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The origins, dynamics and generation of Trypanosoma brucei rhodesiense epidemics in East Africa
Abstract
The history of sleeping sickness in East Africa has provoked controversy not only about the origins and spread of the disease, but also the identity of the causative organisms involved. Molecular methodology(1) has shed new light on the genetic makeup of the organisms involved in recent epidemics. Here, Geoff Hide, Andrew Tait, Ian Maudlin and Susan Welburn discuss these new data in relation to previous theories about the origins of epidemics in East Africa which emphasized the importance of the introduction of new strains.
... Independent of the stimulus, PCD usually involves alteration in the mitochondrial membrane permeability, caspase activation, phosphatidylserine (PS) exposure, nuclear and cytoplasmic condensation, DNA fragmentation and breakage of the cell into apoptotic bodies, which are engulfed by the surrounding macrophages (Vaux and Strasser, 1996). PCD is a process found in virtually all nucleated metazoan cells, and it has been recently associated with several species of unicellular eukaryotes, notably kinetoplastids (Figarella et al., 2005, Ameisen et al., 1995, Welburn et al., 1996, Moreira et al., 1996, Ridgley et al., 1999, Arnoult et al., 2002, Zangger et a.,l 2002, yeast , and amitochondrion parasites (Chose et al, 2002, Mariante et al, 2003. ...
... It has been shown that trypanosomes can be induced to undergo apoptosis after stimulation with Con A and that the process of death is associated with de novo gene expression (Welburn et al., 1996, Murphy & Welburn 1997. To provide an overview of the genetic changes occurring Prostaglandin D 2 induces programmed cell death in Trypanosoma brucei bloodstream form . Owing to the lack of caspases in T. brucei, a caspase-dependent apoptosis or paraptosis was excluded. ...
... The results show that early case treatment is most effective against Gambian infections when there is no animal reservoir (Fig. Ia). The presence of an animal reservoir reduces the relative effectiveness more for Rhodesian than for Gambian infections because the duration of infectiousness is greater in the latter and so transmission in humans accounts for a greater proportion of the total R 0. In Fig. Ib, we see that chemoprophylaxis of animals is most effective for [16][17][18] , evidence of genetic exchange among field populations has never been conclusively demonstrated 19,20 . This debate as to whether mating takes place at all in natural populations is of interest outside the confines of population genetics because, if recombination is a normal part of the trypanosome life cycle, then such a panmictic (randomly mating) structure 16 ...
... The presence of an animal reservoir reduces the relative effectiveness more for Rhodesian than for Gambian infections because the duration of infectiousness is greater in the latter and so transmission in humans accounts for a greater proportion of the total R 0. In Fig. Ib, we see that chemoprophylaxis of animals is most effective for [16][17][18] , evidence of genetic exchange among field populations has never been conclusively demonstrated 19,20 . This debate as to whether mating takes place at all in natural populations is of interest outside the confines of population genetics because, if recombination is a normal part of the trypanosome life cycle, then such a panmictic (randomly mating) structure 16 ...
... Ugandan policy-makers and researchers were keen to point out. Research on the topic is partially reviewed, and further developed with previously published Ugandan data by Hide et al. (1996), who state: ...
... This research moved through basic proof of the concept, through studies of which cattle in a herd were differentially bitten by flies, and thus most effective to treat. Most relevant to the SOS Campaign were findings (from research carried out on-station in Zimbabwe) that the tsetse fly bites the legs and belly of cattle differentially, so that treating these parts would be considerably more cost-effective than whole-body treatment (Torr et al., 2007 18 Researchers funded by this programme and its predecessors, Maudlin (manager of the Programme) and Welburn also of the University of Edinburgh, were also co-authors of the papers by Hide et al., 1996, Fèvre et al., 2001and Hutchinson et al., 2003 The tsetse work was also funded by DFID's Livestock Production Programme ...
... Domestic animals, such as bovine and porcine species, have also been identified as reservoirs. [85][86][87] The existence of a reptilian host has been well described, but its contribution to the maintenance of trypanosomes is unlikely, as their body temperature varies considerably, making the survival of parasites improbable. 88 Hence, two situations can be differentiated: there may be areas where the main reservoirs are wild animals; and there may be areas where domestic animals play this role. ...
... Epidemiology of human African trypanosomiasis marginal lands where the contact with tsetse flies increases and can trigger local outbreaks of the disease, 85,120,137,[140][141][142] which is what probably occurred in the huge Busoga epidemic that took place in Uganda in the early 1990s. 5 Large-scale movement of livestock related to economic factors can extend the rhodesiense HAT foci, or even introduce the disease in new areas. ...
Human African trypanosomiasis (HAT), or sleeping sickness, is caused by Trypanosoma brucei gambiense, which is a chronic form of the disease present in western and central Africa, and by Trypanosoma brucei rhodesiense, which is an acute disease located in eastern and southern Africa. The rhodesiense form is a zoonosis, with the occasional infection of humans, but in the gambiense form, the human being is regarded as the main reservoir that plays a key role in the transmission cycle of the disease. The gambiense form currently assumes that 98% of the cases are declared; the Democratic Republic of the Congo is the most affected country, with more than 75% of the gambiense cases declared. The epidemiology of the disease is mediated by the interaction of the parasite (trypanosome) with the vectors (tsetse flies), as well as with the human and animal hosts within a particular environment. Related to these interactions, the disease is confined in spatially limited areas called “foci”, which are located in Sub-Saharan Africa, mainly in remote rural areas. The risk of contracting HAT is, therefore, determined by the possibility of contact of a human being with an infected tsetse fly. Epidemics of HAT were described at the beginning of the 20th century; intensive activities have been set up to confront the disease, and it was under control in the 1960s, with fewer than 5,000 cases reported in the whole continent. The disease resurged at the end of the 1990s, but renewed efforts from endemic countries, cooperation agencies, and nongovernmental organizations led by the World Health Organization succeeded to raise awareness and resources, while reinforcing national programs, reversing the trend of the cases reported, and bringing the disease under control again. In this context, sustainable elimination of the gambiense HAT, defined as the interruption of the transmission of the disease, was considered as a feasible target for 2030. Since rhodesiense HAT is a zoonosis, where the animal reservoir plays a key role, the interruption of the disease’s transmission is not deemed feasible.
... It also contributes to the understanding of changes in vector distribution observed at the local and regional levels. In another example of the importance of scale, genetic research conducted on the microscopic scale allows for the identification of trypanosome species, strains, genotypes, and isolated clusters (Hide et al., 1996; Hide, 1999). This research has contributed to the understanding of sleeping sickness patterns at the regional and national scales, revealed new information on which trypanosome species may have caused the 1900–1920 Ugandan outbreak (Hide et al., 1996; Welburn et al., 2001), and highlighted the role of cattle movements in parasite spread (Fèvre, 2001; Fèvre et al., 2001). ...
... In another example of the importance of scale, genetic research conducted on the microscopic scale allows for the identification of trypanosome species, strains, genotypes, and isolated clusters (Hide et al., 1996; Hide, 1999). This research has contributed to the understanding of sleeping sickness patterns at the regional and national scales, revealed new information on which trypanosome species may have caused the 1900–1920 Ugandan outbreak (Hide et al., 1996; Welburn et al., 2001), and highlighted the role of cattle movements in parasite spread (Fèvre, 2001; Fèvre et al., 2001). Research, by necessity, focuses on a particular temporal and spatial scale. ...
Sleeping sickness continues to be a significant public health burden in southeastern Uganda. Continued spread of the disease into new areas of Uganda highlights our inability to understand and predict the distribution of infection. Multiple factors influence the distribution of sleeping sickness, including climate, land cover, cattle movements, prevention and control activities, and social conflict. We draw on a systems approach to conceptualize and characterize the multiple interacting forces and processes that influence the spatial and temporal dynamics of sleeping sickness in Uganda. This synthesis reveals a complex system of interactions among human and biophysical systems, feedback, and scale dependence. We identify some common analytical modeling approaches relative to our system characterization and identify opportunities for sleeping sickness research and improved understanding of disease dynamics in Uganda.
... Over the last three decades, population genetic research has provided important insights into the biology of T. brucei and the epidemiology of sleeping sickness [14,15,16,17,18,19,20,21,22,23,24]. But the fine scale ecological and evolutionary processes underlying disease dynamics and the distinction of the different parasite forms are still not very well understood. ...
... For example, Cluster 5 and Cluster 8 are each composed of SRA-positive (type 1) and SRA-negative trypanosomes that are more closely related to each other than they are to trypanosomes in the other cluster. The same is true for Cluster 7 and Cluster 9. Previous work has revealed that human infective and animal-restricted trypanosomes from the same focus showed distinct allele sets, suggesting little recent exchange [18,19]. On the other hand, our results, which place the results from individual foci in the context of broader geographical sampling, demonstrate that parasites sampled in a restricted time and space often consist of SRA-positive and SRA-negative individuals that may be more closely related to each other than to SRA-positive and SRA-negative parasites recovered from another time and place. ...
Characterizing the evolutionary relationships and population structure of parasites can provide important insights into the epidemiology of human disease.
We examined 142 isolates of Trypanosoma brucei from all over sub-Saharan Africa using three distinct classes of genetic markers (kinetoplast CO1 sequence, nuclear SRA gene sequence, eight nuclear microsatellites) to clarify the evolutionary history of Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), the causative agents of human African trypanosomosis (sleeping sickness) in sub-Saharan Africa, and to examine the relationship between Tbr and the non-human infective parasite T. b. brucei (Tbb) in eastern and southern Africa. A Bayesian phylogeny and haplotype network based on CO1 sequences confirmed the taxonomic distinctness of Tbg group 1. Limited diversity combined with a wide geographical distribution suggested that this parasite has recently and rapidly colonized hosts across its current range. The more virulent Tbg group 2 exhibited diverse origins and was more closely allied with Tbb based on COI sequence and microsatellite genotypes. Four of five COI haplotypes obtained from Tbr were shared with isolates of Tbb, suggesting a close relationship between these taxa. Bayesian clustering of microsatellite genotypes confirmed this relationship and indicated that Tbr and Tbb isolates were often more closely related to each other than they were to other members of the same subspecies. Among isolates of Tbr for which data were available, we detected just two variants of the SRA gene responsible for human infectivity. These variants exhibited distinct geographical ranges, except in Tanzania, where both types co-occurred. Here, isolates possessing distinct SRA types were associated with identical COI haplotypes, but divergent microsatellite signatures.
Our data provide strong evidence that Tbr is only a phenotypic variant of Tbb; while relevant from a medical perspective, Tbr is not a reproductively isolated taxon. The wide distribution of the SRA gene across diverse trypanosome genetic backgrounds suggests that a large amount of genetic diversity is potentially available with which human-infective trypanosomes may respond to selective forces such as those exerted by drugs.
... Rhodesiense HAT is found in sixty foci spread across thirteen African countries ( Figure 2) (30, 45). It is a zoonosis; its transmission cycle mainly involves non-human reservoirs: Wild animals or livestock (46)(47)(48)(49). The routes of transmission are strictly related to the geographical distribution of the reservoir. ...
According to both definitions of US Centers for Disease Control and Prevention and World Health Organization, Neglected Tropical Diseases (NTDs) are a group of preventable and treatable parasitic, viral, and bacterial diseases that affect more than one billion people globally. They generally afflict the more indigent patients of the world and historically have not received as much attention as other diseases. NTDs tend to thrive in low-income regions, where water quality, sanitation and access to health care are substandard. They are common in several countries of Africa, Asia, and Latin America. In this literature review, we want to focus on Human African Trypanosomiasis (HAT), also known as “sleeping sickness”, one of the most common neglected diseases in Africa. It is caused by infection with the subspecies of the parasitic protozoan Trypanosoma brucei, and it is transmitted by the bite of the tsetse fly. It puts 70 million people at risk throughout sub-Saharan Africa and it is usually fatal if untreated or inadequately treated. This review covers several aspects of the disease. We focused our interests on most recent epidemiological data, novel diagnostic methods with their advantages and limitations, new improved treatment and orphan drugs and eradication programs, including vector control, according to a “One Health” approach, to achieve the new goals recently set by WHO.
... Field studies were undertaken to confirm the modeling work and showed that spraying 25% of cattle using RAP could be effective in preventing re-infection of cattle with trypanosomes in south-east Uganda, protecting humans from rHAT as well as controlling AAT (28). In south-east Uganda, it has been shown that cattle act as the main reservoir for rHAT (13,(29)(30)(31). A study in Dokolo and Kaberamaido districts in south-east Uganda found that injection of cattle with the trypanocide diminazene aceturate followed by the use of RAP reduced the prevalence of Trypanosoma vivax from 5.9 to 0.5% in cattle (32). ...
Background: The endemic vector-borne diseases transmitted by tsetse and ticks impose heavy burdens on the livestock keepers in Africa. Applying deltamethrin to the belly, legs, and ears of cattle offers a possibility of mitigating these losses at a cost affordable to livestock keepers. Although studies have quantified the impacts of individual diseases on livestock productivity, little is known about the dual economic benefits of controlling both tsetse and ticks, nor about the number of cattle that need to be treated to confer these benefits. Alongside an epidemiological study in south-east Uganda, a farm level assessment was done to investigate the benefits and costs of spraying different proportions of the village cattle population using this restricted application protocol.
Methods: A study comprising 1,902 semi-structured interviews was undertaken over a period of 18 months. Financial data on household income and expenditure on cattle was collected, and cost-benefit analysis was done pre- and post-intervention and for different spraying regimes. The total cost of the intervention was obtained from the implementation costs of the epidemiological study and from expenses incurred by participating farmers enabling examination of benefit-cost ratios and incremental benefit-cost ratios for each treatment regime.
Results: The benefit-cost analysis of spraying 25%, 50%, and 75% of the cattle population yielded average benefit-cost ratios of 3.85, 4.51, and 4.46. The incremental benefit-cost ratios from spraying each additional 25% of the cattle population were 11.38, 3.89, and 0.79, showing a very high return on investment for spraying 50% of the population, with returns reducing thereafter.
