin.
The morphology of bloodstream forms of T. b. rhodesiense exposed to trifluralin analogues was studied using electron microscopy and immunofluorescence to determine the ultrastructural changes these compounds induce as a result of binding to tubulin. All compounds tested induced severe irreparable damage in T. b. rhodesiense, including perturbation of subpellicular microtubules, extensive cytoplasmic swellings, axoneme and paraflagellar rod malformation, disconfiguration around the flagellar pocket and membrane disintegration. These results suggest that the mechanism of action of these trifluralin analogues is through the disruption of polymerization of tubulin into microtubules as a result of binding to alpha-tubulin.
The potential for recombinant trypanosomal tubulins to be used as vaccine candidates was assessed by monitoring parasitaemia and length of survival of mice immunised with the proteins and challenged with a lethal infection of T. b. rhodesiense. Although all the mice vaccinated with recombinant tubulin developed a patent parasitaemia and did not survive, they were partially protected because their patency period and length of survival were significantly greater than the control groups. Furthermore, plasma collected from mice immunised with recombinant trypanosomal tubulin contained antibodies that recognized tubulin in a soluble extraction from T. b. rhodesiense. The results of this thesis confirm the potential for the structural protein, tubulin, to be used as a target for anti-trypanosomatid drug discovery and vaccine development.
20
Liu, Yajuan. "A role of sympathetic nervous system in immunomodulation of early experimental African trypanosomiasis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-113-X/.
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Kaushik, Radhey Shyam. "Macrophage cytokines as correlate of differential resistance to African trypanosomiasis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0014/NQ37893.pdf.
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Gould, Matthew K. "Putative phosphodiesterase inhibitors as potential new chemotherapies against African Trypanosomiasis." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1410/.
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African trypanosomiasis is a disease caused by the Kinetoplastida parasites Trypanosoma brucei rhodesiense and T. b. gambiense. The distribution of the disease is split geographically with T. b. rhodesiense found in eastern sub-Saharan Africa and T. b. gambiense in the west of the continent. Current treatment for this fatal disease is wholly unsatisfactory with problems such as extreme toxicity, affordability and the emergence of resistance. The case for the generation of new potential chemotherapies is compelling and urgent. Phosphodiesterase (PDE) enzymes degrade the secondary signalling molecule cyclic adenosine monophosphate (cAMP) to AMP by hydrolysis, thereby modulating and regulating the signal transduction to the effector proteins. The phosphodiesterase enzymes in the PDEB family in T. brucei were shown to be essential to the host-infective bloodstream forms and validated as good drug targets using RNA-interference (Zoraghi, R. and Seebeck, T., 2002; Oberholzer, M., 2007). Prompted by these findings, two series of putative trypanosomal PDE inhibitors, from different sources, were thoroughly assessed in this project for their anti-trypanosomal activity and their intracellular effects on the trypanosome. The whole-cell in vitro efficacy for each compound, against T. brucei wildtype and the drug-resistant strain TbAT1 knockout, was established by the standard resazurin reduction assay. 25 compounds from Series 1 had EC50 values below 0.5 µM, with 7 under 100 nM and the most active having an EC50 value of 5.8 ± 3.4 nM. For the much smaller Series 2 (GJS Compounds), the most active compound was GJS-128 with an EC50 value of 79.4 ± 10.3 nM. This demonstrates that a number of compounds from both series have potent in vitro activity against trypanosomes that is better than or equal to the current chemotherapeutic compound diminazene, and some Series 1 compounds are on a par with pentamidine and melarsoprol. No major cross-resistance was displayed by the TbAT1 knockout strain to either Series 1 or the GJS series. Similarly, a panel of Series 1 compounds tested against the B48 strain (resistant to pentamidine and melaminophenyl arsenical drugs), and also against Trypanosoma equiperdum wildtype and diminazene resistant (PBR) strains, showed no major cross-resistance displayed by the other resistant strains. This suggests that there would also be little or no cross-resistance from refractory strains in the field, and also that the compounds are active against multiple Trypanosoma species. A small panel of Series 1 compounds were also tested for efficacy against trypanosomes in infected mice. 4 daily doses of 20 mg/kg bodyweight of Compound 48 significantly reduced parasitaemia by approximately 60% compared to untreated controls, however higher concentrations were