Over one third of the human population is currently infected by one or more species of parasitic helminth, but the immune responses elicited by these infections remain poorly defined. Studies in helminth-exposed human populations and laboratory models suggest that helminth infection elicits a range of different effector cell types and that protective immunity and resistance to immune-mediated pathology depends on the balance between these responses. The aim of this thesis was to investigate how cytokines, the molecular mediators of the immune system, can be used to characterise human immune phenotype during natural and experimental helminth infection. Cytokines associated with innate inflammatory (TNFα, IL-6 and IL-9), Thl (IFNγ, IL-2 and IL-12p70), Th2 (IL-4, IL-5 and IL-13), Th17 (IL-17A, IL-21 and IL-23) and regulatory (IL-10 and TGFβ)immune phenotypes were analysed to provide the most comprehensive analysis of cytokine responses in human helminth infection conducted to-date. Using a multivariate statistical approach cytokines were analysed as combined immune profiles to reflect their complex interactions in vivo. In the first part of the study venous blood samples collected from a cross-sectional cohort of 284 Zimbabweans (age range: 3 -86 years) endemically-exposed to Schistosoma haematobium were cultured with antigens from different stages of the parasite's life-cycle(cercariae, adult worms and eggs) and the anti-schistosome vaccine candidate antigen glutathionine-S-transferase (GST). Cytokines responses were quantified in culture supernatants via enzyme-linked immunosorbent assay (ELISA). These assays were repeated 6 weeks after clearance of infection by anti-helminthic treatment. Parasitological and demographic characterisation of the cohort before, 6 weeks, 6 and 18 months after treatment allowed cytokine responses to be related to epidemiological patterns of infection before treatment and the risk of re-infection after treatment. The main findings of this study were:Cytokine responses to the antigens of S. haematobium cercariae are more proinflammatory than those elicited by adult worms and eggs prior to treatment, reflecting the distinct proteomes and exposure patterns of the 3 life-cycle stages Young children (5-10 years old) have a more regulatory and Th17-polarised cytokine response to S. haematobium antigens than older children and adults. These responses are significantly associated with schistosome infection intensity and may contribute to the development of resistance to schistosomiasis with age and exposure to infection Anti-helminthic treatment leads to a shift in S. haematobium cercariae, egg and GST specific cytokine responses towards a more pro-inflammatory phenotype The magnitude of change in S. haematobium-specific cytokine profiles after treatment is dependent on schistosome infection intensity at the time of treatment Individuals who remain un-infected up to 18 months after treatment to clear schistosome infection have a more pro-inflammatory and IL-21-polarised response to S. haematobium antigens 6 weeks after treatment than those who become re-infected, suggesting that post-treatment cytokine profiles promote resistance to re-infection. The second part of the study assayed systemic, parasite and allergen-specific cytokine responses in 45 adults with seasonally exacerbated allergy to grass pollen who were experimentally exposed to Trichuris suis. Cytokine responses in infected individuals were compared to those of 44 un-infected controls. This aspect of the study showed that: Exposure to T. suis promotes systemic and parasite-specific Th2 and regulatory cytokine responses, but does not alter cytokine responses to environmental allergens.

A multifaceted Schistosoma haematobium study aimed at assessing five different diagnostic techniques of surveillance was conducted. Their use in varying operational circumstances with particular reference to Primary Health Care was conducted in three areas of varying prevalence of disease namely; Mpolweni Mission (44.1%), Empangeni (30.3%) and Verulam (72.0%), KwaZulu-Natal, South Africa. This study incorporated both theoretical and applied components. The theoretical components included freshwater snail surveys, review of literature of S. haematobium diagnostic techniques and an assessment of five diagnostic techniques with particular emphasis on diagnostic performance and cost analyses. Added to these components was migration and the assessment of the prevalence of disease amongst occupants of informal settlements in and around the greater Pietermaritzburg city centre. The applied component included the initiation of a holistic S. haematobium control programme based along the World Health Organisation Guidelines. The study provided insight into several of the countries health issues relevant to both schistosomiasis and other diseases and highlighted weaknesses that may hinder the successful implementation of the current National Framework for Parasite Control. The presence of urban schistosomiasis was noted for the first time in the city of Pietermaritzburg. The present schistosomiasis distribution could be influenced by the rural-urban migration that is impacting upon major metropolitan areas. Without intermediate host snail surveys and schistosomiasis prevalence surveys amongst members of the population, the real geographic distribution of the disease will not be known. The diagnostic methods that were compared included sedimentation, filtration, three brands of chemical urinalysis strips, urine colour scales and an indirect questionnaire. Sensitivity, specificity, positive predictive, negative predictive and efficiency values were determined. Using these values, diagnostic performance ranges were established. The ranges were influenced by the cut-off values used, technique and prevalence and intensity of infection of the study area. The chemical urinalysis strips at cut-off 10erythrocyes/μl (73.7% - 93.2%) were highly sensitive whereas urine colour scales (97.1% - 99.4%) and indirect questionnaire (80.4% - 90.3%) were highly specific. The relationship between the community prevalence rates measured by all five techniques varied significantly. A cost-analysis of the techniques/sample demonstrated a wide price range (20c - R4.32). Therefore their use would be dictated more by the availability of funding than by any operational advantages each individual technique may have demonstrated. Within the public health services a need for: (1) staff training programmes, (2) core staff based within the PHC system that is dedicated to parasite control and (3) a strengthening of infrastructure was demonstrated. These may be achieved via workshops, improved communication, education courses, specific time allocation to parasite programmes i.e. parasite week, project co-ordinators and the designation of tasks. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 1998.

Temperature and rainfall vary spatially within South Africa and they in turn affect the parasites and intermediate host snails involved in schistosomiasis transmission. The primary goal of this study was to investigate the relationship between these two abiotic variables and schistosomiasis in South Africa using a Geographic Information System (GlS) as a spatial analytical tool. The secondary goal was to estimate the population exposure to schistosomiasis. Prevalence data for Schistosoma haematobium and S. mansoni obtained from a national hardcopy atlas and two long-term, retrospective, high resolution climate datasets were used to produce two models (temperature-suitability and regression analysis) based on different GIS methodologies. The temperature-suitability model defined areas that are suitable and unsuitable for disease transmission by relating documented temperature regimes to the schistosomes' larval biology. The map outputs show that temperature minima corresponded better with the disease data than temperature maxima. Based on different climate and population data permutations, between approximately 3 903 734 and 4 379 079 school-aged children live in these temperature-suitable zones. The regression model tested the hypothesis that temperatures, especially during spring and summer favoured schistosomiasis transmission more than those of autumn and winter. Positive associations were expected with the rainfall variables. A logistic equation was used to predict, as accurately as possible within the model's limitations, the probability of schistosomiasis occurring in a given area. Increasing annual rainfall, as well as spring and autumn temperature maxima and minima predicted an increase in S. haematobium prevalence rates. Schistosoma haematobium prevalence rates of 11-25% and 26-50% were predicted in the north-eastern and eastern coastal regions. A prevalence rate of 71 to 100% was predicted from Limpopo to KwaZulu-Natal. Increasing the average monthly rainfall, spring temperature maxima and autumn temperature minima, increased the likelihood of S. mansoni transmission. Schistosoma mansoni prevalence rates of 26-50% and 71 to 100% were predicted in Limpopo, Mpumalanga, KwaZulu- Natal and Eastern Cape. This is the first time GIS has been used to correlate climate variables and schistosomiasis occurrence in South Africa. The regression model requires further refinement and it is not as applicable as the temperature-suitability model for practical purposes. / Thesis (M.Sc.)-University of Natal, Durban, 2003.