Conclusion: Comparing the gross margins per bovine, the study found that increasing the proportion of cattle sprayed yielded increasing benefits to the farmers, but that these benefits were subject to diminishing returns. From a practical viewpoint, this study recommends spraying only draft cattle to control trypanosomiasis and tick-borne diseases in this area as they make 38.62% of the cattle population, approaching the 50% threshold. In areas with a lower proportion of draft males, farmers could be advised to also include cows.
... Field studies were undertaken to con rm the modeling work and showed that spraying 25% of cattle using RAP could be effective in preventing re-infection of cattle with trypanosomes in south-east Uganda, protecting humans from rHAT as well as controlling AAT (28). In south-east Uganda, it has been shown that cattle act as the main reservoir for rHAT (13,(29)(30)(31). A study in Dokolo and Kaberamaido districts in south-east Uganda found that injection of cattle with the trypanocide diminazene aceturate followed by use of RAP reduced the prevalence of T. vivax from 5.9% to 0.5% in cattle (32). ...
Background
The endemic vector-borne diseases transmitted by tsetse and ticks impose heavy burdens on Africa’s livestock. Cattle offers the possibility of mitigating these losses at a cost affordable to livestock keepers, by applying deltamethrin just to the belly, legs and ears of cattle. Although studies have quantified the impacts of individual diseases on livestock productivity, little is known about the dual economic benefits of controlling both tsetse and ticks, nor about the number of cattle who need to be treated to confer these benefits. Alongside an epidemiological study in south-east Uganda, a farm level assessment was done to investigate the benefits and costs of spraying different proportions of the village cattle population using this restricted application protocol. MethodsA study comprising 1,902 semi-structured interviews was undertaken over a period of 18 months. Financial data on household income from and expenditure on cattle was collected and cost benefit analysis done, pre and post intervention and for different spraying regimes. The total cost of the intervention was obtained from the epidemiological study’s implementation costs and from expenses incurred by participating farmers enabling examination of benefit-cost ratios and incremental benefit-cost ratios for each treatment regime. ResultsThe benefit-cost analysis of spraying 25%, 50% and 75% of the cattle population yielded average benefit-cost ratios of 1.55, 3.85, 4.51 and 4.46. The incremental benefit-cost ratios from spraying each additional 25% of the cattle population were 11.38, 3.89 and 0.79 respectively, showing a very high return on investment for spraying 50% of the population, with returns reducing thereafter. Conclusion
Comparing the gross margins per bovine, the study found that increasing the proportion of cattle sprayed yielded increasing benefits to farmers, but that these benefits were subject to diminishing returns. From a practical viewpoint this study recommends spraying only draft cattle to control trypanosomiasis and tick-borne diseases in this area as they make 38.62% of the cattle population, approaching the 50% threshold. In areas with a lower proportion of draft males, farmers could be advised to also include cows.
... From the human health perspective, human African trypanosomiasis (HAT) or sleeping sickness caused by Trypanosoma brucei rhodesiense is a major public health concern in over 36 sub-Saharan African countries (Lundkvist et al. 2004;Simarro et al. 2011). The presence of a wide range of wild and domestic animals that act as reservoirs throughout southern and Eastern Africa makes it possible for T. brucei rhodesiense to circulate, thereby making transmission to humans possible in the presence of the tsetse fly vectors (Hide et al. 1996;Waiswa et al. 2003Waiswa et al. , 2006Welburn et al. 2009). For example, a prevalence of Trypanosoma brucei (subspecies T. brucei brucei and T. brucei rhodesiense) of up to 40% has been reported among some Ugandan cattle populations (Welburn et al. 2009). ...
African animal trypanosomiasis (AAT), a disease complex caused by tsetse fly–transmitted Trypanosoma brucei brucei, T. congolense savannah ITS, and T. vivax, continues to inflict heavy losses to the animal industry in terms of decreased livestock production and productivity. Live bait technology and chemotherapy have been used as a control strategy in northern Uganda since 2006 with minimal success. Here, we report the results of a cross-sectional study carried out in Lango subregion, Uganda, to assess the species prevalence of bovine trypanosome in cattle using the internal transcribed spacer (ITS) of trypanosome ribosomal DNA (rDNA). Blood samples were collected from 1090 cattle by ear vein puncture and screened using a single pair of primers designed to amplify ITS ribosomal DNA (rDNA). Our results indicate an overall prevalence of 40.18% (438/1090, 95% CI 30.82–54.51). T. vivax constituted 32.66% (356/1090), T. congolense 2.39% (26/1090), T. brucei 1.28% (14/1090), T. godfreyi 0.09%(1/1090), T. brucei and T. congolense 0.36% (4/1090), T. brucei and T. vivax 1.47% (16/1090), T. vivax and T. congolense 1.65% (18/1090), T. vivax and T. simiae 0.18% (2/1090), and T. vivax and T. godfreyi 0.09% (1/1090) of infections. Over 91.7% of infections involved single species, while 9.5% were mixed infections. Over 90.2% (37/41) of the mixed infections involved T. vivax as one of the species, while 53.7% (22/41) involved T. congolense. The high prevalence of AAT and the continued presence of T. brucei raise public health concerns because of the zoonotic implications. An integrated approach that involves mass treatment of cattle, vector, and animal movement control should be adopted to reduce the risk of both AAT and HAT.
... Field studies were undertaken to confirm the modeling work and showed that spraying 25% of cattle using RAP could be effective in preventing clinical re-infection of cattle with trypanosomes in south-5 eastern Uganda, protecting humans from zoonotic HAT as well as controlling AAT [27]. In southeastern Uganda, it has been shown that cattle act as the main reservoir for T. b. rhodesiense, zoonotic HAT [28], [29], [30]. A study in Dokolo and Kaberamaido districts in south-eastern Uganda found that use of RAP and injection of cattle with the trypanocide diminazene aceturate reduced the prevalence of T. vivax from 5.9% to 0.5% in cattle [31]. ...
Background The tsetse-transmitted African trypanosomiases affect humans and animals. Trypanosoma. brucei rhodesiense sleeping sickness, or human African trypanosomiasis is a zoonosis, for which cattle are the main reservoir of infection in south-eastern Uganda. Transmission of human and animal infective trypanosomes can be reduced by the application of deltamethrin insecticide to the belly and legs of cattle, thus reducing tsetse fly populations. Alongside an epidemiological study in southeastern Uganda, a farm level assessment was done to calculate the average and incremental benefit-cost ratios of spraying different proportions of the village cattle population using this restricted application protocol.
Method A study comprising 2,400 semi-structured interviews was undertaken over a period of 18 months. Financial data on household income and expenditure on cattle provided the basis for the marginal analyses. The benefit of RAP to farmers was assessed using gross margin analysis whereas the costs were obtained from expenses incurred by farmers in participating in the RAP intervention. Subsequently, the RAP intervention villages were compared with a control village to determine the average and incremental benefit-cost ratio across all households.
Results The benefit-cost analysis of spraying 25%, 50% and 75% of the cattle population yielded benefit-cost ratios of 6.22, 5.56 and 4.46. The incremental benefit-cost ratios from spraying each additional 25% of the population cattle were 14.32, 3.97 and 0.79 respectively, showing a very high return on investment in spraying 25% of the population, with returns reducing thereafter.
Conclusion Comparing the gross margins per bovine of applying RAP to different proportions of the cattle population to a pre-intervention situation and a control, the study found that increasing the proportion of cattle sprayed yielded increasing benefits to farmers, but that these benefits were subject to diminishing returns. Given the high proportion of draft males in the cattle population (37%) their important contribution to livestock output and farmers’ preference for treating these animals, from a practical viewpoint this study recommends spraying only draft cattle to control trypanosomiasis in this area, although in areas or households with a lower proportion of draft males, farmers could be advised to also include cows.
... En revanche, la transmission directe, impliquant la contamination de l'environnement, permet aux agents pathogènes de rencontrer les différentes espèces présentes dans l'environnement. Pour les agents pathogènes transmis par des vecteurs généralistes, qui représentent la majorité des arthropodes hématophages (Kettle 1995), la combinaison de la préférence trophique, des patrons de dispersion du vecteur et de l'abondance des hôtes détermine les opportunités de transmission interspécifique (Hide et al. 1996, Woolhouse et al. 1997). ...
La variation de la diversité des communautés d’hôtes réservoirs peut modifier le risque de maladies impliquant ces espèces. En particulier, l’introduction d’une espèce potentiellement réservoir est susceptible d’augmenter le risque de maladie, en agissant comme un réservoir supplémentaire et/ou en amplifiant la circulation des agents pathogènes chez les réservoirs autochtones. L’objectif du travail de thèse est de quantifier la contribution, d’une espèce introduite, le tamia de Sibérie (Tamias sibiricus barberi), au risque d’une maladie multi-hôtes, la borréliose de Lyme, due à des bactéries appartenant au complexe d’espèces Borrelia burgdorferi sensu lato et transmises par des tiques, principalement Ixodes ricinus en Europe. Dans un premier temps, nous avons testé si le tamia est un réservoir compétent pour la maladie de Lyme en milieu naturel, c'est-à-dire s’il est capable de transmettre B. burgdorferi sl aux tiques I. ricinus et de maintenir l’infection. Le tamia est fortement infesté par les tiques et infecté par les bactéries et il peut transmettre B. burgdorferi sl aux tiques. Nos résultats ne montrent pas clairement que le tamia peut maintenir l’infection. Une des deux composantes du risque de la maladie de Lyme pour l’homme est le risque acarologique, c'est-à-dire la densité de nymphes infectées en quête d’hôtes. Dans un deuxième temps, nous avons calculé la contribution du tamia au risque acarologique et l’avons comparé à celles du campagnol roussâtre (Myodes glareolus) et du mulot sylvestre (Apodemus sylvaticus), réservoirs avérés de B. burgdorferi sl. Puis, nous avons étudié la variation temporelle de la contribution du tamia et testé si sa présence influençait la contribution des réservoirs rongeurs natifs. Pour calculer la contribution au risque, nous avons utilisé deux approches, l’une basée sur des captures des rongeurs, et l’autre sur l’identification des espèces hôtes sur lesquelles se sont gorgées les tiques. Le tamia produit plus de nymphes infectées à l’affût que le campagnol et le mulot. La contribution du tamia varie entre années suivant la densité de tamias et intra-années suivant la disponibilité en tiques. Sa plus forte infestation par I. ricinus et infection par B. burgdorferi sl, que les rongeurs natifs, peuvent être expliquées par sa plus forte exposition aux tiques. En conclusion, le tamia semble un réservoir compétent pour B. burgdorferi sl, avec une forte contribution au risque acarologique et une amplification possible de la circulation des pathogènes dans les communautés natives. Sa présence peut augmenter le risque pour la borréliose de Lyme chez l’homme en augmentant la prévalence d’infection des nymphes, mais pas les densités de nymphes à l’affût.
... The distribution of the causative organism is mostly restricted to the African continent and Asia. However, T. vivax has been observed to cross the Atlantic moving upwards towards South America through mechanical transmission by biting flies (Hide et al., 1996;Naessens, 2006). In addition T. evansi have also been observed to have a wide host range causing infection in livestock such as buffalo and camel in some parts of Asia (Njiru et al., 2004;Naessens, 2006). ...
Objective: This case report describes the management of a clinical case of trypanosomosis in an adult Friesian Sahiwal cow. Materials and methods: An adult cow aging 3 years was presented with a complain of wound infection, weakness and inappetence. Physical examination was carried out and samples were collected for laboratory investigations. Results: The clinical history revealed generalised enlargements of the pre-scapular and pre-femoral lymph nodes, pale mucous membrane and weight loss. Laboratory investigation showed that the cow had normocytic normochromic anemia with hyperproteinemia. Thin blood smear examination revealed the presence of Trypanosoma evansi . Treatment was instituted with Diminazene aceturate dosed at 3.5 mg/kg bwt through intramuscular (IM) route for 3 days, 20 mL of Fercobsang for 3 days, IM, Flunixin meglumine dosed at 1.1 mg/kg bwt, IM, and Oxytetracycline dosed at 20 mg/kg bwt, IM once. The wounds were cleaned daily for one week. Examination of the blood film after therapy showed no parasite. Conclusion: The findings of this case report demonstrate the importance of an effective treatment regimen in managing bovine trypanosomosis in an endemic farm. http://doi.org/10.5455/javar.2016.c164
... T.b. rhodesiense is a zoonosis [5,6], with a number of wildlife [7] and domestic animal species known to act as reservoirs. Where wildlife is not abundant, domestic species, particularly cattle, are the main reservoir [8], with livestock demography driving outbreaks [9]. T.b. gambiense is generally not considered zoonotic-it can be isolated from animal hosts [10,11], but large-scale control campaigns targeting only the human reservoir (active screening and treatment of human cases) are able to locally eliminate transmission [12,13], and theoretical assessments of control options [14] confirm that from an epidemiological perspective, the presence of animal hosts is unlikely to mean they serve as a reservoir of infection for humans [15] (such hosts and their potential as a source for re-introduction of the parasite to the human population would need to be considered if ever aiming for total elimination of the disease, however). ...
Human African Trypanosomiasis (HAT), a once largely forgotten disease, is back on the agenda. A public-private partnership between the World Health Organization (WHO), pharmaceutical companies and international donors succeeded in curbing the recent epidemic, but active transmission is still ongoing in several countries. The burden of the disease in affected individuals is high. Untreated the disease is always fatal and estimates of the Disability Adjusted Life Years (DALYs) lost per premature death range from 25 to 33 years. Even for successfully treated patients, the burden on households and livelihoods is high – between 1.5 and 10 months’ income, even when diagnostics and HAT drugs are provided for free. Costs ranging from $10–17 per DALY averted for case-finding and treatment places the control of T.b. gambiense HAT firmly in the category of highly cost-effective health interventions.