not tolerated by the mice so a cure could not be demonstrated. A high-throughput method for monitoring the speed of action of test compounds on trypanosomes in real time was developed, based on the fluorescence of propidium iodide when bound with DNA. Optimisation of the protocol to 96-well plates and low cell densities provided higher resolution and accurate traces of the lysis of trypanosomes in a cell suspension compared to previously used methods, as well as a greatly increased capacity. The propidium iodide assay could also be converted to provide end-point EC50 values that were directly comparable to those established by the standard resazurin reduction assay. The majority of Series 1 compounds did not increase the intracellular concentration of cAMP on incubation with bloodstream form trypanosomes; those that did only induced a minor elevation of the intracellular concentration of the signalling molecule. Since genetic disruption to phosphodiesterase enzymes resulted in large increases in cAMP levels (Oberholzer, M. et al, 2007; Zoraghi, R. and Seebeck, T., 2002), the lack of increase in cAMP by the Series 1 compounds strongly suggest that they do not sufficiently inhibit the PDEs in live trypanosomes and kill the cells via an alternative pathway. In contrast, incubation with the GJS compounds did result in significant increases in intracellular cAMP concentration with the most active being GJS-128 recording an approximately 3-fold increase in cAMP over 3 hours at just 30 nM. The concentrations that begin to increase cAMP level are consistent with the EC50 values for trypanosomes cultured in vitro (this study), and is also in line with inhibition data of recombinant TbrPDEB enzymes (work conducted by Dr. Herrmann Tenor, ALTANA Pharma, and Prof. Thomas Seebeck, University of Bern). This gives a clear and consistent link between the cause of cAMP rise (inhibition of PDEB by GJS compounds) and the effect of that concentration increase on bloodstream form trypanosomes (cell death), demonstrating that the GJS series are inhibitors of trypanosomal PDEs and chemically validate PDEs as drug targets for potential new chemotherapies against African trypanosomiasis. The effect of PDE inhibition on the physiology of the bloodstream form trypanosomes was also investigated. Flow cytometry analysis and the assessment of DNA configuration by fluorescence microscopy after DAPI staining determined that PDE inhibition by GJS-128 resulted in a precise block of the cell cycle in cytokinesis. The replicating trypanosome synthesized and segregated its DNA into two nuclei and kinetoplasts as normal and proceeded to initiate the physical separation of mother and daughter cells. The cleavage furrow between the old and new flagella progressed normally until the point of abscission, at which point division was halted with only a small section of plasma membrane connecting the two almost separated cells. Both cells appeared viable and underwent subsequent rounds of DNA replication, segregation and attempted physical separation that was always blocked near completion. This indicates cAMP signalling plays an important role in the correct physical separation of the replicating bloodstream form trypanosomes. A trypanosome cell line resistant to GJS-128 was developed by chemical mutagenesis and continuous culture with gradually increasing, but sub-lethal concentrations of the PDE inhibitor. This cell line, termed R0.8, was >15-fold less sensitive to GJS-128 and displayed significant cross-resistance to the other GJS compounds, as well as to stable, membrane permeable cAMP analogues. The mode of resistance was investigated by comparing the cAMP profile of the R0.8 and parental wildtype strains on incubation with GJS-128. No major differences were observed suggesting that both the adenylyl cyclase and phosphodiesterase activities remained unchanged in the PDE inhibitor-resistant strain. In support of this, the sequencing of TbrPDEB1 and TbrPDEB2 in both strains, while uncovering the loss of heterozygosity in the R0.8 line, revealed no mutations that would impact on enzyme function or inhibitor binding in the resistant cell line. These data strongly suggest that the adaptation resulting in resistance to PDE inhibitors is located in the effector proteins downstream of the PDEs and adenylyl cyclases in the cAMP signalling pathway. Identifying a compound that inhibits phosphodiesterases in trypanosomes and elevates cAMP concentrations, along with the generation of a PDE inhibitor-resistant cell line will allow more detailed examination of all aspects of the cAMP signalling pathway in T. brucei and across the Kinetoplastida. Phosphodiesterases have also been demonstrated to be chemically inhibitable in trypanosomes and could prove to be the target of a new generation of chemotherapies against African trypanosomiasis.
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Giordani, Federica. "New approaches to fluorescence-based diagnostics for human African trypanosomiasis." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2454/.
