The global human population is expected to exceed 9 billion individuals by 2050, putting greater strain on the natural resources needed to sustain such a population. To feed this many people, some expect agricultural production will have to double and agrochemical use will have to increase anywhere from two- to five-fold relative to the turn of the century. Although industrial agriculture has provided many benefits to society, it has caused declines in biodiversity, both directly (e.g., through conversion of habitat) and indirectly (e.g., through contamination of adjacent natural habitats). Agricultural activity has also been linked to increased prevalence and intensity of trematode infections in wildlife and humans - directly by increasing available aquatic habitat for the snail intermediate hosts of trematode parasites and indirectly by altering the biological composition of aquatic habitats in ways that increase snail density. While the effects of single agrochemical contaminants on aquatic communities and trematode disease risk have been examined, agrochemical pollution typically occurs as mixtures of multiple chemical types in surface waters and the effects of mixtures on aquatic communities have received less attention. Moreover, given the high number of chemicals approved for agricultural use, the number of potential combinations of agrochemicals renders testing all possible combinations implausible. Thus, there is a critical need to develop better risk assessment tools in the face of this complexity. I developed and tested a theoretical framework that posits that the net effects of agrochemical mixtures on aquatic communities can be predicted by integrating knowledge of each functional group's 1) sensitivity to the chemicals (direct effects), 2) reproductive rates (recovery rates), 3) interaction strength with other functional groups (indirect effects), and 4) links to ecosystem properties. I conducted a freshwater mesocosm experiment to quantify community- and ecosystem-level responses to pairwise mixtures of four major agrochemical types (fertilizer, herbicide, insecticide, and fungicide) and single chemical treatments. The responses of biodiversity and ecosystem properties to agrochemicals alone and in mixtures were indeed predictable. Moreover, these results show that community ecology theory holds promise for predicting the effects of contaminant mixtures and offer recommendations on which types of agrochemicals to apply together and separately to reduce their impacts on aquatic ecosystems. I extended this framework to test if the direct effects of pesticides can be predicted by chemical class and/or mode of action. I performed standard toxicity trials on two invertebrate predators of snails (crayfish and giant water bugs) exposed to six insecticides belonging to two chemical classes (organophosphates and pyrethroids) to determine if environmental risk can be generalized to either insecticide class or insecticide exposure. Survival analyses demonstrated that insecticide class accounted for 55.7% and 91.1% of explained variance in crayfish and water bug survival, respectively. Simulated environmental exposures using US EPA software suggested that organophosphate insecticides present relatively low risk (as defined by the US EPA) to both crayfish and water bugs, while pyrethroid insecticides present consistently high risk to crayfish but not to water bugs, where only λ-cyhalothrin produced consistently high-risk exposure scenarios. Thus, risk to non-target organisms is well predicted by pesticide class. Furthermore, identifying insecticides that pose low risk to aquatic macroarthropods might help meet increased demands for food while mitigating against potential negative effects on ecosystem functions. Because evidence from field data and manipulated experiments demonstrated both top-down and bottom-up effects of agrochemical pollution that increased snail densities and trematode infections in wildlife, I conducted an additional agrochemical mixture experiment with freshwater communities containing the snail hosts of schistosomiasis, which has also been linked to agriculture. As expected, top-down and bottom-up effects of insecticide, herbicide, and fertilizer exposure indirectly increased snail densities, individually and as mixtures. Agrochemical exposure and snail density together accounted for 88% of the variation in the density of infected snails. Thus, agrochemical pollution has great potential to increase human exposure to schistosome parasites, and underscores the importance of identifying low-risk alternative pesticides. A subsequent mesocosm experiment with the same six insecticides used previously in laboratory trials confirmed that insecticide exposure indirectly mediates the densities of snail hosts that can transmit schistosomiasis through the direct effects of insecticides on crayfish mortality. Importantly, crayfish mortality in semi-natural mesocosm trials closely matched mortality from controlled laboratory trials. Thus, standard laboratory toxicity tests can be a useful tool for identifying alternative insecticides that might pose lower environmental risks to important predators that regulate snail densities. Identifying practices or agrochemicals that minimize this risk is critical to sustainably improving human health in schistosome-endemic regions. The theoretical framework presented here demonstrates the feasibility of predicting the effects of contaminant mixtures and highlights consistent effects of major agrochemical types (e.g. fertilizers, insecticides, etc.) on freshwater aquatic community composition. Furthermore, the strong top-down effects of invertebrate snail predators highlight that managing for high snail predator densities in might be a particularly effective strategy for reducing the burden of schistosomiasis in tropical countries.