... In Trypanosoma brucei rhodesiense the role of non-human reservoirs is considered to be much more important. Originally bushbuck were identified as a reservoir for Trypanosoma brucei rhodesiense (Heisch et al., 1958), since that time domestic cattle are now thought to play the most important role in the transmission of human rhodesiense sleeping sickness (Hide et al., 1996). In fact, study suggests that between 21% and 33% of Trypanosoma brucei infected animals (especially cattle) can be infected with human infective trypanosomes, at least during an epidemic and that a fly infected with T.b.rhodesiense is five times more likely to have picked up the infection from domestic cattle than from a human . ...
The epidemiological study of pathogens largely depends on three technologies,
serology, microscopy and the polymerase chain reaction (PCR). Serological
methods are unable to differentiate between current and past infections.
Microscopy has historically been the mainstay of epidemiological study. In
recent times the use of microscopy has been in decline, as it has been shown to
have an inherent lack of sensitivity and specificity and produces many false
negative results. PCR is now the method of choice for screening samples for the
presence or absence of pathogens. Although PCR is widely regarded as an
extremely sensitive technique, the fact that it assays a very small volume of
sample is often overlooked. If the target pathogen is not present in the tiny
aliquot of sample from an infected host, then a false negative results will occur.
In endemic situations were the pathogen is present at low infection intensities,
then the potential for false negatives results of this type is high. This intensity
related false negative effect can lead to serious underestimation of diagnosed
prevalence and incidence with consequent misinterpretation of the resulting
data. This phenomenon has been reported in the literature for a range of
pathogens and especially for epidemiological study of schistosomiasis. The
extensive occurrence of false negatives during study of schistosomiasis
samples was such an obstacle to epidemiological study it prompted the world
health organisation to repeatedly call for quantitative methods to be employed to
combat the problem.
The main objectives of this thesis are to rationalise and simplify the methods of
diagnosing African trypanosomes in epidemiological studies and to investigate
the consequences of, and methods of dealing with infection intensity related
false negative results that occur as a result of widespread sub-patent infections
in the study population
A new PCR assay was developed that was capable of analysing whole blood
placed onto treated filter paper. The PCR assay was capable of differentiating
between all the important African trypanosome species, producing a unique size
of amplicon for each species of trypanosome. Initial results from repeated
screening of human and cattle samples known to be parasitologically positive
indicated that many false negative results occur. A more extensive analysis of
thirty five bovine blood samples randomly chosen from a collection of field
samples revealed that false negative results occurred regularly. The prevalence of infection after a single screening was 14.3% whereas the cumulative
prevalence after over 100 repeated screenings rose to 85.7%. This showed that
a severe underestimation of prevalence occurs from a single screening of the
samples.
In order to investigate the consequences of, and develop methods of dealing
with this problem, computer based simulations were used to model the
dynamics of screening samples with sub-patent infections. In order to construct
the model the data obtained from repeat screening of the thirty-five bovine blood
samples was fitted to a number of mathematical distributions. A negative
binomial distribution best described the distribution of trypanosomes across the
hosts. Exploration of the phenomenon with the resulting model showed the
extensive underestimation of true prevalence that is possible. The simulations
also showed that it is possible for populations with very different patterns of
infection and true prevalence to all have the same diagnosed prevalence from a
single screening per sample. Statistical comparison of these very different
populations by diagnosed prevalence alone would conclude there was no
significant difference between the populations. It was therefore concluded that
the diagnosed prevalence from a single (or even multiple) screenings is an
inadequate and potentially misleading measure of both infected hosts and
parasite numbers.
In order to deal with these problems new methods were evaluated for use in
epidemiological studies. A simple method of producing quantitative measures of
infection was advocated. The insensitivity of existing screening methods in
detecting significant difference between populations was highlighted and a
greatly improved methodology was shown. Finally, a method for inferring the
true population prevalence from the data obtained from repeat screening of
samples was suggested. Although some of these new methodologies have
limitations, they represent a great improvement on the use of a single diagnostic
test for each host. The work presented in this thesis highlights a serious
potential limitation to our understanding of the epidemiology of pathogens that
exist at sub-patent levels, and develops some possible methods of overcoming
these limitations.
... Using the SRA marker, up to 18% of cattle in Soroti District were found to be infected with T. b. rhodesiense (Welburn et al., 2001b ), compared with 1% using previous methods (Hide et al., 1994 ), and it is clear that infections in animals had been missed using field methods then available. Tsetse exhibit a strong feeding preference for cattle (Waiswa et al., 2006) and the risk of becoming infected by a fly infected from an infected cow is five times more likely than from a human (Hide et al., 1996). ...
Sleeping sickness is used to describe two quite distinct human diseases in sub-Saharan Africa that are separated by the Great Rift Valley: the Rhodesian form caused by Trypanosoma brucei rhodesiense is an acute infection, fatal within 6-8 months if left untreated; the Gambian form caused by Trypanosoma brucei gambiense is a chronic infection, usually fatal in around 3 years in the absence of treatment.The two diseases have very different epidemiologies requiring different control strategies. The reservoir of Gambian sleeping sickness is mainly human and control is best achieved by active case finding using mobile teams. Treatment involves melarsoprol, a toxic arsenical that unfortunately results in approximately 5% fatalities. Search for new drugs to treat Gambian sleeping sickness is urgent because of the rise in treatment failures with melarsoprol and consequent breakdown in disease control programs. Domestic livestock are the major reservoir for T. b. rhodesiense transmission and control strategies must aim to interrupt animal-human transmission, usually by removing the tsetse fly vector where technically and economically feasible. Sleeping sickness has a serious economic impact on households and controlling the disease is cost-effective.
... The epidemiology of sleeping sickness in East Africa is complicated by the fact that the morphologically identical human-infective Trypanosoma brucei rhodesiense and non-human-infective Trypanosoma brucei brucei sub-species circulate together in domestic livestock , principally cattle reservoirs (Onyango et al., 1966, Hide et al., 1996). The recent development of a genetic marker based on the detection of a serum resistance associated (SRA) gene in Trypanosoma brucei rhodesiense (Welburn et al., 2001, Gibson et al., 2002) has enabled the division of the two T. brucei sub-species and therefore identification of animal reservoirs harboring the human-infective sub-species T. b. rhodesiense. ...
We describe the development of a single-primer amplification system, which uses the trypanosomal mobile genetic element RIME as a molecular marker for the differentiation of Trypanosoma brucei stocks. Using a well-characterised set of T. brucei stocks from southeast Uganda, Kenya and Zambia, we have evaluated the application of this technique, termed MGE-PCR (mobile genetic element PCR) for the typing of trypanosome strains. The technique revealed considerable variation between stocks and was sufficiently specific to amplify trypanosomal DNA in the presence of host DNA. The results showed a clear distinction between human-infective and non-human-infective stocks. Comparative studies on these stocks using markers for the human serum resistance associated (SRA) gene, which identifies human-infective stocks, demonstrated complete agreement between MGE-PCR derived groups and human-infectivity status. Furthermore, MGE-PCR detects high levels of variability within the T. b. brucei and T. b. rhodesiense groups and is therefore a powerful discriminatory tool for tracking individual T. brucei genotypes and strains.
... 30 Epidemics for T.b. rhodesiense have been frequently linked to social or environmental disruptions that force people and livestock to move to areas where there is increased contact with tsetse flies, that can trigger local outbreaks of the disease. [43][44][45][46][47] Such disruptions have played a pivotal role in epidemiological shifts of T.b. rhodesiense in the northwestern part of the country. 48 With the cessation of the military conflict in northern Uganda, efforts to restock post-conflict districts with cattle have led to further expansion of T.b. rhodesiense to northern districts already endemic for T.b. gambiense. ...
Objectives: Human migration and concomitant HIV infections are likely to bring about major changes in the epidemiology of zoonotic parasitic infections. Human African trypanosomiasis (HAT) control is particularly fraught with intricacies. The primarily zoonotic form, T.b. rhodesiense, and the non-zoonotic T.b. gambiense co-exist in Northern Uganda, leading to a potential geographic and genetic overlap of the two foci. This region also has the highest HIV prevalence in Uganda plus poor food security. We examine the bottlenecks facing the control program in a changed political and economic context. Method: We searched the literature in July 2015 using three databases: MEDLINE, Google Scholar, and Web of Science. Findings: Decentralized zoonotic HAT control for animal reservoirs and vectors compromise sustainability of the control programs. Human transmission potential may be underestimated in a region with other endemic diseases and where an HIV-HAT epidemic, could merge two strains. Conclusion: Our comprehensive literature review concludes that enhanced collaboration is imperative not only between human and animal health specialists, but also with political science. Multi-sectorial collaborations may need to be nurtured within existing operational national HIV prevention frameworks, with an integrated surveillance framework.
... Using the SRA marker, up to 18% of cattle in Soroti District were found to be infected with T. b. rhodesiense (Welburn et al., 2001b), compared with 1% using previous methods (Hide et al., 1994), and it is clear that infections in animals had been missed using field methods then available. Tsetse exhibit a strong feeding preference for cattle (Waiswa et al., 2006) and the risk of becoming infected by a fly infected from an infected cow is five times more likely than from a human (Hide et al., 1996). ...
Management of zoonotic disease risk arising from interactions between animals, humans and the environment, demands integrated action from both human and animal health sectors, support from other sectors or industries with a stake in health governance and key inputs from the environmental sector (Cook et al., 2004; Okello et al., 2011; Welburn, 2011; Zinsstag et al., 2012).
In this chapter, we describe evidence that the evolution of a One Health (OH) approach has been key to the sustainability of control of human African trypanosomiasis (HAT) or ‘sleeping sickness’ in Uganda. We summarise critical elements of design, events and outcomes of the Stamp Out Sleeping Sickness campaign (SOS), a One Health approach to management of an emerging zoonotic disease in Uganda, and look at the possibility of sustainable longterm disease management. Prevention of disease outbreaks is preferable and less costly in the long term but this requires long-term financial
commitments that become difficult to sustain when the health impact, or consequences of emerging neglected zoonoses, are not recognized in global terms (Maudlin et al., 2009).
... Indeed, genetic diversity is the 'fuel' for populations' evolution and adaptation to new conditions [6], and estimating the extent and the geographic structure of genetic diversity, as well as identifying the evolutionary forces behind (demography, gene flow, and adaptation) are thus major challenges in the current context of global changes. Moreover, retracing populations' evolutionary histories is fundamental to understand species histories and species interactions (such as host-pathogen coevolution [7] [8] and disease emergency [5] [9] [10] [11]), and to control threatened or -on the contrary-harmful populations [12] [13]. ...
Understanding genomic evolution in wild populations is of particular importance because evolution is a central process in our understanding of populations’ history and their future response to global changes. In addition to fundamental knowledge, the study of populations’ evolution has wide applications such as conservation/restoration genetics or epidemiology. Indeed, genetic diversity is the ‘fuel’ for populations’ evolution and adaptation to new conditions, and estimating the extent and the geographic structure of genetic diversity, as well as identifying the evolutionary forces behind (demography, gene flow, and adaptation) are thus major challenges in the current context of global changes.
A particular attention is currently devoted to the process of genetic divergence in wild populations, with emphases on gene flow, local adaptation, and their interactions. Indeed, adaptation in wild populations is supported in many species by many kinds of experiments based on both quantitative phenotypic traits and molecular data. However, the processes governing populations’ evolution are poorly understood in the tropical rainforest of Amazonia, and the relative influence of neutral and adaptive processes are continuously discussed.
I am a young scientist interested in the process of genomic divergence in wild (tree) populations. I aimed at understanding how evolution structures the genetic diversity and governs molecular divergence in wild populations, with particular emphases on gene flow and local adaptation. During five years as a young scientist, I worked on answering the following questions, focusing on two tree species occupying vulnerable areas: mainly Eperua falcata in Amazonia and, to a lesser extent, Abies alba in the Mediterranean area.
Scientific questions:
- Which evolutionary drivers are responsible of the structure of genetic diversity in wild populations occupying wide areas? This question was addressed at different geographical scales: from large (regional) to very local (microgeographic) scales.
- What is the relative influence of neutral (gene flow, inbreeding) and adaptive drivers in the process of genetic divergence?
- Is microgeographic adaptation possible in spite of extensive gene flow between populations occupying the extreme boundaries of an ecological gradient?
- What is the extent of natural selection in the (whole) genome of wild populations?
My research work is at the interface between three promising disciplines: Evolutionary genomics (i.e. the study of populations evolution and the evolutionary drivers behind), Bioinformatics (i.e. the treatment of next-generation data), and Bayesian modelling (i.e. the empirical calibration of complex mechanistic model). I intend to take advantage of the recent advances in sequencing and informatic technologies to bring up to date the field of ecological genetics and evolutionary biology, by developing modern research strategies to study the process of genomic divergence in wild populations.
http://prodinra.inra.fr/record/286326
... Cependant, depuis la découverte de la diploïdie, plusieurs auteurs se sont interrogés sur une éventuelle reproduction sexuée des trypanosomes. Des échanges génétiques ont été mis en évidence au cours du cycle chez le vecteur par des expériences de croisement en laboratoire Sternberg et al., 1988;Gibson, 1989;Degen et al., 1995;Tait et al., 1996). Ces échanges, non-obligatoires, auraient lieu dans l'intestin postérieur (Schweizer & Jenni, 1991) et dans les glandes salivaires de la glossine (Gibson & Whittington, 1993). ...
... • The first one began in 1896, lasted until 1906, and affected mainly Congo Basin and Uganda (WHO, 2006). It was a devastating epidemic with 300,000 people estimated to have died in the Congo Basin (De Raadt, 2005) and almost 500,000 in East Africa (Hide et al., 1996). T. b. gambiense was thought to be the causative agent, although at that time the more familiar East African subspecies, T. b. rhodesiense had yet to be described. ...
FOREWORD
It is now almost fithteen years since the Pan African Tsetse and Trypanosomiasis Campaign (PATTEC) Initiative has been decided by the Head of States of Africa. Most countries have developed plans and strategies for the implementation of a national PATTEC programme; several countries have initiated action on the ground aimed at eradicating tsetse and trypanosomiasis; and two countries, Botswana and Namibia, have been successfully rendered tsetse and trypanosomiasis-free. In others countries (e.g. Guinea), some well-delimited and isolated areas are in the way of totally being tsetse and trypanosomiasis freed. In spite of these encouraging results, the Campaign is longing to be effective in many countries because of various reasons among which, the lack or insuficiency of technical capacities.