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In the absence of any vaccine, prophylactic drug and effective vector control, the fight against human African trypanosomiais (HAT) is based on the the combination of active case-finding and consequent drug treatment of identified positive cases. Unfortunately, low sensitivity and specificity of current diagnostic techniques often result in misdiagnosis, leaving infected patients without cure or exposing them to inappropriate chemotherapy protocols, which use dangerous and expensive drugs. The development of more efficient, simple, cheap and field-robust diagnostic tests is, therefore, urgently needed. In the field, direct observation by light microscopy of trypanosomes in human fluids (blood, lymph node aspirate, cerebrospinal fluid) is considered the ideal way of confirming HAT infection. However, in practice this approach is problematic, especially for the Gambian form of the disease, where patients may present with very low parasitaemia. Detection limits of parasitological techniques can be improved by adding a preliminary step of sample concentration, although this further increases the laboriousness of HAT diagnostic algorithm. Recent advances in fluorescence microscopy could be exploited to facilitate trypanosome detection. The introduction and implementation of fluorescence microscopy in HAT endemic countries would offer the advantages of an increased overall sensitivity of microscopical examination and a more rapid screening of the specimen. In contrast to traditional, expensive and fragile fluorescence microscopes, new LED-illuminated instruments are relatively cheap, very efficient and portable, lending themselves to utilisation in poorly equipped rural settings. In order to design a new diagnostic tool that exploits LED technology, however, selective and reliable fluorescent markers to label trypanosomes in human fluids are needed. The development of new tools to assist in the diagnosis of African trypanosomiasis by use of LED fluorescence microscopy was the overall objective of this project. The work was mainly focused on testing various fluorescent compounds for their ability to selectively stain trypanosomes. Fluorophores were otained from commercial and academic sources, or else directly synthesised during the project. An important requirement evaluated was the compounds’ compatibility with the currently available SMR LED Cytoscience fluorescence microscope, developed and kindly provided by our collaborator Prof. D. Jones (Philipps University, Marburg). The utility of a UV LED-driven microscope in performing the arsenical drug resistance test was also assessed. This assay, developed in our laboratory to detect trypanosome strains resistant to arsenical and diamidine compounds, could represent a useful tool for chemotherapeutic decision making in the field, where resistance to arsenical drugs is a rising problem.
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Peregrine, Andrew Seaton. "Factors influencing the duration of isometamidium prophylaxis against bovine trypanosomiasis." Thesis, University of Glasgow, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305789.
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Gichuki, Charity Wangui. "The role of astrocytes in the neuropathogenesis of African trypanosomiasis." Thesis, University of Glasgow, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294595.
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Amadou, Ibrahim Ahamed. "Economics of animal trypanosomiasis control in the Adamawa Plateau, Cameroon." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319241.
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Barrett, John Charles. "Economic issues in trypanosomiasis control : case studies from Southern Africa." Thesis, University of Reading, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385554.
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Sullivan, Lauren. "Discovery and development of diagnostic biomarkers for human African trypanosomiasis." Thesis, University of Dundee, 2012. https://discovery.dundee.ac.uk/en/studentTheses/e6c3197a-849b-4148-8326-58a2b13f5072.
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Human African Trypanosomiasis (HAT) or African Sleeping Sickness is a disease prevalent in many parts of Sub-Saharan Africa. HAT is a parasitic infection caused by two species, Trypanosoma brucei gambiense and T. b. rhodesiense. Clinical diagnosis is not sufficient as symptoms from other endemic diseases, such as Malaria, are similar. Currently the diagnosis of T. b. gambiense infection mainly relies on the Card Agglutination Test for Trypanosomiasis (CATT), which has severe limitations. Other diagnostic tests for T. b. gambiense and T. b. rhodesiense infections require lab based equipment, trained personnel and have varying degrees of sensitivity and specificity. New approaches are needed, firstly to identify new diagnostic biomarkers, and secondly to find a more suitable platform for the test. Our aim was to develop a lateral flow test based on trypanosome antigens. We used sera from T. b. gambiense infected and non-infected patients to identify infection specific diagnostic trypanosome proteins. The trypanosome proteins identified were then cloned into E. coli for recombinant expression and purification. The recombinant proteins were then screened by ELISA against 145 patients’ sera from the WHO HAT specimen bank. Invariant Surface Glycoprotein (ISG) 65 and a soluble Variant Surface Glycoprotein (VSG) were selected for development into a lateral flow format and 80 randomised patients’ sera were used to evaluate these prototypes. Here we describe the results showing that un-optimised proto-type lateral flow tests match the reported CATT sensitivity and specificity scores.
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Fèvre, Eric M. "The epidemiology of trypanosomiasis, a re-emerging zoonosis in Uganda." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/29756.
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Cattle market data shows that in Soroti, 54% of animals traded in the market in question originated from outside the district, from known sleeping sickness risk areas, and that up to 12.5% of the monthly imports from these areas may have been carriers of T.b. rhodesiense parasites. The theoretical impact that the alternative control options of mass chemotherapy or selective treatment following screening by microscopy would have had on reducing this risk are also considered, highlighting the limitations of field microscopy as a diagnostic tool for trypanosomiasis. Results from the case-control study showed that the epicentre of the outbreak which started in 1998 was Brookes Corner cattle market, the site through which most of the cattle in the restocking programme passed. Although residence in a village in proximity to the market was a highly significant risk factor for becoming a sleeping sickness case at the start of the outbreak, the average distance of cases to the market increased with time, indicating that the outbreak is expanding away from that point source. The results of the molecular analyses confirm that the parasites circulating in Soroti were similar to strains from the established sleeping sickness regions further south in Uganda, and shed further light on the nature of trypanosome population structures. The results are discussed in relation to the management of human trypanosomiasis in the cattle reservoir, with particular attention given to the implications of trypanosomiasis control policies aimed at livestock but which also benefit the health of the human population. Policies aimed at controlling disease in this way need to be made at a national level, and the importance of collaboration between medical and veterinary authorities for zoonotic disease control is stressed.