Les maladies inflammatoires chroniques de l’intestin font partie des pathologies immunitaires. Leur pathogenèse est directement liée à une réponse immune exagérée dirigée contre des bactéries commensales normalement présentes dans l’intestin, chez des individus génétiquement prédisposés. Parmi les facteurs favorisants, on trouve l’amélioration du niveau d’hygiène ainsi qu’une diminution des infections parasitaires. Des études épidémiologiques ont suggéré une relation entre la prévalence des infections par les helminthes et l’incidence des maladies inflammatoires chroniques de l’intestin dans les pays en développement. Ces infections parasitaires induisant une réponse immune de type Th2, il est donc proposé qu’elles participent la régulation des maladies inflammatoires médiées par une réponse immune de type Th1, comme la maladie de Crohn.Notre équipe s’est intéressée à l’effet immuno-modulateur d’une protéine du Schistosome, la P28GST (Glutathion S-transferase) dont les propriétés immunogénétiques pro-Th2 ont été démontrées précédemment dans des modèles expérimentaux et chez l’homme. Au cours de notre travail, nous avons montré que l’immunisation avec la P28GST était capable de diminuer de manière façon significative la colite expérimentale dans deux modèles animaux. L’immunisation avec cette enzyme parasitaire, produite sous forme recombinante, a réduit les scores cliniques et histologiques obtenus après induction de colite expérimentale par injection de l’haptène TNBS chez des rats Sprague Dawley rats ainsi que chez des souris C57Bl/6. Cet effet est associé à une diminution des marqueurs de l’inflammation (Myéloperoxidase) et de lexpression de l’ARN messager codant pour des cytokines pro-inflammatoires (IL-1β, IL-17 et TNF) dans le colon des animaux. Nous détectons une modulation de la réponse immune caractérisée par une diminution du profil Th1 mesuré par la présence d’ARN messager codant pour l’IFNγ vers un profil de type Th2, associé à une augmentation de l’ARN messager codant pour l’IL-4, l’IL-5 et l’IL-13. L’augmentation du rapport ARN messager Arg1/iNOS2 ainsi que la détection de cellules Arginase positives par immuno-histo chimie dans le colon des animaux immunisés suggèrent la présence de macrophages alternatifs (AAM), dont on connait le rôle anti-inflammatoire et l’association à une réponse de type Th2. Des résultats similaires ont été obtenus dans un autre modèle expérimental, chez la souris.Nous avons comparé l’effet de cette protéine du Schistosome avec l’effet de l’infection par des larves du parasite grâce à deux modèles d’infection : soit une infection au long cours (associé avec une réponse immune de type Th2), soit une infection récente (avec une réponse immune de type Th1). Nos résultats montrent que l’immunisation par une seule protéine de schistosome, la P28GST, réduit l’inflammation intestinale aussi bien que l’infection au long cours, tandis que les animaux récemment infectés n’étaient pas protégés de la colite. En conclusion, notre étude présente les premières évidences que l’immunisation avec une protéine recombinante de Schistosome pourrait réduire de manière préventive la colite expérimentale induite par l’injection d’une haptène dans deux modèles de rongeurs. Si les mécanismes d’action précis doivent encore être élucidés, nos travaux suggèrent que l’effet anti-inflammatoire de la P28 GST puisse avoir des applications dans la prévention