In accordance with its core functions of capacities building and training, the PATTEC coordination office has initiated a number of activities, including training to build the necessary technical capacity and competence required to carry out activities in the implementation of PATTEC projects. To support this undertaking, a Training Manual for Tsetse and trypanosomiasis eradication has been written and edited with the help of differents experts.
This Training Manual is an overview of main principles leading to the successful of a PATTEC project: from the conception, planning, and executing a project, to the strengthening of acquired results with a highlight on tsetse and trypanosomiasis control strategies.
The manual is expected to provide useful knowledge for a PATTEC project execution, to guide and support the process of capacities building in tsetse and trypanosomosis programmes.
By Hassane MAHAMAT HASSANE, PATTEC Coordinator
... Although the maintenance of T. b. gambiense HAT foci relies on the presence of a human reservoir, population densities can vary greatly: from under 20 per km 2 as discussed above for the forest zone of Côte d'Ivoire [5] and the 500 per km 2 estimated for the north-western Uganda study zone costed here. In the T. b. rhodesiense focus of south-eastern Uganda [8], where cattle have been shown to be the major reservoir [22] of the disease, the human population density at the time was 100 per km 2 . In areas with lower human population densities, tsetse habitat is likely to be more dense, access more difficult, terrain could be rugged, overnight stays or camping may be required and local labour be less easy to recruit. ...
To evaluate the relative effectiveness of tsetse control methods, their costs need to be analysed alongside their impact on tsetse populations. Very little has been published on the costs of methods specifically targeting human African trypanosomiasis.
In northern Uganda, a 250 km2 field trial was undertaken using small (0.5 X 0.25 m) insecticide-treated targets ("tiny targets"). Detailed cost recording accompanied every phase of the work. Costs were calculated for this operation as if managed by the Ugandan vector control services: removing purely research components of the work and applying local salaries. This calculation assumed that all resources are fully used, with no spare capacity. The full cost of the operation was assessed at USD 85.4 per km2, of which USD 55.7 or 65.2% were field costs, made up of three component activities (target deployment: 34.5%, trap monitoring: 10.6% and target maintenance: 20.1%). The remaining USD 29.7 or 34.8% of the costs were for preliminary studies and administration (tsetse surveys: 6.0%, sensitisation of local populations: 18.6% and office support: 10.2%). Targets accounted for only 12.9% of the total cost, other important cost components were labour (24.1%) and transport (34.6%).
Comparison with the updated cost of historical HAT vector control projects and recent estimates indicates that this work represents a major reduction in cost levels. This is attributed not just to the low unit cost of tiny targets but also to the organisation of delivery, using local labour with bicycles or motorcycles. Sensitivity analyses were undertaken, investigating key prices and assumptions. It is believed that these costs are generalizable to other HAT foci, although in more remote areas, with denser vegetation and fewer people, costs would increase, as would be the case for other tsetse control techniques.
... Progression in molecular technologies toward the end of the twentieth century established the domestic cattle population as the most significant animal reservoir in Uganda, essential for the maintenance of T. br. rhodesiense within human populations (10)(11)(12). Major HAT epidemics in Uganda's history have been associated with large cattle losses; over a million Ugandan cattle died in the 1890s, Rinderpest outbreaks across the country, resulting in large tracts of overgrown grazing land conducive to escalating tsetse infestations. It is thought that the tsetse flies "ran short" of cattle to feed on during this time, reverting to human blood meals, which perpetuated the spread of disease during this period (9). ...
Rapid changes in human behavior, resource utilization, and other extrinsic environmental factors continue to threaten the current distribution of several endemic and historically neglected zoonoses in many developing regions worldwide. There are numerous examples of zoonotic diseases which have circulated within relatively localized geographical areas for some time, before emerging into new regions as a result of changing human, environmental, or behavioral dynamics. While the world’s focus is currently on the Ebola virus gaining momentum in western Africa, another pertinent example of this phenomenon is zoonotic human African trypanosomiasis (HAT), endemic to south and eastern Africa, and spread via infected cattle. In recent years, the ongoing northwards spread of this disease in the country has posed a serious public health threat to the human population of Uganda, increasing the pressure on both individual families and government services to control the disease. Moreover, the emergence of HAT into new areas of Uganda in recent years exemplifies the important role of veterinary policy in mitigating the severe human health and economic impacts of zoonotic disease. The systemic challenges surrounding the development and enforcement of veterinary policy described here are similar across sub-Saharan Africa, highlighting the necessity to consider and support zoonotic disease control in broader human and animal health systems strengthening and associated development programs on the continent.
... Movement of such cattle has introduced parasites to districts formerly free of human disease but where tsetse are present and able to transmit disease. In Tororo District 23% of cattle were found to be infected with T. b. rhodesiense [16] as were 18% of cattle being traded in Soroti District [17]; cattle were shown to be the main reservoir of infection for humans in this area [18]. ...
BACKGROUND: Uganda has active foci of both chronic and acute HAT with the acute zoonotic form of disease classically considered to be restricted to southeast Uganda, while the focus of the chronic form of HAT was confined to the northwest of the country. Acute HAT has however been migrating from its traditional disease focus, spreading rapidly to new districts, a spread linked to movement of infected cattle following restocking. Cattle act as long-term reservoirs of human infective T. b. rhodesiense showing few signs of morbidity, yet posing a significant risk to human health. It is important to understand the relationship between infected cattle and infected individuals so that an appropriate response can be made to the risk posed to the community from animals infected with human pathogens in a village setting. METHODOLOGY/PRINCIPAL FINDINGS: This paper examines the relationship between human T. b. rhodesiense infection and human infective and non-human T. brucei s.l. circulating in cattle at village level in Kaberamaido and Dokolo Districts, Uganda. The study was undertaken in villages that had reported a case of sleeping sickness in the six months prior to sample collection and those villages that had never reported a case of sleeping sickness. CONCLUSIONS AND SIGNIFICANCE: The sleeping sickness status of the villages had a significant effect with higher odds of infection in cattle from case than from non-case villages for T. brucei s.l. (OR: 2.94, 95%CI: 1.38-6.24). Cattle age had a significant effect (p
... The majority of cases are due to infection with the chronic form of the disease, caused by T. b. gambiense, found throughout western and central Africa and mainly transmitted by human-tsetse contact [6]. Acute HAT is a zoonotic disease caused by T. b. rhodesiense and present throughout southern and eastern Africa where a wide range of wild and domestic animals act as reservoirs of infection [7,8]. Sleeping sickness epidemiology is driven by a variety of factors, including the nature of the parasite, tsetse flies, reservoir hosts, human populations and biophysical phenomena whose complex interactions drive the emergence of epidemics. ...
The northwards spread of acute T. b. rhodesiense sleeping sickness in Uganda has been linked to cattle movements associated with restocking following the end to military conflict in 2006. This study examined the number of cattle traded from T. b. rhodesiense endemic districts, the prevalence of the parasite in cattle being traded and the level of trypanocidal treatment at livestock markets.
Between 2008 and 2009 interviews were carried out with government veterinarians from 20 districts in Uganda, 18 restocking organisations and numerous livestock traders and veterinarians. Direct observations, a review of movement permit records (2006 to 2008) and blood sampling of cattle (n = 1758) for detection of parasites were also conducted at 10 livestock markets in T. b. rhodesiense endemic districts.
Records available from 8 out of 47 identified markets showed that 39.5% (5,238/13,267) of the inter-district cattle trade between mid-2006 and mid-2008 involved movement from endemic areas to pathogen-free districts. PCR analysis showed a prevalence of 17.5% T. brucei s.l. (n = 307/1758 [95% CI: 15.7-19.2]) and 1.5% T. b. rhodesiense (n = 26/1758 [95% CI: 0.9-2.0]) from these same markets. In a two-year period, between late-2006 to late-2008, an estimated 72,321 to 86,785 cattle (57, 857 by 18 restocking organisations and 10,214 to 24,679 by private traders) were imported into seven pathogen-free northern districts, including districts that were endemic for T. b. gambiense. Between 281 and 1,302 of these cattle were likely to have carried T. b. rhodesiense. While governmental organisations predominantly adhered to trypanocidal treatment, most Non-Governmental Organisations (NGOs) and private traders did not. Inadequate market infrastructure, poor awareness, the need for payment for drug treatments, and the difficulty in enforcing a policy of treatment at point of sale contributed to non-compliance.
With increasing private trade, preventing the spread of Rhodesian sleeping sickness in Uganda requires government support to ensure mandatory trypanocidal treatment at livestock markets, investment in market infrastructure and possible drug subsidy. Mapping the northern reaches of T. b. rhodesiense in livestock and preparation of risk assessments for cattle trading could mitigate future outbreaks.
... In this scenario, one would predict that T. b. rhodesiense would undergo genetic exchange, show high levels of diversity and not be distinguishable from T. b. brucei except by the presence of the SRA gene. The available evidence does not support this as firstly we have shown (in Soroti and Tororo) that the populations are of low diversity with frequent identical genotypes and secondly previous studies have shown that T. b. brucei can be distinguished from T. b. rhodesiense by RFLP and minisatellite markers [10,60], demonstrating that they are genetically isolated. Based on these considerations, one hypothesis to explain the results is that Ugandan T. b. rhodesiense has lost the ability to undergo genetic exchange. ...
African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda) and Southern (Malawi) Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics.
... With changes in human population density, land-use and dramatically decreasing wildlife populations, the dominant reservoir-host for Rhodesian sleeping sickness has moved from wildlife to cattle in Uganda [18][19][20][21]. Since the late 1980s, the geographical range for Rhodesian HAT has increased from 13,820 to 34,843 km 2 threatening to overlap with the T. b. gambiense foci [22]. ...
Caused by trypanosomes and transmitted by tsetse flies, Human African Trypanosomiasis and bovine trypanosomiasis remain endemic across much of rural Uganda where the major reservoir of acute human infection is cattle. Following elimination of trypanosomes by mass trypanocidal treatment, it is crucial that farmers regularly apply pyrethroid-based insecticides to cattle to sustain parasite reductions, which also protect against tick-borne diseases. The private veterinary market is divided between products only effective against ticks (amidines) and those effective against both ticks and tsetse (pyrethroids). This study explored insecticide sales, demand and use in four districts of Uganda where mass cattle treatments have been undertaken by the 'Stamp Out Sleeping Sickness' programme.
A mixed-methods study was undertaken in Dokolo, Kaberamaido, Serere and Soroti districts of Uganda between September 2011 and February 2012. This included: focus groups in 40 villages, a livestock keeper survey (n = 495), a veterinary drug shop questionnaire (n = 74), participatory methods in six villages and numerous semi-structured interviews.
Although 70.5% of livestock keepers reportedly used insecticide each month during the rainy season, due to a variety of perceptions and practices nearly half used products only effective against ticks and not tsetse. Between 640 and 740 litres of insecticide were being sold monthly, covering an average of 53.7 cattle/km2. Sales were roughly divided between seven pyrethroid-based products and five products only effective against ticks. In the high-risk HAT district of Kaberamaido, almost double the volume of non-tsetse effective insecticide was being sold. Factors influencing insecticide choice included: disease knowledge, brand recognition, product price, half-life and mode of product action, product availability, and dissemination of information. Stakeholders considered market restriction of non-tsetse effective products the most effective way to increase pyrethroid use.
Conflicts of interest between veterinary business and vector control were found to constrain sleeping sickness control. While a variety of strategies could increase pyrethroid use, regulation of the insecticide market could effectively double the number of treated cattle with little cost to government, donors or farmers. Such regulation is entirely consistent with the role of the state in a privatised veterinary system and should include a mitigation strategy against the potential development of tick resistance.
... Bloodmeals from G.f. fuscipes now show that the flies feed on reptiles and cattle with almost no feeding on wild game in this once game-rich region. Infection rates in G.f. fuscipes remain low, 1:300 T. brucei s.l. and less than 1:1,000 T.b. rhodesiense (Hide et al. 1996), while T. brucei s.l. infection rates in cattle (Welburn, Picozzi et al. 2001) and pigs (Waiswa et al. 2003) are very high (T. ...
... A cattle-herder in the area at the time of the study stated that while he had been informed about animal trypanosomiasis from the District veterinary officer and treated his cattle for trypanosomiasis, he had not been informed that certain species of trypanosomes could infect, and be fatal to humans. This situation exemplified the disjunction between the management and treatment of animal (coordinated by MoLDF) and human trypanosomiasis (coordinated by MoHSW) in Urambo, despite strong evidence supporting their inter-relatedness [15][16][17][18] . ...
The public health and socio-economic burden of Human African Trypanosomiasis (HAT) in East Africa is not well documented. Understanding the epidemiology and impact of HAT in such settings is difficult due to a lack of robust surveillance and reporting systems, restricting evidence-based policy development and contributing to the continued neglect of this disease.
To investigate the burden of HAT in Urambo District, Tanzania in order to inform future public health policy.
A rapid participatory appraisal (RPA) using a combination of qualitative and quantitative methods was conducted, that included key informant interviews, hospital record analysis, and tools adapted from participatory learning and action.
Three villages adjacent to Ugala Game Reserve appeared to be the most affected. High levels of under-reporting were noted due to a lack of diagnostic tools at peripheral health care facilities and limited access to specialist services. Community stakeholders perceived the health and socio-economic burden of HAT to be similar to that of malaria.
The burden of HAT in remote rural communities is difficult to capture through routine surveillance systems alone. The RPA represents an efficient mechanism for engaging communities in public health action for trypanosomiasis control in northwest Tanzania.
... Dans les foyers d'Afrique de l'Est, où le parasite, T. b. rhodesiense détermine une forme beaucoup plus sévère de la maladie, il semble que les mêmes mécanismes soient impliqués dans la transmission. Une revue récente souligne l'existence de processus de persistance et de résurgence de la maladie dans ces foyers [40]. Une autre recherche développe la notion de seuil de densités humaines dont les variations entretiendraient l'infection [41]. ...