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Park, Suh Yeong. "Modeling Tsetse Fly Host Preference and African Trypanosomiasis in Cameroon." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1306862287.
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Mabbott, Neil A. "Nitric oxide : host-protective or host-destructive during African trypanosomiasis." Thesis, University of Aberdeen, 1995. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU543723.
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The aims of the research presented in this thesis were concerned with investigating the effect of inducible nitric oxide (NO) synthase expression during Trypanosoma brucei infections on both host and parasite. NO was shown to exhibit a potent cytostatic effect on parasite proliferation. Oxyhaemoglobin is a potent scavenger of NO. The cytostatic effects of NO on the trypanosomes were completely prevented through the addition of erythrocytes to the cultures. This implies that in the host blood-stream, NO is unlikely to be involved in the eradication of the parasites. Through the adoptive transfer of suppressor macrophages from T.brucei-infected donor mice to naive recipients, it was demonstrated that NO mediates a suppressive effect on host lymphocyte responses in vivo. Furthermore, suppressor macrophages were shown to have a finite life-span and undergo NO-mediated apoptosis. Evidence also suggested that elevated NO production in the bone marrow of T.brucei -infected mice is likely to play a significant role in the anaemia resulting from T.brucei infection. Experiments demonstrated that a soluble lysate prepared from freeze-thawed blood-stream form T.brucei, activated interferon (IFN)-gamma primed macrophages to express high levels of NO synthase. Experiments also demonstrated that viable blood-stream forms, but not procyclic form trypanosomes, released a soluble factor which in combination with IFN-gamma induced NO synthase. The absolute requirement of IFN-gamma priming for NO synthase activation by T.brucei was studied using macrophages from mutant mice lacking functional IFN-gamma receptors (IFN-gamma R -/- mutant mice). In comparison to macrophages from wild-type mice, cells from IFN-gamma-R-/- mutant mice were unable to produce NO following stimulation in vitro or infection in vivo. Finally, utilising mice with specific immunodeficiencies it was demonstrated that natural killer cells and a/b T-lymphocytes were important sources of IFN-gamma during murine T.brucei infections.
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Jaye, Assan. "Characterisation of Trypanosoma (Nannomonas) congolense-specific antigen : identification as a thiol protease precursor." Thesis, Brunel University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296197.
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Middendorf, Barbara. "Einfluss von Melarsoprol in der Therapie der afrikanischen Trypanosomiasis auf den Glukosemetabolismus des Menschen." Doctoral thesis, kostenfrei, 2008. http://nbn-resolving.de/urn/resolver.pl?urn=nbn:de:bvb:20-opus-28312.
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Whitecavage, Kellie Ann. "The characterization of a novel and essential trypanosome protein." Click here for download, 2008. http://proquest.umi.com/pqdweb?did=1490081941&sid=1&Fmt=2&clientId=3260&RQT=309&VName=PQD.
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Guegan, Fabien. "Caractérisation des sialidases chez le parasite Trypanosoma vivax : rôle dans l’anémie." Thesis, Bordeaux 2, 2010. http://www.theses.fr/2010BOR21775/document.
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La trypanosomiase animale africaine (TAA) est une pathologie qui sévit en Afrique sub-saharienne et qui représente un obstacle majeur à l’élevage du bétail et à la production agricole. Cette pathologie est causée principalement par les parasites T. congolense et T. vivax. Elle affecte le bétail, les animaux domestiques et sauvages, sur un territoire de 10 millions de km2 où ces animaux cohabitent avec l’insecte vecteur, la mouche Tsé-Tsé. L’infection du bétail par ces parasites provoque une anémie sévère pouvant entraîner la mort de l’animal. Dans ce contexte, nous nous sommes intéressés à l’étude des mécanismes impliqués dans le développement de l’anémie lors de l’infection de l’animal par T. vivax. Pour cela, nous avons développé un modèle murin d’infection par T. vivax. Nous avons démontré que l’infection à T. vivax induit d’importantes modifications des acides sialiques présents à la surface des érythrocytes. De plus, nous avons établi un système expérimental « ex-vivo » qui nous a permis de montrer que l’anémie observée au cours de l’infection était dépendante du mécanisme d’érythrophagocytose. Les modifications en acides sialiques des érythrocytes constitueraient un signal de reconnaissance des érythrocytes par les cellules phagocytaires de l’hôte. Par ailleurs, nous avons mis au point des conditions de culture in vitro pour tous les stades parasitaires de T. vivax et T. congolense afin de développer des outils de génomique fonctionnelle. Ces avancées nous ont notamment permis d’identifier des enzymes de type sialidase et trans-sialidase et de détecter les activités enzymatiques correspondantes dans les formes infectieuses de ces parasites. Nous avons exprimé des trans-sialidases recombinantes et démontré qu’elles