Over the past two decades movement of cattle towards the north of Uganda has enabled the Trypanosoma brucei rhodesiense focus in south-eastern Uganda to spread into previously unaffected districts. This thesis brings together important epidemiological data regarding the impact of mass cattle drug treatment on the point prevalence of several different species of trypanosome in a newly endemic area of human sleeping sickness. Crucially the findings illustrate mass drug treatment is effective in reducing the prevalence of T. b. rhodesiense in cattle, thus minimising the reservoir potential of these animals in the epidemiology of human disease. During 2006 a control programme was launched to halt the northward spread of this zoonotic parasite. This programme, entitled ‘Stamping Out Sleeping Sickness’ (SOS) proposed to reduce the prevalence of Human African Trypanosomiasis (HAT) in the newly affected districts by reducing the prevalence of this parasite in the main animal reservoir of infection – domestic cattle. Cattle were mass treated using trypanocides to clear infections. Previous work demonstrated the prevalence of T. brucei s. l. and T. b. rhodesiense in cattle was higher in the districts of Dokolo and Kaberamaido than in the other SOS intervention districts (Selby 2011). To determine whether animals in these areas were also exposed to pathogenic cattle trypanosomes samples were screened for the presence of T. vivax and T. congolense savannah using PCR. Chapter three of this thesis determined the prevalence of these trypanosomes in cattle in these districts. Before treatment had taken place the prevalence of T. vivax was 2% (4/200, 95% CI 3.57 – 0.12%) in Dokolo and 7.3% (21/310, 95% CI 10.17 - 4.24 %) in Kaberamaido. The prevalence of T. congolense savannah at baseline was 3.5% (7/200, 95% CI 7.08–1.42 %) in Dokolo and 9.1% (21/230, 95% CI13.6–5.7 %) in Kaberamaido. Monitoring was conducted three, nine and 18 months post treatment and both pathogens were detected at all time points. The impact the treatment had on point prevalence varied by trypanosome species and between the two districts. Several clusters of villages in Dokolo and Kaberamaido continued to report cases of HAT after the initial SOS intervention due in part to their proximity to livestock markets (Batchelor et al., 2009). In 2008 re-treatment of these ‘high risk’ areas was undertaken. Monitoring was performed before and six months after treatment. Cattle blood samples were collected at 20 village sites from ten ‘case-positive villages’ (from which human sleeping sickness cases had been reported six months prior to June 2007) and from ten ‘case-negative villages’ (no reported human sleeping sickness cases six months prior to June 2007). These samples were screened for all of the aforementioned trypanosomes using species specific PCR protocols. Chapter five details the results of this screening, and assessed whether re-treatment in Dokolo and Kaberamaido was effective in reducing the prevalence of trypanosomiasis. The re-treatment had a dramatic effect, significantly reducing the point prevalence of overall trypanosomiasis in the 20 villages screened from 38.1% (95% CI = 40.5 – 35.79%) at baseline to 26.9% (95% CI 28.96 – 24.97, p < 0.0001) at six months. Looking at each species separately, point prevalence of three out of four detected species of trypanosome fell significantly, including T. b. rhodesiense, which was reduced to 25% of its baseline prevalence. Finally the two SOS treatment cycles were compared both statistically and spatially with emphasis on trends at village level and the occurrence of mixed infections.

La trypanosomose est la maladie parasitaire la plus dévastatrice en Afrique, et affecte à la fois les hommes et le bétail. Vu l’inefficacité des stratégies de contrôle actuelles, une stratégie alternative dite “anti-maladie” a été proposée dans le cadre de la trypanosomose animale. Elle vise à neutraliser les effets de la maladie plutôt qu’à éliminer le parasite. Une telle stratégie nécessite une meilleure compréhension du développement de la pathologie ainsi qu’une caractérisation détaillée des facteurs de virulence impliqués. Dans ce contexte, nous nous sommes intéressés à l’étude de l’interaction hôte/pathogène entre les trypanosomes Africains et l’endothélium de l’hôte mammifère. En comparant quatre espèces différentes de trypanosomes Africains, nous avons montré que leurs capacités d’activation des cellules endothéliales étaient distinctes. Nous avons clairement démontré que T. congolense, T. vivax et T. b. gambiense activent les cellules endothéliales via la voie de NF-ƘB, alors que T. b. brucei est incapable d’activer cette voie. Cette activation a induit une résponse pro-inflammatoire in vitro et in vivo, ce qui souligne l’importance de ce mécanisme dans le développement de la maladie. Pour la première fois, nous avons identifié une activité sialidase chez le parasite de l’homme T. brucei gambiense, et nous avons démontré que les trans-sialidases trypanosomales sont les médiateurs de cette activation endothéliale et de la réponse inflammatoire consécutive, et ceci à la fois chez les trypanosomes africains d’homme et d’animaux. De plus, nous avons montré que l’activation endothéliale implique l’activité lectin-like des trans-sialidases et non pas l’activité catalytique, ainsi que des récepteurs sialylés sur la surface endothéliale. En conclusion, ce travail a apporté des avancées considérables dans la compréhension de la relation hôte/pathogène et a permis de désigner les sialidases comme un facteur de virulence central dans le dialogue intermoléculaire durant les trypanosomoses, en faisant une cible de choix pour le vaccin « anti-maladie ». / Trypanosomiasis remains by far the most devastating parasitic disease in Africa affecting both humans and livestock. The current control strategies being not efficient, an alternative “anti-disease” strategy aiming to neutralize the pathological effects of the parasite rather than to eliminate it, was proposed. Therefore, it is essential to understand the development of pathogenesis and characterize the involved pathogenic factors. In this context, we wanted to elucidate the host-pathogen interaction between the African trypanosomes and the mammalian host endothelium. By comparing four different trypanosomes species, we showed that they displayed distinct capacities for activation of endothelial cells. We clearly demonstrated that T. congolense, T. vivax and T. b. gambiense activate the endothelial cells via the NF-ƘB pathway, but not T. b. brucei. This activation caused a pro-inflammatory response in vitro and in vivo, showing the importance of this mechanism in the development of pathogenesis. For the first time, we identified sialidase activity in the human parasite T. brucei gambiense, and demonstrated that the trypanosomal trans-sialidases are the mediators of this endothelial activation and its consequent inflammatory response, for both human and animal trypanosomes. Additionnally, we showed that endothelial cell activation is mediated by the lectin-like domain of the trans-sialidase rather than the catalytic site, and involves sialylated receptors of the endothelial cell surface. In conclusion, our study brings considerable insights into the host-pathogen relationship and designates sialidases as a central virulence factor in the molecular crosstalk during trypanosomiasis, which makes it a perfect target for the anti-disease strategy.