de l’inflammation intestinale permettant d’envisager une utilisation chez l’homme, notamment dans la prévention des rechutes de la maladie de Crohn. / Inflammatory bowel diseases are considered part of immune-mediated inflammatory disorders. Their pathogenesis was linked to an inappropriate exaggerated immune response to commensal bacteria normally present in the bowel, in genetically predisposed individuals. Increase of the level of hygiene and decrease exposure to helminthic infections was suggested as predisposing factors to IBD. Epidemiologic data have given a clue on the relation of prevalence of helminthic infections and the incidence of inflammatory bowel diseases in developing countries. The Th2 polarized T cell response driven by helminthic infection has been linked to the attenuation of Th1 driven inflammatory responses, preventing some Th1 mediated autoimmune diseases in their host, including Crohn’s disease.Our work focused on the immuno-modulatory effect of a Schistosome protein – P28GST (a Glutathion S-transferase). Its immuno-genetique, pro-Th2, characters have been previously demonstrated in experimental models as well as clinical trials. We showed that immunization with P28GST was able to significantly reduce experimentally induced colitis in two animal models.Immunisation with this recombinant parasitic enzyme reduced clinical and histological scores of the TNBS induced colitis in both Sprague Dawley rats as well as in C57Bl/6 mice. This effect was associated with a decrease in the expression of inflammatory markers (Myeloperoxidase) as well as mRNA expression of pro-inflammatory cytokines (IL-1β, IL-17 and TNF) in the colon of sacrificed animals. We detected a shift of the immune response characterized with decrease of Th1 immune response assessed by the mRNA expression of IFNγ towards a less pathological Th2 immune response assessed by the mRNA expression of IL-4, IL-5 and IL-13. An increase in the ratio of mRNA expression of Arg1/iNOS2, as well as the immuno-histochemical detection of Arginase positive cells in the colon of the sacrificed animals suggested the presence of alternatively activated macrophages (AAMs) characterized by their anti-inflammatory effect and their association with the Th2 immune response. Similar results have been obtained in another animal model, the C57Bl/6 mice.We have also compared the effect of a single recombinant Schistosome protein to two models of infection with living schistosome parasites, either with long standing infection (associated with a Th2-type response) or with a recent onset exposure (a Th1-type response). Our results showed that immunisation with a single Schistosome protein, the P28GST; give similar results to established infection in term of reduction of intestinal inflammation, whereas recently infected rats were not protected against colitis.In conclusion, this study provides the first evidence that immunization with a recombinant protein from the Schistosome helminth parasite prevents hapten-induced colitis in two models of rodents. Although further studies are needed to illustrate the exact mechanisms of action implicated in the immuno-modulatory effect, P28GST is a promising molecule exerting a potent anti-inflammatory role in the prevention of colitis. The potential effect of this helminthic enzyme is actually taken in consideration in the prevention of Crohn’s disease relapses in humans.