étaient capables de reproduire in vitro certaines des caractéristiques pathologiques définies in vivo : modifications en acides sialiques des érythrocytes et augmentation de l’érythrophagocytose. Par conséquent, ces travaux ont permis pour la première fois de mettre en évidence un lien entre l’expression des sialidases et trans-sialidases chez le parasite T. vivax et le développement de l’anémie au cours de la TAAAfrican animal trypanosomiasis (AAT) is a parasitic disease occurring in sub-Saharan Africa. It impairs livestock development and agricultural production. This disease is mainly caused by T. congolense and T. vivax parasites and is present in livestock, domestic and wild animals, covering an area of over a 10 millions km2, that is known as the Tsé-Tsé fly belt. These infections cause severe anaemia leading to animal death in most cases. In this context, we were interested in unravelling the mechanisms responsible for anaemia caused by T. vivax infection. We developed a murine model for T. vivax infection and our data pointed out important sialic acid modifications of the mouse erythrocyte surface during infection. Additionally, an ex-vivo experimental model was established which proved that anaemia associated with infection depends on erythrophagocytosis. Consequently, we propose that sialic acid modifications associated with infection are involved in the erythrophagocytosis mechanism. Furthermore, in order to develop genetic tools we established in vitro culture conditions for all parasite forms of T. vivax and T. congolense. Parasite cultivation allowed the detection of sialidase and trans-sialidase activity and identifies the presence and function of these proteins in the mammalian form of the parasite. Moreover, trans-sialidase recombinant proteins reproduced some of the T. vivax infection characteristics such as sialic acid modification and increased erythrophagocytosis. Consequently, this work provides the first evidence that links the expression of sialidases and trans-sialidases in T. vivax with the development of anemia during AAT
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Akiode, Olukemi Adejoke. "Examination and management of human African Trypanosomiasis propagation using geospatial techniques." Thesis, Abertay University, 2014. https://rke.abertay.ac.uk/en/studentTheses/9419b401-6604-4530-9938-57ab03234e67.
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Human African Trypanosomiasis (HAT) is a vector-borne disease transmitted by the bite of the tsetse fly that results in high human morbidity and mortality. The propagation of the disease has been linked to environmental factors, and understanding the vector’s habitat is vital to its control. There is no HAT vaccine, but biological control of the vector has been successful in reducing HAT incidence. However, in recent years the disease has re-emerged and spread. Due to insufficient knowledge of HAT endemic foci, the disease management remains challenging. To achieve effective deployment of control strategies, accurate knowledge of the spatial distribution of the HAT vector is vital. The current study is based in Nigeria, and looks at part of Delta State, and a part of Jigawa State, in which HAT has been identified. The work utilizes remote sensing satellite imaging and fuzzy logic to develop a HAT vector habitat classification scheme, to explore the dynamics of HAT propagation. The goal was to develop a surveillance methodology to identify factors that influence HAT epidemiology. Land cover and ancillary data were integrated to classify HAT vector habitat using geospatial-fuzzy multicriteria analysis. The work highlights the significance of geospatial techniques where epidemiological data are limited, for improving understanding of HAT. This study helped distinguish HAT vector habitat into different zones (breed, feed and rest), which allowed the direction and magnitude of HAT, a n d factors influencing propagation to be determined. This helped identify ‘HAT priority intervention areas’. The study findings suggested propagation of HAT resulted from suitability of water bodies, shrub and less-dense forest for the HAT vector, and continued exposure of human populations to these land cover classes. Overlapping of HAT vector habitat zones within built-up areas was also a cause. The study also found that HAT propagation was multidirectional, and that this may have been influenced by landscape characteristics. This novel approach can also be used in other part of Nigeria as well as adapted to investigate other diseases. In conclusion, the HAT vector habitat classification scheme is a transparent tool for policy makers for identifying vulnerable and at risk areas.
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Hamadien, Maha. "Parasite signalling and host responses in experimental and human African trypanosomiasis /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-266-3.
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Msangi, Atway. "Fluorescent pigments and age determination in tsetse fly vectors of trypanosomiasis." Thesis, Bangor University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332333.
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Anderson, Neil Euan. "Investigation into the ecology of trypanosomiasis in the Lungawa Valley, Zambia." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4392.