Les foyers historiques de maladie du sommeil à #Trypanosoma brucei gambiense$ présentent une remarquable capacité de persistance, parfois depuis la fin du siècle dernier. A partir d'un modèle recemment mis au point, les auteurs explorent les aspects cinétiques de la transmission. Afin d'appréhender la vitesse des processus épidémiologiques, un nouvel indice est introduit : T0, qui est le temps nécessaire pour que la prévalence soit divisée ou multipliée par deux selon que le taux de reproduction de base du système est inférieur ou supérieur à 1. Ce modèle à cinq compartiments est brièvement décrit et les équations données en annexe. Certaines configurations du système induisent une dynamique très lente (T0 de plus de 5 ans) expliquant le maintien à bas bruit de l'endémie sur de longues périodes. La résurgence sur un mode épidémique peut résulter de légères modifications d'un seul paramètre épidémiologique. Nous examinons particulièrement les changements (1) des effectifs des populations humaines et/ou vectorielles, (2) du taux de repas de sang pris par les vecteurs sur les humains, (3) de la virulence de la souche du parasite envers la population concernée. Dans ce modèle avec la population vectorielle ouverte, une faible immigration de tsé-tsé infectées suffit à maintenir une forte prévalence de malades à l'équilibre et peut expliquer le développement de la maladie au sein de populations sensibles et son essaimage dans des foyers secondaires. Ces hypothèses, confrontées aux données de terrain, rendent compte de la manière pertinente des observations réalisées sur des foyers ivoiriens, congolais et centrafricains. (Résumé d'auteur)
... infections in cattle, sufficient parasites are present to infect tsetse [40]. Cattle are the most important reservoir of T. b. rhodesiense in this region [41,42], with up to 18% of cattle infected in an epidemic focus in Uganda [43]. The comparatively low prevalence of T.b. rhodesiense detected in cattle and pigs during the current study nevertheless still poses a threat to human health in this area of Western Kenya, as was demonstrated by a case of sleeping sickness reported from Busia District in early 2006 [2] and the last recorded case from neighbouring Teso District, diagnosed in 2008 (Alupe Hospital, Western Kenya, pers. ...
Background:
Trypanosomiasis is regarded as a constraint on livestock production in Western Kenya where the responsibility for tsetse and trypanosomiasis control has increasingly shifted from the state to the individual livestock owner. To assess the sustainability of these localised control efforts, this study investigates biological and management risk factors associated with trypanosome infections detected by polymerase chain reaction (PCR), in a range of domestic livestock at the local scale in Busia, Kenya. Busia District also remains endemic for human sleeping sickness with sporadic cases of sleeping sickness reported.
Results:
In total, trypanosome infections were detected in 11.9% (329) out of the 2773 livestock sampled in Busia District. Multivariable logistic regression revealed that host species and cattle age affected overall trypanosome infection, with significantly increased odds of infection for cattle older than 18 months, and significantly lower odds of infection in pigs and small ruminants. Different grazing and watering management practices did not affect the odds of trypanosome infection, adjusted by host species. Neither anaemia nor condition score significantly affected the odds of trypanosome infection in cattle. Human infective Trypanosoma brucei rhodesiense were detected in 21.5% of animals infected with T. brucei s.l. (29/135) amounting to 1% (29/2773) of all sampled livestock, with significantly higher odds of T. brucei rhodesiense infections in T. brucei s.l. infected pigs (OR = 4.3, 95%CI 1.5-12.0) than in T. brucei s.l. infected cattle or small ruminants.
Conclusions:
Although cattle are the dominant reservoir of trypanosome infection it is unlikely that targeted treatment of only visibly diseased cattle will achieve sustainable interruption of transmission for either animal infective or zoonotic human infective trypanosomiasis, since most infections were detected in cattle that did not exhibit classical clinical signs of trypanosomiasis. Pigs were also found to be reservoirs of infection for T. b. rhodesiense and present a risk to local communities.
... Variation in HAT disease severity between foci suggests that there is genetic variation in trypanosome virulence and/or differences in host susceptibility to trypanosomiasis. Isoenzyme and minisatellite analysis of T.b. rhodesiense isolates from the Busoga focus and the Luangwa Valley focus in Zambia have confirmed distinct parasite genotypes between northern and southern East African HAT foci [13,14,15]. Correlation of parasite genotypes with different clinical profiles, however, is limited although analysis of a small number of T.b. rhodesiense isolates from within the Busoga focus (1989 to 1993) identified two main zymodemes (the 'busoga' and 'zambezi' zymodemes), which were associated with different clinical manifestations [16]. ...
Diverse clinical features have been reported in human African trypanosomiasis (HAT) foci caused by Trypanosoma brucei rhodesiense (T.b.rhodesiense) giving rise to the hypothesis that HAT manifests as a chronic disease in South-East African countries and increased in virulence towards the North. Such variation in disease severity suggests there are differences in host susceptibility to trypanosome infection and/or genetic variation in trypanosome virulence. Our molecular tools allow us to study the role of host and parasite genotypes, but obtaining matched extensive clinical data from a large cohort of HAT patients has previously proved problematic.
We present a retrospective cohort study providing detailed clinical profiles of 275 HAT patients recruited in two northern foci (Uganda) and one southern focus (Malawi) in East Africa. Characteristic clinical signs and symptoms of T.b.rhodesiense infection were recorded and the degree of neurological dysfunction determined on admission. Clinical observations were mapped by patient estimated post-infection time. We have identified common presenting symptoms in T.b.rhodesiense infection; however, marked differences in disease progression and severity were identified between foci. HAT was characterised as a chronic haemo-lymphatic stage infection in Malawi, and as an acute disease with marked neurological impairment in Uganda. Within Uganda, a more rapid progression to meningo-encephaltic stage of infection was observed in one focus (Soroti) where HAT was characterised by early onset neurodysfunction; however, severe neuropathology was more frequently observed in patients in a second focus (Tororo).
We have established focus-specific HAT clinical phenotypes showing dramatic variations in disease severity and rate of stage progression both between northern and southern East African foci and between Ugandan foci. Understanding the contribution of host and parasite factors in causing such clinical diversity in T.b.rhodesiense HAT has much relevance for both improvement of disease management and the identification of new drug therapy.
... In Uganda and other parts of East Africa, T. b. brucei and T. b. rhodesiense co-circulate in cattle, other livestock and wild animal species. Outbreaks of human infection occur periodically [8,9], and cattle have been shown to play a key role in the generation of human sleeping sickness epidemics in Uganda [3,10111213 . Understanding the epidemiology of T. brucei s.l. in cattle is important both for understanding and controlling animal trypanosomiasis as well as for estimating the size of the reservoir of human infective parasites and planning appropriate public health control measure [3,13]. ...
In East Africa, animal trypanosomiasis is caused by many tsetse transmitted protozoan parasites including Trypanosoma vivax, T. congolense and subspecies of T. brucei s.l. (T. b. brucei and zoonotic human infective T. b. rhodesiense) that may co-circulate in domestic and wild animals. Accurate species-specific prevalence measurements of these parasites in animal populations are complicated by mixed infections of trypanosomes within individual hosts, low parasite densities and difficulties in conducting field studies. Many Polymerase Chain Reaction (PCR) based diagnostic tools are available to characterise and quantify infection in animals. These are important for assessing the contribution of infections in animal reservoirs and the risk posed to humans from zoonotic trypanosome species. New matrices for DNA capture have simplified large scale field PCR analyses but few studies have examined the impact of these techniques on prevalence estimations.
The Whatman FTA matrix has been evaluated using a random sample of 35 village zebu cattle from a population naturally exposed to trypanosome infection. Using a generic trypanosome-specific PCR, prevalence was systematically evaluated. Multiple PCR samples taken from single FTA cards demonstrated that a single punch from an FTA card is not sufficient to confirm the infectivity status of an individual animal as parasite DNA is unevenly distributed across the card. At low parasite densities in the host, this stochastic sampling effect results in underestimation of prevalence based on single punch PCR testing. Repeated testing increased the estimated prevalence of all Trypanosoma spp. from 9.7% to 86%. Using repeat testing, a very high prevalence of pathogenic trypanosomes was detected in these local village cattle: T. brucei (34.3%), T. congolense (42.9%) and T. vivax (22.9%).
These results show that, despite the convenience of Whatman FTA cards and specific PCR based detection tools, the chronically low parasitaemias in indigenous African zebu cattle make it difficult to establish true prevalence. Although this study specifically applies to FTA cards, a similar effect would be experienced with other approaches using blood samples containing low parasite densities. For example, using blood film microscopy or PCR detection from liquid samples where the probability of detecting a parasite or DNA molecule, in the required number of fields of view or PCR reaction, is less than one.
... T.b. rhodesiense is a zoonosis [5,6], with a number of wildlife [7] and domestic animal species known to act as reservoirs. Where wildlife is not abundant, domestic species, particularly cattle, are the main reservoir [8], with livestock demography driving outbreaks [9]. T.b. gambiense is generally not considered zoonotic-it can be isolated from animal hosts [10,11], but large-scale control campaigns targeting only the human reservoir (active screening and treatment of human cases) are able to locally eliminate transmission [12,13], and theoretical assessments of control options [14] confirm that from an epidemiological perspective, the presence of animal hosts is unlikely to mean they serve as a reservoir of infection for humans [15] (such hosts and their potential as a source for re-introduction of the parasite to the human population would need to be considered if ever aiming for total elimination of the disease, however). ...
Human African trypanosomiasis (HAT, or sleeping sickness) is a protozoan parasitic infection caused by Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense. These are neglected tropical diseases, and T.b. rhodesiense HAT is a zoonosis. We review current knowledge on the burden of HAT in sub-Saharan Africa, with an emphasis on the disability-adjusted life year (DALY), data sources, and methodological issues relating to the use of this metric for assessing the burden of this disease. We highlight areas where data are lacking to properly quantify the impact of these diseases, mainly relating to quantifying under-reporting and disability associated with infection, and challenge the HAT research community to tackle the neglect in data gathering to enable better evidence-based assessments of burden using DALYs or other appropriate measures.
Human African Trypanosomiasis (HAT) found only in sub-Saharan Africa is caused by the parasite Trypanosoma brucei, which is transmitted by tsetse flies. Only two sub-species of T. brucei are pathogenic for humans: T. b. gambiense and T. b. rhodesiense. HAT is endemic in 36 sub-Saharan countries, and 98% of all reported HAT cases are due to T. b. gambiense. Fifty-five million persons in Africa are at risk of HAT. The number of HAT cases reported globally decreased fivefold in the last decade, which encouraged WHO to set a target to eliminate HAT as a public health problem by the year 2020, aiming for zero transmission by the year 2030. Tsetse flies do not lay eggs, but the female fly deposits a single mature larva in humid soil. The larva pupates and emerges as an adult fly 20 to 80 days later. A female fly produces only 3–5 larvae during her lifetime that typically lasts for 3 months making the intrinsic growth rate of tsetse populations rather low. An infected tsetse fly injects the infective form of the parasites into the mammalian host when it feeds. These parasites undergo, and can switch, their antigenic variation of their variant surface glycoprotein (VSG) coat, allowing them to escape the host immune response. This phenomenon of antigenic variation makes the development of an effective vaccine unlikely. The disease affects mainly the lymphoid system, heart, lungs, and brain, manifesting as intermittent fever, general malaise, severe headache, joint pains and muscle aches, pruritus, urticaria, or facial oedema. Lymphadenopathy is common with the classical Winterbottom’s sign. Patients with the meningo-encephalitic stage suffer continuous headaches with poor response to painkillers and show more specific neurological signs of the rather typical sleep disturbances. Diagnosis of HAT is a three-step procedure: (1) screening test to identify HAT suspects, (2) confirmatory parasitological tests, and (3) staging. Treatment is based on the stage of illness, with current options being pentamidine, suramin, melarsoprol, eflornithine, fexinidazole, and the nifurtimox-eflornithine combination therapy (NECT). Two strategies are used for the reduction or interruption of HAT transmission: elimination of the parasite reservoir and vector control. This last decade has seen several breakthroughs in clinical R&D for HAT, bringing new diagnostics and drugs to patient care, but the effective and efficient implementation of these new tools in HAT control and proper treatment of patients will require further research.
This reviews work published since 2007. Relative efforts devoted to the agents of African trypanosomiasis and their tsetse fly vectors are given by the numbers of PubMed accessions. In the last 10 years PubMed citations number 3457 for Trypanosoma brucei and 769 for Glossina. The development of simple sequence repeats and single nucleotide polymorphisms afford much higher resolution of Glossina and Trypanosoma population structures than heretofore. Even greater resolution is offered by partial and whole genome sequencing. Reproduction in T. brucei sensu lato is principally clonal although genetic recombination in tsetse salivary glands has been demonstrated in T. b. brucei and T. b. rhodesiense but not in T. b. gambiense. In the past decade most genetic attention was given to the chief human African trypanosomiasis vectors in subgenus Nemorhina e.g., Glossina f. fuscipes, G. p. palpalis, and G. p. gambiense. The chief interest in Nemorhina population genetics seemed to be finding vector populations sufficiently isolated to enable efficient and long-lasting suppression. To this end estimates were made of gene flow, derived from FST and its analogues, and Ne, the size of a hypothetical population equivalent to that under study. Genetic drift was greater, gene flow and Ne typically lesser in savannah inhabiting tsetse (subgenus Glossina) than in riverine forms (Nemorhina). Population stabilities were examined by sequential sampling and genotypic analysis of nuclear and mitochondrial genomes in both groups and found to be stable. Gene frequencies estimated in sequential samplings differed by drift and allowed estimates of effective population numbers that were greater for Nemorhina spp than Glossina spp. Prospects are examined of genetic methods of vector control. The tsetse long generation time (c. 50 d) is a major contraindication to any suggested genetic method of tsetse population manipulation. Ecological and modelling research convincingly show that conventional methods of targeted insecticide applications and traps/targets can achieve cost-effective reduction in tsetse densities.