The potential role of sanctuary areas for biological control of Schistosomiasis and development of sustainable fisheries was investigated at Cape Maclear, Lake Malawi National Park (LMNP). There has been a recent increase in the incidence of schistosomiasis infection which is a threat to the local community as well as the tourism industry which is the major source of income to LMNP as well as Chembe Village. At the same place there is increasing fishing pressure due to growing human population and declining fish resource. The increase in the incidence of schistosomiasis transmission was attributed in part to over-fishing of the molluscivorous fish which are believed to control the vector snails for schistosomiasis. Four molluscivorous fish species, Trematocranus placodon; Trematocranus microstoma; Mylochromis sphaerodon and Mylochromis anaphyrmus were reported to account for more than 90% of the fishes (by numerical abundance) which feed on the gastropods above 15 metre depth. The gastropod numbers was reported to be highest at 1.5 to 4.5 metre depth. Of the four molluscivores, T. placodon was proposed as a biological control agent for schistosomiasis based upon the previous observations of its feeding habits in artificial conditions. Captive propagation of T. placodon for reintroduction at Cape Maclear in Lake Malawi has been proposed. The present study aimed at providing baseline data required to test the hypotheses that: 1) Over-fishing of the molluscivorous fish has resulted to the increased incidence of schistosomiasis at Cape Maclear. A sub hypothesis to this was that an extension of the LMNP can act as a sanctuary area for the biological control of schistosomiasis by protecting molluscivorous fish which could control schistosomiasis vector snails. 2) A park initially designed to protect the colourful rock dwelling fish and for promotion of tourism may not effectively protect the food fish. To test the first hypothesis, the biology and ecology of T. placodon were investigated with a view to evaluating the effect this species could have on the schistosomiasis vector snail population and hence the control of bilharzia in the lake. The proportions of various gastropod species at Cape Maclear was compared with those found in T. placodon guts. Comparisons of T. placodon abundance and demographic structure inside and outside LMNP were made. To test the second hypothesis, this study investigated the food fish species that use LMNP 100 m protected zone and some basic ecological factors to appreciate the extent to which the adjacent fishery might benefit from their use of the park waters. T. placodon numerical abundance (number of individuals per unit area) ranged from 5.7 to 40.5 /200 m² and it significantly (P< 0.05) varied between sampling sites. Otter Point and Mitande which are inside the park had the lowest abundance as compared to the other three sites; Nguli inside the park; Fisheries and Nchenga outside the park. Two sites in the park, Otter Point and Mitande, had a greater proportion of mature T. placodon individuals than all other sites. The abundance of T. placodon fluctuated significantly from month to month at Nchenga, Nguli and Fisheries (X² test, P<0.0001 for all the three sites) and insignificantly (P>0.05) at Otter Point and Mitande (X² test). T. placodon densities found in the present study corresponded to the peak density of 30 individuals / 200 m² reported in 1986 but did not correspond to that of 1.0 / 200 m² for 1994. There was no evidence to support the previous reports that T. placodon abundance had decreased tremendously from 1986. The reason suggested to account for the discrepancies of T. placodon abundance reported in the present study and other studies was inadequate sampling in the previous studies which did not take into account spatial and temporal variability in T. placodon abundance. The findings reported in this thesis show that there is no need for captive propagation of T. placodon to be reintroduced into the lake at Cape Maclear and that it may prove to be unsuccessful. However, since juvenile T. placodon dominated in abundance at the three sites along the major beach which is outside the park boundaries, it is suggested that the park boundaries be extended to this area so that T. placodon should be protected to allow individuals to grow to bigger size which would be more effective for gastropod control. T. placodon between 60 mm and 80 mm TL fed on benthic insects, phytoplankton and from detritus material. Individuals between 80 mm and 100 mm fed on a mixture of benthic insects, fish scales and small gastropods and at sizes greater than 100 mm individuals