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The Luangwa Valley is recognised as a focus of endemic infection with human sleeping sickness caused by Trypanosoma bruceirhodesiense. Extensive infection of the wildlife population with many species of trypanosome has been identified and livestock keeping is almost non-existent due to losses from trypanosomiasis and predation by wild animals. The aim of this study was to investigate the ecology of trypanosomiasis in this mult-host wildlife community, relatively free from anthropogenic influences. Particular focus was to be applied to the role of common warthog, phacocoerus aethipicus, within the reservoir community. The thesis initially reviews the history of protected area management in the Luangwa Valley. Remotely sensed imagery is then used in a study of the vegetation units of Luambe National Park. A supervised classification algorithm utilising fuzzy logic is used to generate a land cover classification of the part with an overall accuracy of 71%. Surveys of the tsetse and wild mammal population in Luambe national park are then presented. Data collected from the tsetse survey are analysed using generalised linear models with mixed effects to investigate factors influencing the trypanosome prevalence in tsetse, as well as the distribution and apparent density of tsetse. The density of tyhe host mammal population is assessed using distance sampling techniques and the distribution of warthog burrows mapped. Finally, a cross-sectional survey of trypanosome prevalence in the wild animal population of the Luangwa Valley is described, using novel molecular techniques for diagnosis. Risk factors for infection are analysed using logistic regression analysis and the host distribution for each trypanosome species described.
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Esena, Reuben K. "Studies on cattle trypanosomiasis in the coastal savannah zone of Ghana." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367520.
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Jones, Amy. "Melarsoprol cyclodextrin inclusion complexes for the treatment of human African trypanosomiasis." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2713/.
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Human African trypanosomiasis (HAT) is a parasitic disease caused by the protozoan parasites T. b. rhodesiense and T. b. gambiense. The disease is currently endemic in 36 sub-Saharan countries with an estimated 60 million people at risk from the infection. The disease progresses through two stages; an early or haemolymphatic stage where the parasites are confined to the peripheral compartment and a late or encephalitic stage where the parasites penetrate the blood-brain barrier (BBB) and invade the CNS. Without treatment the disease is invariably fatal but at present chemotherapy is reliant on a small handful of drugs. Pentamidine and suramin are available for the treatment of the early stage of the disease while the CNS stage of the disease is treated with a combination of nifurtimox and eflornithine known as NECT therapy or melarsoprol. NECT therapy is only effective in the treatment of T. b. gambiense infections meaning treatment of T. b. rhodesiense infections is completely dependant on the trivalent arsenical melarsoprol. Melarsoprol is an extremely toxic compound, the administration of which is very painful and associated with numerous adverse reactions. The most series of which is a post treatment reactive encephalopy (PTRE). The PTRE occurs in up to 10% of all patients given melarsoprol of which 50% die as a result of the complication. This gives melarsoprol an overall fatality rate of 5% which is unacceptably high. There is therefore an urgent need for new trypanocides, which are safe and easily administrable. To improve the physiochemical and pharmacokinetic properties of melarsoprol the drug was complexed with two cyclodextrin molecules, hydroxypropyl-cyclodextrin (HPCD) and randomly methylated-cyclodextrin (RAMCD) to produce; mel/HPCD and mel/RAMCD. Cyclodextrins are cyclic oligosaccharides, widely used within the pharmaceutical industry to improve the solubility and oral bioavailability of poorly soluble lipophilic drugs. In this study, the trypanocidal activity of the melarsoprol cyclodextrin complexes was investigated in-vitro and in an in-vivo CNS stage model of T. b. brucei infection. The trypanocidal activity of melarsoprol is retained following its complexation with HPCD and RAMCD. The in-vitro trypanocidal activity of the melarsoprol cyclodextrin complexes against bloodstream T. b. brucei trypanosomes was comparable to that of contemporary melarsoprol. Furthermore, in an in-vivo murine model of CNS stage T. b. brucei the melarsoprol cyclodextrin complexes, mel/HPCD and mel/RAMCD produced 100% cure rates when administered orally at a dose of 0.05mmol/kg, daily, for seven consecutive days. Contemporary melarsoprol when administered by the same route and schedule only cured 33.3% of the animals. The cyclodextrins HPCD and RAMCD thus increase the oral bioavailability of melarsoprol whilst retaining the compounds trypanocidal activity. An oral administrable, water soluble formulation of melarsoprol instantly eliminates the problems associated with the intravenous administration of conventional melarsoprol. Furthermore, an orally available formulation would be of great benefit in the resource poor, isolated settings in which HAT occurs, as patients would not