Human African trypanosomiasis (HAT) found only in sub-Saharan Africa is caused by the parasite Trypanosoma brucei which is transmitted by tsetse flies. Only two subspecies of T.brucei are pathogenic for humans: T.b. gambiense and T.b. rhodesiense. HAT is endemic in 36 sub-Saharan countries, and 98 % of all reported HAT cases are due to T. b. gambiense. Sixty-nine million persons in Africa are at risk of HAT. The number of HAT cases reported globally decreased fivefold in the last decade which has encouraged WHO to set a target to eliminate HAT as a public health problem by the year 2020, aiming for zero transmission by the year 2030. Tsetse flies do not lay eggs, but the female fly deposits a single mature larva in humid soil. The larva pupates and emerges as an adult fly 20–80 days later. A female fly produces only three to five larvae during her lifetime that typically lasts for 3 months, making the intrinsic growth rate of tsetse populations rather low. An infected tsetse fly injects the infective form of the parasites into the mammalian host when it feeds. These parasites undergo, and are able to switch, their antigenic variation of their variant surface glycoprotein (VSG) coat, allowing them to escape the host immune response. This phenomenon of antigenic variation makes the development of an effective vaccine unlikely. The disease affects mainly the lymphoid system, heart, lungs and brain manifesting as intermittent fever, general malaise, severe headache, joint pains and muscle aches, pruritus, urticaria or facial oedema. Lymphadenopathy is common with the classical Winterbottom’s sign. Patients with the meningo-encephalitic stage suffer continuous headaches with poor response to painkillers and show more specific neurological signs of the rather typical sleep disturbances. Diagnosis of HAT is a three-step procedure: (i) screening test to identify HAT suspects, (ii) confirmatory parasitological tests and (iii) staging. Treatment is based on the stage of illness, current options being pentamidine, suramin, melarsoprol, eflornithine and the nifurtimox-eflornithine combination therapy (NECT). Two strategies are used for the reduction or interruption of HAT transmission: elimination of the parasite reservoir and vector control. This last decade has seen several breakthroughs in clinical R&D for HAT, bringing new diagnostics and drugs to patient care, but effective and efficient implementation of these new tools in HAT control and proper treatment of patients will require further research.
One of the enduring problems in the epidemiology of sleeping sickness is that there are 3 morphologically indistinguishable subspecies of Trypanosoma brucei involved in a complex transmission cycle between humans, tsetse and reservoir hosts. Two subspecies, T. b. gambiense and T. b. rhodesiense, are infective to man and cause gambian and rhodesian sleeping sickness, respectively. The third subspecies T. b. brucei cannot by definition infect humans, but coexists with the other trypanosomes in reservoir hosts and vectors.
The apparent pathogenicity of the tsetse fly bite to horses in southern Africa as revealed by Vardon, led Westwood (1850) and then Arnaud (1852) to suggest trypanosomiasis was caused by ordinary inoculation of venin by an insect. In 1875 Mégnin argued the swampy shores of lakes and big rivers must be poisoned with endemic anthrax-like infections and septic liquids which attack large herbivores, and these could be transported and inoculated by tsetse and other blood-sucking flies. This was the only explanation as to why some animals were affected and not others.
SUMMARY Considering the epidemic situation of gambiense human African trypanosomiasis (HAT) at the end of the twentieth century, the World Health Organization (WHO) and partners strengthened disease control and surveillance. Over the last 15 years, the activities implemented through the National Control Programmes have brought gambiense HAT under control and now its elimination is deemed as an achievable goal. In 2012, WHO targeted gambiense HAT for elimination as a public health problem by 2020. The final goal will be the sustainable disease elimination by 2030, defined as the interruption of the transmission of gambiense HAT. The elimination is considered feasible, because of the epidemiological vulnerability of the disease, the current state of control, the availability of strategies and tools and international commitment and political will. Integration of activities in the health system is needed to ensure the sustainability of the elimination. The development of user-friendly diagnostic and treatment tools will facilitate the integration process. Adequate funding is needed to implement activities, but also to support research that will make the elimination sustainable. A long-term commitment by donors is needed and ownership of the process by endemic countries is critical.
This chapter discusses the basic principles of the epidemiology of parasites and surveys the application of modem molecular biology technology to the understanding of parasite epidemiology. One of the primary problems in parasite epidemiology is the correlation of a given disease with its causative organism. Identification of the primary causative parasite is crucial not only to treatment procedures but also to the understanding of the epidemiology of the disease. In some cases, the causative parasite species is easily identified as in the cases of larger, morphologically distinct, parasites such as Ascaris lumbricoides or Taenia spp. Other parasites, such as protozoa, are more difficult to distinguish and can appear to be morphologically very similar but have different disease characteristics. For example, the malaria parasites are morphologically similar but have different levels of virulence, with P. falciparum being the most serious. A considerable amount of information has been accumulated covering the epidemiology of most parasitic diseases, using classical parasitological and medical studies.
The log–logistic probability distribution function was employed to model trappability of Glossina fuscipes fuscipes, with respect to distance from the edge of two types of habitat. The parameters of the model were obtained using the nonlinear maximum likelihood approach. Asymptotic standard errors of the maximum likelihood estimates were computed for the parameters, and the χ2 goodness-of-fit test used to assess the predicted trap catches. Simulation technique was used to estimate the radius of attraction of the unbaited biconical trap for the fly, taking the efficiency of the trap into consideration. The log–logistic model fitted well to a series of observed field data. The model enabled the estimation of optimum trapping distances from the different habitat types for G. f. fuscipes. There is an indication that flies were attracted to, and got trapped optimally with, unbaited biconical traps, at distances that are characteristic of both sex of the fly and the type of habitat.
Les trypanosomes africains, dont la plupart sont transmis par les glossines ou mouches tsétsé, déterminent à la fois la maladie du sommeil et des affections d'une grande importance économique chez les animaux domestiques. Cette revue présente les connaissances actuelles sur les trypanosomes et les trypanosomoses. L'accent est mis sur les particularités biologiques de ces parasites, et sur les réponses immunitaires à l'infection. Si certaines particularités biologiques, telles que la variation antigénique, constituent des mécanismes d'échappement aux défenses de l'hôte, d'autres sont en revanche des points d'attaque potentiels pour le développement de nouvelles thérapeutiques.
Climate warming over the next century is expected to have a large impact on the interactions between pathogens and their animal and human hosts. Vector-borne diseases are particularly sensitive to warming because temperature changes can alter vector development rates, shift their geographical distribution and alter transmission dynamics. For this reason, African trypanosomiasis (sleeping sickness), a vector-borne disease of humans and animals, was recently identified as one of the 12 infectious diseases likely to spread owing to climate change. We combine a variety of direct effects of temperature on vector ecology, vector biology and vector-parasite interactions via a disease transmission model and extrapolate the potential compounding effects of projected warming on the epidemiology of African trypanosomiasis. The model predicts that epidemics can occur when mean temperatures are between 20.7°C and 26.1°C. Our model does not predict a large-range expansion, but rather a large shift of up to 60 per cent in the geographical extent of the range. The model also predicts that 46-77 million additional people may be at risk of exposure by 2090. Future research could expand our analysis to include other environmental factors that influence tsetse populations and disease transmission such as humidity, as well as changes to human, livestock and wildlife distributions. The modelling approach presented here provides a framework for using the climate-sensitive aspects of vector and pathogen biology to predict changes in disease prevalence and risk owing to climate change.
Graduation date: 2011 Like other species interactions in ecological systems, host-pathogen interactions are influenced by environmental factors, landscape characteristics and the broader community context. My thesis explores the potential influences of food-web interactions (Chapter 2), climate change (Chapter 3), landscape structure and host movement patterns (Chapter 4), and the combined influences of local community context and regional processes (Chapter 5) on host-pathogen interactions. Infectious diseases transmitted by vectors depend on the interactions between the vector and other species within the community. In Chapter 2 I develop a theoretical model integrating predator-prey and host-pathogen theory to examine the effect of predator-vector interactions on vector-transmitted diseases. Predation on a vector may drastically slow a pathogen's spread, and increase host abundance by reducing—or eliminating—infection in the host population. The introduction of a predator can lead to a negative relationship between prevalence and vector fecundity, with the pathogen being driven out of the system at high rates of predation or fecundity. Chapter 3 examines how temperature influences the biology of a parasite, Trypanosoma brucei rhodesiense, and its tsetse fly vector in order to examine the potential effects of global warming on sleeping sickness. Model results indicate that projected warming over the next 50–100 years is likely to significantly shift the distribution of sleeping sickness in Africa. The modeling approach presented in Chapter 3 provides a framework for using the climate-sensitive aspects of vector and pathogen biology to predict changes in disease prevalence and risk due to climate change. The spread and persistence of generalist pathogens that infect multiple host species are influenced by spatial heterogeneity in host composition and the movement patterns of different host species. Chapter 4 uses a metapopulation disease model to identify the potential effects of landscape connectivity, patch heterogeneity, and host community composition on the spread, prevalence, and persistence of multi-host pathogens at the local and regional scales. In an observational study of barley and cereal yellow dwarf viruses (B/CYDV) in a set of Cascades meadows, I found that patterns of disease prevalence are primarily driven by the diversity and composition of the local host community (Chapter 5).
East African sleeping sickness, caused by Trypanosoma brucei rhodesiense, is prominent in Uganda and poses a serious public health challenge in the region. This publication attempts to provide key components for designing a strategy for a nationwide initiative to provide insecticide-treatment of the animal reservoir to control T. b. rhodesiense. The contents of this article will focus on insecticide-based vector control strategies, monitoring and evaluation framework, and knowledge gaps required for future initiatives.
Human 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.
We propose a general theory of clonal reproduction for parasitic protozoa, which has important medical and biological consequences. Many parasitic protozoa have been assumed to reproduce sexually, because of diploidy and occasional sexuality in the laboratory. However, a population genetic analysis of extensive data on biochemical polymorphisms indicates that the two fundamental consequences of sexual reproduction (i.e., segregation and recombination) are apparently rare or absent in natural populations of the parasitic protozoa. Moreover, the clones recorded appear to be stable over large geographical areas and long periods of time. A clonal population structure demands that the medical attributes of clones be separately characterized; ubiquitous clones call for priority characterization. Uniparental reproduction renders unsatisfactory Linnean taxonomy; this needs to be supplemented by the "natural clone" as an additional taxonomic unit, which is best defined by means of genetic markers.
Numerical taxonomy was used to review isoenzyme variation in isolates of Trypanosoma brucei obtained from cattle, tsetse, humans and wildlife from the Lambwe Valley, Kenya. From isoenzyme information alone, it was possible to classify isolates as to source through the use of linear discriminant functions analysis, with an error rate of only 2% in humans, and 14% over all groups. Differentiation was mostly dependent on patterns in the enzymes ASAT, PEP1, and ICD. Parasites from non-human sources, especially tsetse, were characterized by high isoenzyme diversity, and many unique zymodemes. Observed frequencies of genotypes for ICD, ALAT, and ASAT did not agree with expected frequencies based on random mating of a diploid organism. Deviations were particularly large for tsetse isolates, and were mostly due to a deficiency of one homozygote. Cluster analysis revealed complex relationships among isolates, with patterns evolving through time. Major human zymodemes from the 1970s clustered together with most wildlife isolates from East Africa. This chronic human-wildlife transmission cycle was characterized by ASAT pattern I. Other, minor human zymodemes were associated with a human-cattle transmission cycle characterized by ASAT pattern VII. These original chronic transmission cycles appeared to change in 1980 with the appearance of two new zymodemes in humans. These zymodemes involved changes in ALAT and/or PGM to patterns typical of tsetse and cattle isolates. A resultant epidemic was halted with repeated aerial spraying of endosulfan in 1981. Since then, a variety of new zymodemes of unknown human infectivity have appeared. The origins of these changes are discussed in terms of genetic exchange in tsetse, adaptation to human and cattle transmission cycles, and selection resulting from chronic use of insecticides.
This study represents an analysis of trypanosome strains circulating within a confined location over a short period of time during a sleeping sickness epidemic in S.E. Uganda. A large number of Trypanosoma brucei isolates (88) were collected from a variety of hosts (man, cattle, pigs and tsetse) from villages within a 10 km radius and were analysed for variation in isoenzyme patterns, restriction fragment length polymorphism (RFLP) in repetitive DNA sequences and susceptibility to human serum. The human infective stocks form a clearly distinguishable population when compared with other stocks circulating in the domestic cattle reservoir. The data here support the occurrence of genetic exchange between the cattle stocks while an 'epidemic' population structure involving limited genetic exchange is a characteristic of the human infective stocks. Furthermore, it is shown that when both RFLP and isoenzyme analysis are carried out most stocks appear to have individual genotypes. Stocks which were formerly grouped as zymodemes are better considered as a collected of distinct individuals.
Data from multilocus enzyme electrophoresis of bacterial populations were analyzed using a statistical test designed to detect associations between genes at different loci. Some species (e.g., Salmonella) were found to be clonal at all levels of analysis. At the other extreme, Neisseria gonorrhoeae is panmictic, with random association between loci. Two intermediate types of population structure were also found. Neisseria meningitidis displays what we have called an "epidemic" structure. There is significant association between loci, but this arises only because of the recent, explosive, increase in particular electrophoretic types; when this effect is eliminated the population is found to be effectively panmictic. In contrast, linkage disequilibrium in a population of Rhizobium meliloti exists because the sample consisted of two genetically isolated divisions, often fixed for different alleles: within each division association between loci was almost random. The method of analysis is appropriate whenever there is doubt about the extent of genetic recombination between members of a population. To illustrate this we analyzed data on protozoan parasites and again found panmictic, epidemic, and clonal population structures.
Many protozoan organisms can be difficult to identify because of morphological similarities between strains or species. This is particularly true in the case of the African trypanosomes (Trypanosoma spp.). These trypanosomes are important medical and veterinary protozoan parasites that are transmitted between hosts by the tsetse fly. Correct identification is essential for the control and treatment of the diseases they cause (sleeping sickness in humans; “nagana” in cattle). The taxonomy of the African Trypanosoma spp. is complex but the most economically important species are T. congolense, T. vivax, and the T. brucei “complex” (1). All three species infect domestic cattle, whereas two subspecies of T. brucei (T. b. rhodesiense and T. b. gambiense) infect humans. The two human infective subspecies are morphologically identical, differing in geographical locality and symptoms caused, and, in addition, both are morphologically identical to the subspecies that infects cattle (T. b. brucei). Two levels of identification are necessary: the distinction of species and the identification of strains within a species (2,3). In the former case, the practical applications of identification include determining the presence or absence of infection and the trypanosome species responsible for the disease (diagnosis). In the latter case, identification of strains can play an important role in understanding the epidemiology of the disease.