specialized feeding on gastropods. Gastropods of five genera were taken and they were: Melanoides , Bulinus, Gabiella, Lanistes and Bellamya. Of these genera Melanoides fonned the greatest part of T. placodon diet. Bulinus was the second most abundant genus but compared to Melanoides its proportion was very small. Of the three Bulinus species taken by T. placodon, B. globosus, is a confirmed vector for Schistosoma haematobium which is prevalent at Cape Maclear. This species was eaten in the least quantities. A comparison ofthe five gastropod proportions in T. placodon diet and in the habitats they occupy showed that Melanoides were taken in proportionately more quantities than Bulinus at most sites. These findings contrasted the previous reports that T. placodon preferred Bulinus to Melanoides. By applying the optimal foraging theory which predicts that an animal species searching for food will go for the type of prey with the highest profitability, it is concluded that the Bulinus cannot be eliminated completely by molluscivores because if their population size falls below a certain level, the fish will switch to other gastropod types. It is concluded that the increase in schistosomiasis may not be necessarily due to overfishing the molluscivorous fish but could be due to the fact that there has been an increase in the proportion of the B. globosus albeit in small numbers which are infected with schistosomiasis parasites. An integrated approach to schistosomiasis control at Cape Maclear comprising vector control, improved water supply, sanitation and health education is suggested since no method can be effective in isolation. Few food fish species were observed to use the park at various times, varying from one species to another with regards to duration, life history stages and abundance. Only a few fish species taken by the adjacent artisanal and commercial fisheries were represented among those observed in the park. This was attributed to the limited diversity of habitat types covered. Only small population size of some species visited the protected area and only part of the life cycle of some species were observed in the park. The use of the park area was seasonal for some species and the protected zone boundaries can be crossed more than once within a day because 100 m distance is just a few minutes swim by fish. Under such circumstances the park cannot function as an effective sanctuary for food fish. An increase of the park size may be a better option to effectively protect the food fish.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-12T15:05:40Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE_MEDICINA TROPICAL_IANA RAFAELA SALES.pdf: 2843724 bytes, checksum: 82befaa22a5a011cd9ceede497871d36 (MD5) / Made available in DSpace on 2016-04-12T15:05:40Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE_MEDICINA TROPICAL_IANA RAFAELA SALES.pdf: 2843724 bytes, checksum: 82befaa22a5a011cd9ceede497871d36 (MD5) Previous issue date: 2015-02-27 / CAPEs / A alta prevalência de esquistossomose crônica em gestantes, bem como em mulheres em idade fértil, tem sido amplamente relatada. Esta condição materna é capaz de alterar a resposta imune do descendente em longo prazo. O presente estudo teve o objetivo de avaliar o efeito in vitro do leite materno de mães infectadas pelo Schistosoma mansoni em esplenócitos e caracterizar os peptídeos encontrados nesse leite. Para isso, camundongos fêmeas infectadas ou não, tiveram seu leite coletado no 12º dia após o parto. Os esplenócitos jovens (15 dias) e maduros (6 semanas) foram cultivados com o Leite de Mães Infectadas (LMI) e com Leite de Mães Não Infectadas (LMNI) na presença de estimulador policlonal. Além disso, foram utilizados controles experimentais: Células pulsadas na ausência (BASAL) e apenas com estimulador policlonal (MITÓGENO) e células cultivadas com LMNI adicionado de antígenos solúveis dos ovos do S.mansoni (LMNI+SEA). Posteriormente, os ensaios de citometria de fluxo foram realizados para dupla marcação: Linfócitos T (CD3+ ou CD4+) marcados com CD28, CD154, CTLA4, IL-10 ou FoxP3. Além disso, foram analisadas a expressão de CD80, CD86 e CD40 na superfície de Macrófagos (CD14) e Linfócitos B (CD45R), e ainda a expressão de IL-10 por esse último. Para a análise dos peptídeos presentes no leite materno, um gel unidimensional foi confeccionado e as bandas obtidas no LMI, LMNI+SEA e LMNI foram processados para análise por espectometria de massa. Além disso, foram realizadas análises de antígenos parasitários: SEA e SWAP (antígeno solúvel do verme adulto). Esplenócitos jovens pulsados apenas com o mitógeno apresentaram maior frequência de células