require hospitalisation during treatment thus alleviating the pressure on local hospitals. In the current investigation quantitative taqman PCR was utilised to investigate the rate of parasite clearance from the CNS during complexed melarsoprol treatment. Both mel/HPCD and mel/RAMCD were rapidly trypanocidal. Twenty-four hours after administration of one dose the number of trypanosomes within the brain was reduced by greater than 80% and all trypanosomes were eliminated from the brain by twenty-four hours after administration of four doses of mel/HPCD and five doses of mel/RAMCD. The elimination of all trypanosomes from the CNS following four doses of mel/HPCD and five doses of mel/RAMCD, indicates that it may be possible to reduce the dosage schedule from seven daily doses to four daily doses of mel/HPCD and five doses of mel/RAMCD. A short, simple, easily administrable treatment protocol is an essential requirement of any new trypanocide as if the treatment schedule is prolonged and complicated patients are unlikely to comply. CNS stage trypanosome infection is associated with a breakdown of the blood-brain barrier (BBB). Ideally following successful chemotherapy BBB function should be restored. In this investigation the effect of curative mel/HPCD treatment on the BBB was investigated in a murine model of CNS T. b. brucei infection using small bore MRI analysis. Mel/HPCD treatment results in a rapid restoration of BBB function as by twenty-four hours after the completion of mel/HPCD therapy the integrity of the BBB was fully restored. However, a very mild neuroinflammatory reaction persisted in the brain for up to fifteen days after completion of chemotherapy. This suggests that the BBB damage observed in trypanosome infection may be due to either the parasites directly or their secretory products and not as a result of the ongoing neuroinflammatory reaction. Despite melarsoprol being in use for over 60 years its pharmacokinetics are poorly understood and a sensitive assay by which to quantify the concentration of arsenic reaching tissues following administration of the compound is not available. In this study a gas chromatography mass spectrometry (GC-MS) technique was developed to quantify the concentration of arsenic reaching the plasma and brain following oral and intravenous administration of the melarsoprol cyclodextrin complexes, mel/HPCD and mel/RAMCD. The GC-MS assay had a limit of detection of 5ng/ml and a precision (expressed as the inter-day coefficient of variation) of 13.2%. The concentration of arsenic within the brain following the oral and intravenous administration of mel/HPCD was below the limit of quantification of the assay. The pharmacokinetics of mel/HPCD and mel/RAMCD could therefore not be determined in the present study. This study demonstrates that the melarsoprol cyclodextrin complexes mel/HPCD and mel/RAMCD are highly trypanocidal with no overt signs of toxicity and more importantly orally available. Following the oral administration of mel/HPCD or mel/RAMCD the melarsoprol is slowly released over a prolonged period of time from the cyclodextrin cavity. Patients are therefore not exposed to a ‘bolus’ of the drug as is the case in the intravenous administration of contemporary melarsoprol. The slow and sustained release of melarsoprol from the cyclodextrins should result in less adverse reactions and a decreased incidence of the PTRE. Furthermore, the complexed melarsoprol treatment protocol is shorter than the currently used 10 day concise melarsoprol treatment schedule therefore the total amount of melarsoprol administered to patients will be reduced. Patients should therefore experience fewer adverse reactions. In conclusion the results from this study demonstrate that the melarsoprol cyclodextrin complexes mel/HPCD and mel/RAMCD are promising oral candidates for the treatment of HAT.
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Ebiloma, Godwin Unekwuojo. "Identification of new lead compounds for the treatment of African trypanosomiasis." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8340/.
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Cullen, Danica Renae. "Development of tetrahydroisoquinoline analogues: Towards a treatment for Human African Trypanosomiasis." Thesis, Curtin University, 2016. http://hdl.handle.net/20.500.11937/52988.
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This research describes the exploration of a new scaffold with the potential to be developed in to a new drug for the treatment of Human African Trypanosomiasis (HAT), a neglected disease endemic in sub-Saharan Africa. Derivatives of an isoquinoline scaffold were synthesised and evaluated for their in vitro activity against T.b.rhodesiense, the causative agent of HAT. Five derivatives were identified with inhibition of T.b.rhodesiense in the sub-micromolar range with good selectivity over mammalian cells.
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Hickey, Meghan C. "Exploring an unusual beta-hydroxybutyrate dehydrogenase from Trypanosoma brucei." Click here for download, 2010. http://proquest.umi.com.ps2.villanova.edu/pqdweb?did=2011158651&sid=1&Fmt=7&clientId=3260&RQT=309&VName=PQD.
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Jamnadass, Harmanjeet Ramni. "Identification and characterisation of an extrachromosomal element from a multidrug-resistant isolate of Trypanosoma brucei brucei." Thesis, Brunel University, 1995. http://bura.brunel.ac.uk/handle/2438/4314.