• 1)The first recognized cases of T. rhodesiense sleeping sickness occurred in Northern Rhodesia, Nyasaland, and Southern Rhodesia between 1908 and 1912. At this time sporadic cases only occurred in the Rhodesias, but there was an epidemic in Nyasaland.
• 2)The epidemic spread northwards reaching Central Tanganyika in the 1920's, and Uganda and Kenya in the 1940's. With each extension, the disease has become more acute and the strains more rapidly lethal to experimental animals.
• 3)In Southern Rhodesia the disease remains sporadic and relatively chronic, with the occurrence of “healthy carriers.”
• 4)In Northern Rhodesia epidemics have occurred, but the disease remains relatively chronic as compared with the epidemic areas of East Africa.
• 5)In Ngamiland and the Chobe districts of Bechuanaland sporadic cases have occurred since 1934 (possibly since 1909), but since 1957 minor epidemic conditions have appeared.
• 6)In areas which have been affected by epidemic Rhodesian sleeping sickness, after the disease has been controlled, sporadic cases continue to occur, and these cases in time gradually become less acute.
• 7)T. brucei was present in Tanganyika before 1914. Epidemic T. rhodesiense was absent, but invaded the Territory during the first World War: it is not surprising, therefore, that there is a wide distinction between these two “species” in terms of infectivity to man.
• 8)T. brucei in domestic stock and T. rhodesiense in man both occur sporadically in Southern Rhodesia. Since the time of European settlement there has been no recorded epidemic of sleeping sickness: it is unlikely, therefore, that such a marked distinction in human infectivity exists as in Tanganyika; i.e., the theories of Kinghorn and Yorke (1912a) and of Bruce (1915) on the identity of T. brucei and T. rhodesiense still await experimental proof.
• 9)Several cases of sporadic trypanosomiasis caused by T. rhodesiense (as here defined) have occurred in man in areas outside the normal “rhodesiense area.”
• 10)In the better authenticated instances the strains from these sporadic cases from outside the “rhodesiense area” might have been derived either from T. brucei or T. gambiense, since both exist in the areas concerned. The original strain, from which the epidemic form of T. rhodesiense has been derived, arose in the Zambezi basin, this is so far removed from any known focus of T. gambiense as to make it unlikely that the strain was derived from anything other than T. brucei.
Concerted evolution is a distribution pattern of mutations in multiple copy sequences such that there is a greater similarity in sequence among the members of a repeated family from within a species than there is among the members of the family drawn from different species. There are several genomic mechanisms responsible for such patterns, which are involved, in their different ways, with the nonreciprocal transfer of information between members of a family. Prominent among these turnover mechanisms are unequal crossing-over and gene conversion, but other mechanisms such as DNA transposition, RNA-mediated sequence transfers, and DNA slippage are also involved. The continual, stochastic, or biased gain and loss of sequence variants within individuals can ultimately lead to the concomitant spread (molecular drive) of a variant through a family (homogenization) and through a sexual population (fixation). Molecular drive is a process, consequential on the mechanisms of DNA turnover that can explain observed patterns of concerted evolution. It can bring about, like natural selection and genetic drift, a long-term change in the genetic composition of a population with respect to a given family of sequences.
The differentiation of Trypanosoma brucei from T. rhodesiense, the causative agent of human sleeping sickness, depends on their relative sensitivities to the cytotoxic effects of normal human serum. The molecule responsible for the specific lysis of T. brucei has now been isolated. Serum lipoproteins were fractionated and purified by ultracentrifugal flotation and chromatography on Bio-Gel A-5m. Trypanocidal activity was recovered in the high density lipoprotein fraction (density, 1.063-1.216 g/ml). Contamination by other serum proteins was checked by crossed immunoelectrophoresis and sodium dodecyl sulfate/acrylamide gel electrophoresis. Only a trace of beta-lipoprotein was found. The trypanocidal activity of pure human high density lipoprotein was identical to that of unfractionated serum when the following were tested: (i) time course of in vitro lysis of T. bruceli; (ii) in vivo destruction of T. brucei; (iii) relative resistance of T. rhodesiense to lysis. Rat or rabbit high density lipoprotein had no trypanocidal activity. Identification of the trypanocidal factor as high density lipoprotein was confirmed by the finding that serum from patients with Tangier disease, an autosomal recessive disorder characterized by a severe deficiency of high density lipoprotein, had no trypanocidal activity.
A contingency table approach was used to explore the influence of location, host species and time on the genetic composition of a Trypanosoma brucei population in Lambwe Valley, Kenya. Significant differences in zymodeme frequencies were noticed over comparatively short geographical distances suggesting that transmission of T. brucei is somewhat localized. A significant association was observed between zymodeme and the mammalian host from which T. brucei was derived. The association was consistent in different localities in Lambwe valley and remained stable for at least 32 months. These observations indicate that zymodemes are adapted to different host species and that genetic exchange has not disrupted host associations over this time-scale. A major change in the composition of the T. brucei population during a sleeping sickness outbreak in 1980 was confirmed. But while new zymodemes emerged, a decline in overall diversity was noted during times of high sleeping sickness incidence. The results can be explained by selection of T. brucei zymodemes for particular transmission cycles. Although it is not necessary to invoke genetic exchange, sex may help T. brucei to adapt to changes in selection pressures. Such a hypothesis helps to explain why T. brucei appears largely clonal in the short term, even though population studies indicate that sex is responsible for much genetic diversity in the long term. It also explains why neighbouring populations of T. brucei are composed of a different range of zymodemes formed from the same alleles. Such a view implies that genetic exchange has an important role in the microevolution of T. brucei populations.
The explosion of new techniques, made available by the rapid advance in molecular biology, has provided a battery of novel approaches and technology which can be applied to more practical issues such as the epidemiology of parasites. In this review, we discuss the ways in which this new field of molecular epidemiology has contributed to and corroborated our existing knowledge of parasite epidemiology. Similar epidemiological questions can be asked about many different types of parasites and, using detailed examples such as the African trypanosomes and the Leishmania parasites, we discuss the techniques and the methodologies that have been or could be employed to solve many of these epidemiological problems.
We describe the use of repetitive DNA probes to characterise the relationships between different stocks of African trypanosomes representing the subspecies of Trypanosoma brucei. Probes derived from the ribosomal RNA genes (coding region and nontranscribed spacer) and another repetitive DNA sequence were used to characterise trypanosome stocks by Southern blotting. Numerical taxonomy methods applied to the resulting restriction enzyme patterns were used to derive a dendrogram depicting the relationships between the stocks examined. We show that three groups of West African human infective stocks can be distinguished: firstly, a group containing exclusively T. b. gambiense; secondly, a group which is indistinguishable from animal isolates in West Africa; and thirdly, a single stock which is indistinguishable from East African T. b. rhodesiense. In addition, we observe that T. b. rhodesiense stocks from East Africa are indistinguishable from animal isolates from the same area. Finally, we show that a group of T. b. rhodesiense stocks, isolated from a 1978 sleeping sickness outbreak in Zambia, are probably derived from a single parasite strain, and that this strain is distinct from T. b. rhodesiense parasites from Kenya and Uganda.
We have previously described a system for characterising the relationships between trypanosome stocks of the T.brucei group based on Southern blotting with repetitive DNA probes followed by cluster analysis of resultant banding patterns (G. Hide et al. Molec. Bioch. Parasitol. 39, 213-226, 1990). In this study, we extend this analysis to examine the relationships between trypanosome stocks isolated from major sleeping sickness foci in Zambia, Kenya, and Uganda. We show that the trypanosome strains responsible for disease in Zambia are quite distinct from those sampled from the Kenya/Uganda foci. Furthermore, the human serum resistant stocks isolated from the Kenya/Uganda foci which were isolated from man (or from animals) were found to form a tight group in the cluster analysis, while stocks isolated from nonhuman sources in the same area or stocks from elsewhere were found in separate groups. Thus, the human infective trypanosome strains found in these foci may have common origins and have, perhaps, arisen by clonal selection from a common source.
Restriction fragment length polymorphism (RFLP) has been analysed in Trypanosoma brucei DNA following hybridization with different DNA probes. This polymorphism seems to be due to allelic variation, and not to variation between sequence duplicates, since the genomic environment of the probed polymorphic fragments is conserved over considerable distances. In an analysis of 35 non-gambiense stocks, we found different combinations of homozygotes and heterozygotes for the four RFLP probes used, in keeping with previous observations that genetic reassortment occurs in T. b. brucei. Moreover, the non-gambiense populations from West and East Africa can be differentiated according to their characteristic allele frequencies. In sharp contrast, we found that the 49 T. b. gambiense stocks, analysed with the same probes, share the same single allelic combination and are all homozygous for each one of the four markers. This characteristic gambiense allele combination is very common among Western non-gambiense isolates, but rare or absent among Eastern ones. Two stocks isolated from man in West Africa turned out to be non-gambiense by all molecular criteria examined, including total nuclear DNA content. Taken together, these observations suggest that human serum-resistant variants may appear among the West African T. b. brucei population, and that T. b. gambiense evolved from one of these resistant variants as a man-adapted subspecies that became genetically isolated from the rest of the West African trypanosome population.
Two trypanosome clones, representing East and West African homozygotes at 2 isoenzyme loci (T. b. rhodesiense MHOM/ZM/74/58 [CLONE B] and T. b. brucei MSUS/CI/78/TSW 196 [CLONE A]), were cotransmitted through tsetse flies and the resulting trypanosome populations checked for the presence of non-parental karyotypes by pulsed-field gel electrophoresis. Ten clones isolated from these populations proved to have 5 different recombinant genotypes by analysis of nuclear and kinetoplast DNA (kDNA) polymorphisms. It is inferred that genetic exchange occurred between the 2 trypanosome clones in the fly, as previously reported for 2 other T. brucei spp. clones by Jenni and colleagues. For the most part, the hybrid clones shared many characteristics with both parents and their genotypes were consistent with segregation and reassortment of parental alleles. The least amount of genetic material exchanged was kDNA alone. Regarding the mechanism of genetic exchange, several hybrid clones had identical and unique nuclear DNA polymorphisms, but different kDNA type. Assuming that the same reassortment of nuclear markers is unlikely to occur by chance, these clones most probably arose from a predecessor carrying both types of kDNA.
Experimental work has established that a sexual process can occur in African trypanosomes (Jenni, Marti, Schweizer, Betschart, Le Page, Wells, Tait, Paindavoine, Pays & Steinert, 1986; Paindavoine, Zampetti-Bosseler, Pays, Schweizer, Guyaux, Jenni & Steinert, 1986; Tait, personal communication). However, the role of the process in natural populations of trypanosomes is poorly understood. This paper considers what information can be gained from analyses of isoenzyme polymorphism. A cladistic approach is used to help determine whether trypanosome diversity could have been produced by mutation alone. When applied to three East African populations of Trypanosoma brucei it provides evidence that some diversity has arisen through a sexual process; this explains the variation observed within a locality and can account for the evolution of differences between localities. However, the extent to which genetic exchange currently operates is less clear. Analysis of genotype frequencies indicates that agreements with Hardy-Weinberg expectations can be obtained even if genetic exchange exerted no influence over genotype frequencies. Moreover, analysis of joint locus frequencies reveals disequilibrium between loci and that trypanosome populations may be lacking several genotype combinations. Thus, genetic exchange may not occur sufficiently frequently, or in such a way as to break up associations between loci. The relevance of these observations to the evolution of strain differences within T. brucei is discussed.
Trypanosomes of the species Trypanosoma brucei reproduce primarily by binary fission, but the frequency of enzyme electrophoretic variants in natural populations of T. brucei has provided indirect evidence for the existence of a sexual cycle. These studies, coupled with studies of restriction fragment length polymorphisms of genes encoding glycolytic enzymes, have also provided evidence for T. brucei being diploid. Here we report direct evidence of gene exchange between two different clones of trypanosomes after mixed infection and full cyclical development in the tsetse fly vector.
A collection of stocks of Trypanosoma brucei rhodesiense isolated in Kenya have been examined for electrophoretic variation in 20 enzymes. The results obtained have been analysed in order to determine whether these trypanosomes are diploid and undergo mating and to determine the genetic distance between T. b. rhodesiense, T. b. brucei and T. b. gambiense. The enzyme electrophoretic markers were further used in experiments involving cyclically transmitted mixtures of stocks aimed at detecting genetic exchange in the laboratory. No genetic exchange was detected. Two novel features of the enzyme electrophoretic results were found. Firstly, the stocks of T. b. rhodesiense were considerably more homogeneous than equivalent collections of stocks of T. b. brucei and secondly, all the stocks examined were heterozygous for two alleles of alkaline phosphatase and showed an excess of heterozygotes at the phosphoglucomutase locus. The degree to which these features are typical of T. b. rhodesiense has been examined in relation to previously published data. The results obtained strongly support the view that T. b. rhodesiense is a set of variants of T. b. brucei rather than a subspecies and a working hypothesis as to the relationship between T. b. brucei and T. b. rhodesiense is proposed to explain the enzyme electrophoretic data obtained.
The nuclear DNAs of 71 trypanosome stocks from different African countries, representative of the three Trypanosoma brucei subspecies, and one T. evansi stock, have been analysed by the combined use of restriction endonuclease digestion, gel electrophoresis and molecular hybridization with both trypanosome surface-antigen-specific and undefined genomic DNA probes. In contrast with T. brucei brucei and T. brucei rhodesiense stocks, all the T. b. gambiense stocks are characterized by a conserved, specific DNA band pattern, regardless of the probe. This allows T. b. gambiense to be non-ambiguously identified. On the contrary, T.b. brucei and T. b. rhodesiense, which could not be discriminated by the same criteria, both yield highly variable DNA band patterns. Our data confirm that domestic animals like pig, dog and sheep constitute a potential reservoir for T.b. gambiense. Using a numerical analysis of the DNA hybridization patterns we have measured the degree of similarity between the 72 trypanosome stocks. This investigation shows that all T.b. gambiense stocks are included in the same homogeneous population, while the stocks from the two other subspecies seem to be distributed in several heterogeneous groups, some of these showing correlation with the geographical origin of the trypanosomes. It is concluded that (i) T.b. gambiense stands out as a real subspecies that has undergone a distinct evolution relative to the 'non-gambiense' group, (ii) the alleged T.b. rhodesiense subspecies does not fit with any of the groups evidenced by our cladistic analysis and hence does not appear as a distinct subspecies and (iii) 'non-gambiense' trypanosomes are probably evolving much more rapidly than T.b. gambiense. Different aspects of trypanosome relationships and evolution are discussed.
220 Trypanosoma (Trypanozoon) brucei sp. stocks isolated between 1969 and 1983 from the Lambwe valley sleeping sickness focus in South Nyanza, Western Kenya,
were characterized by isoenzyme electrophoresis using 12 enzymes. 12 different zymodemes of T. (T.) b. rhodesiense were isolated from patients during the 13-year period and identical stocks were also found in cattle, reedbuck (Redunca redunca) and tsetse (Glossina pallidipes). Cattle may have played an important role in maintaining and increasing peridomestic transmission of trypanosomes during
the 1980 outbreak of sleeping sickness in the valley, even though they themselves suffered heavy mortality. Sleeping sickness
in Lambwe valley is unlikely to have been introduced from elsewhere, since T. (T.) b. rhodesiense stocks isolated from the valley were different from those from neighbouring epidemic areas. Alternatively, the recent outbreak
may have been caused by the increased transmission associated with an expanding tsetse population. The possibility that genetic
exchange contributed to the biochemical diversity of the trypanosomes examined is discussed.
Identification by means of the blood incubation infectivity test (BIIT) of 159 Trypanosoma brucei subgroup strains recently isolated from non-human hosts in the Lambwe Valley, Kenya, has defined the distribution in these hosts of both T. brucei and T. rhodesiense in an endemic sleeping sickness area. The presence of a small third group strongly suggestive of a population intermediate between these two species has also been revealed for the first time.Repeated testing of a number of these strains has shown marked consistency in the results. Strains identified by the BIIT as T. rhodesiense have been isolated for the first time from a reedbuck and a sheep. There appears to be direct relationship between the local prevalence rates of T. rhodesiense in non-human reservoirs and the incidence of sleeping sickness in man.
During the study of an epidemic of T. rhodesiense in Alego Location in 1964, 43 isolates of T. brucei subgroup organisms were obtained from a sample of 203 cattle. 2 of these isolates were inoculated into human volunteers and one produced an infection characteristic of T. rhodesiense, thus revealing the fact that cattle were acting as reservoir hosts for the trypanosomes. It is concluded that in an outbreak of sleeping sickness domestic cattle can act as natural reservoir hosts and therefore their mass treatment is strongly recommended during a control programme.
Arguments are presented for making Trypanosoma (Trypanozoon) gambiense and T. (T.) rhodesiense synonymous with T. (T.) brucei and for classifying them according to their undoubted differences in epidemiology, clinical pattern, and morphology at a subtaxonomic level as "strains" or "demes." Similar arguments cannot, at present, be applied to other members of subgenus Trypanozoon (i.e., T. (T.) evansi, T. (T.) equinum, and T. (T.) equiperdum). The term "clonal pleomorphism" is used to describe the diversity of form which occurs in species of subgenus Trypanozoon in order to avoid confusion with "genetic polymorphism" which is also found in T. (T.) brucei.
Succesful cyclical transmission was achieved through Glossina morsitans of a strain of T. rhodesiense isolated from a cow in Alego to a man, a cow and sheep.
The importance of a reservoir of T. rhodesiene in cattle in which no clinical symptoms occur and where the causative organism is resistant to the drug normally used to
treat cattle trypanosomiasis in the area is discussed.
The 1976–1982 epidemic of human trypanosomiasis in south-east Uganda affected new foci to the north of the old endemic area
bordering Lake Victoria, and was associated with a different vector, Glossina fuscipes fuscipes; isoenzyme studies revealed that the epidemic involved different strains of pathogenic trypanosomes also.
58 Trypanozoon isolates from the epidemic area and from the adjoining endemic area of West Central Kenya were compared by thin-layer starch
gel electrophoresis for 11 enzymes. Six different trypanosome zymodemes were circulating in man in the Ugandan epidemic, including
the zymodeme found before 1976 in the old endemic area; all stocks examined from West Central Kenya belonged to this latter
zymodeme.
Trypanosomes identical to those found in man were found in cattle and a dog in Uganda, and in cattle in Kenya; these animals
were presumably reservoir hosts of the human disease. Four isolates from triturated G. f. fuscipes collected in 1971 were identical but differed from all mammalian isolates examined.
The subgenus Trypanozoon contains several kinds of trypanosome, which are morphologically indistinguishable but differ in their behavior. At various times specific or subspecific status has been accorded to each kind, but, in recent years, those cyclically transmitted by tsetse in Africa have been separated into subspecies of Trypanosoma brucei, while the others, transmitted non-cyclically outside the African tsetse belts, have retained separate species status. However, although such new terminology may be more correct taxonomically, the practical problems of distinguishing the trypanosomes remain. Enzyme electrophoresis is being used on an increasingly wide scale for the intrinsic characterization. However, as the number of enzyme systems being used for identification grows, comparison of stocks becomes increasingly difficult and intricate, particularly when an enzyme occurs in a multibanded form after electrophoresis. After using 12 enzyme systems to characterize 160 Trypanozoon stocks, the results have been analyzed to establish the degree of relatedness of each of the 59 zymodemest encountered. The detailed analysis is presented in this chapter.
The question of whether any sexual process takes place at some stage of the life cycle of the trypanosome has often been raised and crosses between different drug-resistant strains have provided no convincing answer. Multinucleate forms of trypanosomes have been observed by electron microscopy but their significance and origin remain obscure. As part of a study aimed at examining the speciation and genetics of the Trypanosoma brucei complex of trypanosomes, a series of isolates from a population of T.b. brucei have been screened for electrophoretic variation in 19 enzymes. The results of this survey, reported here, provide strong evidence that trypanosomes are diploid and undergo random mating and recombination.
The study characterized 151 Trypanozoon isolates from south-east Uganda by isoenzyme electrophoresis. Stocks were from a range of hosts, including man, cattle, pigs, dogs and Glossina fuscipes fuscipes: 104 isolates were from the Busoga area, 47 were from the Tororo district. Stocks were characterized on thin layer starch gel using eight enzyme systems: ALAT, ASAT, ICD, MDH, ME, NHD, NHI, PGM. Enzyme profiles were generally typical of East Africa; new patterns for ICD and ME were detected. Trypanosomes were classified on the basis of their profile by similarity coefficient analysis and the unweighted pair-group method using arithmetic averages (UPGMA). The majority of trypanosomes were classified in one or other of two genetically distinct groups which corresponded to the strain groups busoga and zambezi, both of which are associated with Rhodesian sleeping sickness in East Africa. Contingency table analyses indicated associations between certain isoenzymes of ICD and PGM, according to host and geographical origin. Significant relationships between trypanosome strain group and geographic origin were also demonstrated for some host groups.
Seventy-eight Trypanosoma brucei s.l. stocks from different hosts, representing the three Trypanosoma brucei subspecies and three Trypanosoma evansi stocks, were studied for variation at 18 polymorphic isozyme loci. The results were used to determine the genetic variability among stocks and to estimate gene flow among populations. Total genetic variability in T. brucei s.l. was less than that in Trypanosoma cruzi, the agent of Chagas' disease. Results support a clonal population structure in T. brucei, but do not preclude a hypothesis of occasional mating. However, some natural clones of T. brucei s.l. appear as genetically stable and should be considered as useful taxonomic units in applied studies. Greater genotypic diversity was observed in trypanosomes isolated from wild mammals. Numerical taxonomy methods identified a group of clones representing most of the human stocks from Central and West Africa. This group probably corresponds to Trypanosoma brucei gambiense "group I" (Gibson, Parasitology Today 2, 255-257, 1986). As reported elsewhere, genetic evidence of the subspecies Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense was ambiguous, suggesting that these taxa represent more "nosodemes" rather than actual genetic clades.
Reproductive processes within the current Ugandan epidemic of sleeping sickness are investigated. Genotype frequencies derived from isoenzyme patterns in 44 stocks of Trypanosoma brucei s.l. collected in 1988 from Tororo, south-east Uganda are analysed by single and multiple loci methods. In the single locus method, the hypothesis of random mating is tested by agreement with Hardy-Weinberg equilibrium. The multiple loci method uses a contingency table approach to detect non-random associations between pairs of loci; this equates to the detection of disequilibrium. The results do not support the concept of a randomly mating population of T. brucei within the current epidemic. Results from the epidemic data set are discussed in relation to the broader problem of genetic exchange in Trypanozoon.
Results reported here show that humans have various levels of trypanocidal activity in their sera. This difference appeared stable when different samples were taken from the same individuals over time. It was not possible to account for the variability between individuals by obvious differences in health, nutrition, or living habits. In addition, the trypanocidal titers did not vary significantly when stored for various lengths of time at -70 C. To examine the relationship between the titer of trypanocidal activity in a host and the degree of human serum resistance of the challenge trypanosome inoculum, mice (C57BL/6J) were pretreated with various amounts of different human serum and then infected with clones having different degrees of resistance to human serum. It was demonstrated that host susceptibility to an African trypanosome infection depends upon 2 variables: the level of trypanocidal activity in individual human serum and the degree of human serum resistance of individual clones of African trypanosomes. Based upon the animal model presented here, it is hypothesized that this relationship is under selective evolutionary pressure and will influence the susceptibility of animals in endemic areas as well as the transmission of human trypanosomiasis.
The great sleeping sickness epidemic that occurred in Busoga at the turn of the century was caused by a trypanosome identified by Bruce as Trypanosoma gambiense. A study of trypanosomes from the recent epidemic in southeast Uganda has shed new light on the origins of the disease in Busoga. Thorsten Koerner, Peter de Raadt and Ian Maudlin suggest that the epidemic of the turn of the century was of T. p. rhodesiense sleeping sickness, brought about then, as now by social upheaval.
The discovery of genetic exchange in African trypanosomes belonging to the Trypanosoma brucei group is an important development in our understanding of these organisms. Genetic exchange is a feature of major importance in relation to population structure and speciation. Furthermore, a convenient laboratory-based mating system would be of considerable value as a tool in trypanosomiasis research. It is now known that although cyclical development of trypanosomes within the tsetse fly does not require mating to occur, genetic exchange may take place under Conditions in which genetically distinct trypanosomes develop within the same fly. During the past few years there has been a considerable body of research on laboratory crosses, and a number of controversial and apparently contradictory models of the mechanism of genetic exchange and the ploidy of different life cycle stages have been proposed. In this article, Andy Tait and Mike Turner review the present state of knowledge regarding gene exchange in T. brucei, and attempt to reconcile the various observations and models available.
Nearly 90 years after the discovery that certain African trypanosornes were killed by normal human serum, we still do not understand how this innate trypanocidal factor works. Biochemical studies have provided us with an unlikely candidate: human high-density lipoprotein (HDL). This trypanosome lytic factor (TLF) from human serum is important since its activity restricts the host range of Trypanosoma brucei brucei, and the expression of this natural killing factor in cattle would represent a novel approach to the control of bovine tryponosomiasis. Here, Steve Hajduk, Kristin Hager and Jeffrey Esko discuss evidence for the TLF being a minor subclass of serum HDL and propose a mechanism for lysis based on the binding, endocytosis and lysosomal targeting of TLF.
Over the past 15 years, molecular investigations, including the study of isozymes and DNA markers, have provided much information on the genetic variation, population structure, breeding system and other population characteristics of parasitic protozoa. For some parasitic protozoa, but not for others, the evidence indicates that their reproduction is prevailingly clonal. In this article, Michel Tibayrenc and Francisco Ayala propose that the issue of whether the predominant mode of reproduction of a given micro-organism is clonal or sexual can only be settled by population genetics information, and they summarize evidence favoring a clonal population structure for a number of parasitic protozoa.
Relationship between human serum
- I R Seed
Seed, I.R. et al. (1993) Relationship between human serum
Isoenzyme characlerization of Tryp-ano---oon isolates from two sleeping sickness areas of south eastern Uganda. Acla 'l'ropica 55, tlT-I 15
- C K Enyaru
Enyaru,/.C.K. el al. (1993) Isoenzyme characlerization of Tryp-ano---oon isolates from two sleeping sickness areas of south eastern Uganda. Acla 'l'ropica 55, tlT-I 15
Different allele frequencies in T~!panosonla bruce{ bruce{ and Tuipanosonla bruce{ ganlbiense populations
- P Paindavoine
Paindavoine, P. et al. (1989) Different allele frequencies in
T~!panosonla bruce{ bruce{ and Tuipanosonla bruce{ ganlbiense
populations. Mol. Biochenl. Parasitol. 32, 61-72
lq90) A clonal theory of parasitic protozoa: the population genetics of E~#anloeba, Giardia, Leishmaalia, Naegleria, Plasmodimn, Trichontonas and Trypanosonla and their medical and taxenomic consequences
- M Tibayrenc
- F Kjellberg
- F J Avala
Tibayrenc, M., Kjellberg, F. and Avala, F.J. (lq90) A clonal theory
of parasitic protozoa: the population genetics of E~#anloeba,
Giardia, Leishmaalia, Naegleria, Plasmodimn, Trichontonas and
Trypanosonla and their medical and taxenomic consequences.
Proc. Natl Acad. Sci. USA 87, 2414-2418
Numerical analysis of enzyme polymorphism
- Gibson