Full textAbstract:
Drug resistance together with difficulties involved in the development of new trypanocides are a major problem in the present control of African trypanosomiasis. DNA based diagnostics for drug resistance would overcome problems in the identification of drug-resistant populations and contribute to effective control measures. However, this requires a detailed knowledge of the mode of action and the mechanisms by which trypanosomes can overcome the toxic effects of trypanocides. In this study, a search for molecular differences between a multidrug-resistant isolate of Trypanosoma brucei brucei, CP 547, and a reference drug-sensitive population, ILTat 1.4, led to the identification of a 6.6 kbp extrachromosomal element in the multidrug-resistant population. In light of the involvement of extrachromosomal elements in drug resistance in Leishmana spp. and cancer cells, the identification of the 6.6 kbp element warranted its characterisation. Several different approaches sere attempted before a sequence which hybridised to the 6.6 kbp element its eventually isolated. This sequence is represented by a 108 bp repeat sequence which forms long arrays of tandem repeats. Since N/a III is the sole restriction enzyme that cuts within the repeat, it has been referred to as an N/a III repeal The repeat is flanked by a 5 bp spacer sequence. However, a unique 5 bp direct repeat flanking two complete, and one partial copy of the N/a III repeat may signify the transposition of these sequences. Hybridisation with the N/a III repeat revealed the presence of 'higher' hybridising elements which also appear to be predominantly composed of long tandem arrays of the N/a Ill repeal Through exploitation of the p01) merase chain reaction using arbitrary primers (AP-PCR), additional sequences were identified which are associated with some of the 6.6 kbp and 'higher' hybridising elements. The 6.6 kbp element and some of the 'higher' hybridising elements display features of circular DNA molecules. The 6.6 kbp element also displays some level of size and sequence heterogeneity within different populations of the same trypanosome isolate. The copy number of the 6.6 kbp element is also not stable and appears to be directly affected by the application of selective drug pressure, but a direct association between the presence of the element and the expression of multidrug resistance could not be determined. The N/a III repeat family represents a newly identified repetitive family specific to members of the Trypanozoon subgenus. This repeat family, representing about 5% of the parasite genome, is dispersed through all size classes of chromosomes, in addition to its presence on the extrachromosomal elements. Transcriptional studies of the N/a III repeats have revealed that their transcription is developmentally regulated, since heterogeneous transcripts ranging from greater than 10 kb to smaller than 300 bp are present in the actively dividing long slender bloodstream and insect stage procyclic forms of the parasite but not nondividing, stumpy bloodstream forms. Lastly, the N/a III repeat lacks an open reading frame and transcripts do not appear to have a spliced leader sequence at the 5' end. Furthermore, there is almost an equal representation of polyadenylatcd and non-polyadenlyated transcripts.
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Silva, Achani Madushika. "Energetic basis of inappetence in an experimental murine infection of African Trypanosomiasis." Thesis, University of Aberdeen, 2015. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=230060.
Full textAbstract:
Trypanosoma brucei is the vector of African trypanosomiasis in both domestic animals (nagana) and sleeping sickness in humans (Human African Trypanosomiasis). These protozoan parasites are transmitted by the bite of infected tsetse flies (Glossina sp.). African trypanosome infections cause parasite-induced anorexia (PIA) and cachexia in livestock, experimental animals and in humans, and are of economic, veterinary and medical importance in sub-Saharan Africa. The overall aim of this project was to characterise the phenomenon of inappetence in relation to overall energy budget in African trypanosome infection and to then identify potential causal factors and mechanisms. A mouse model of T.b. brucei infection was established with a reproducible time course for the development of inappetence and bodyweight loss. Following an initial parasitaemic peak on day 6 post-infection, a profound period of inappetence was observed from days 7 to 11, accompanied by a 10% loss of body mass. Metabolisable energy intake was reduced, while assimilation efficiency increased significantly but not enough to compensate for the severe reduction in food intake. During the course of T.b. brucei infection, both total energy expenditure and physical activity were reduced. Although physical activity was markedly declined in both light and dark phases, trypanosome infected mice maintained their circadian rhythm albeit at a lower amplitude, with most of the activity occurring at the start of the dark phase. Resting metabolic rate was unchanged in infection. Plasma concentrations of the inflammatory cytokines, IL-6 and TNF-α were increased in infected mice and were associated with inappetence. Reductions of leptin and insulin concentration corresponded to a loss in fat mass. The hypothalamic control of appetite appeared to be normal with increases in appetite stimulating AgRP, decreases in the appetite inhibiting POMC and MC4R. There has been no previous data published on the control of appetite and energy expenditure in African trypanosome infections thus the data presented here provides a novel insight into the pathophysiology of this serious disease, and may lead to new therapies to manage the clinical and veterinary consequences of trypanosome infection.
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Witmans, Cornelis Jacobus. "An approach to the rational design of new inhibitors for Trypanosoma brucei Triosephosphate isomerase /." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1995. http://irs.ub.rug.nl/ppn/139946616.
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Ndoutamia, Guelmabye. "Derivation and characterisation of a quinapyramine-resistant clone of Trypanosoma congolense." Thesis, Brunel University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286698.
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Mungongo, Singfrid Gasper. "The design, synthesis and biological evaluation of novel antitrypanosomal drugs." Thesis, University of Sunderland, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284073.
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Roderick, Stephen. "Pastoralist cattle productivity in a tsetse infested area of south west Kenya." Thesis, University of Reading, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262627.
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