CD3+CD28+ e CD45R+IL10+. A adição de LMNI manteve aumento CD3+CD28+ e levou a menor frequência de Tregs, com aumento na expressão de células CD45R+CD40+. Ao ser introduzido o SEA (LMNI+SEA) foi identificada uma menor frequência de células CD3+CD28+ e aumento na expressão de IL-10. O LMI proporcionou menor frequência de linfócitos CTLA4+ e FoxP3+, porém com produção de IL-10 e maior frequência de CD45R+/CD80+. Para os esplenócitos maduros, o LMNI e LMI levaram à menor frequência de células CD3+/CD28+ e maior CD3+/CTLA4+, respectivamente, com aumento sustentado de Treg. Contudo, o LMI diminui a presença de células B IL-10+. A adição do SEA ao LMNI manteve a diminuição de células CD3+CD28+, mas aumentou a frequência de células CD3+/CD154+. O leite de mães esquistossomóticas apresentou peptídeos relacionados à presença do S. mansoni e com variabilidade de função. Destacamos a natureza imunomodulatória dos peptídios aqui identificados (Interleucina 17F, Glutationa s Transferase) que podem atuar na imunidade, seja para antígenos do parasita ou heterólogos, no descendente previamente amamentado. Estes achados enfatizam o caráter dicotômico do leite materno: estimulador em células jovens e tolerogênico em células maduras. Esses achados são relevantes em áreas endêmicas para esquistossomose e reiteram a importância da identificação e caracterização de antígenos parasitários, bem como, uma avaliação do seu papel na interação parasito-hospedeiro no incio da vida. / The high prevalence of chronic schistosomiasis in pregnant women and women of childbearing age has been widely reported. Breastfeeding by mothers with schistosomiasis is capable of altering the long term immune response of offspring. The aim of this study was to undertake an in vitro analysis of the effect of breast milk of mothers with schistosomiasis on young and mature splenocytes and characterize the proteomics in this milk. The milk of female mice infected with Schistosoma mansoni and non-infected female mice was collected on the 12th day postpartum. Young (15 days) and mature (6 weeks) splenocytes were cultivated (24hs) with mitogen (CONTROL), added to the Milk of Infected Mothers (MIM), Milk of Non-Infected Mothers (MNIM) or Milk of Non-Infected Mothers with the addition of soluble egg antigens of parasites (MNIM+SEA), as well as those without in vitro stimulus (BASAL). Double cell labeling was performed for flow cytometry: T Lymphocytes (CD3+ or CD4+) marked with CD28, CD154, CTLA4, IL-10 or FoxP3; Macrophages (CD14) and B Lymphocytes (CD45R) marked with CD80, CD86 or CD40 on the surface and the expression of IL-10 by CD45R+ cells. For analysis of proteomics a one-dimensional gel was made and the bands obtained from MIM, MNIM, MNIM + SEA, were processed for analysis by mass spectrometry. Additionally, the parasite antigens SEA and SWAP (soluble adult worm antigen preparation) were included in the analysis. Young splenocytes pulsed only with mitogen had the greatest CD3+CD28+ and CD45R+IL10+ cell frequency. The addition of MNIM maintained an increase of CD3+CD28+ and produced the lowest frequency of Tregs, with an increase in the expression of CD45R+CD40+ cells. The introduction of SEA (MNIM+SEA) resulted in reduced CD3+CD28+ cell frequency and increased IL-10 expression. MIM resulted in reduced CTLA4+ and FoxP3+ lymphocyte frequency, although there was some IL-10 production and greater CD45R+/CD80+ frequency. MNIM and MIM resulted in the lowest frequency of CD3+/CD28+ and CD3+/CTLA4+ cell frequency, respectively, for mature splenocytes, with a sustained increase of Treg. However, MIM reduced the presence of B IL-10+ cells. The addition of SEA to MNIM maintained a reduction in CD3+CD28+ cells, but increased the frequency of CD3+/CD154+ cells. The breast milk of mothers with schistosomiasis presented peptides related to the presence of S. mansoni and variability of function. The immunomodulatory nature of the peptides identified in the present study (Interleukin 17F, Glutathione-S-Transferase) should be noted, as these can act in the immune process of breastfed offspring, whether for parasite antigens or heterologous antigens. These findings emphasized the dichotomous character of breast milk, which functions as a stimulator in young cells and is tolerogenic in mature cells, yet is capable of improving LB activation. These findings are relevant for areas in which schistosomiasis is endemic and emphasize the importance of the identification and characterization of parasite antigens and the evaluation of their role in parasite-host interaction in the early stages of life, in order to obtain a better understanding of immunoregulatory events.

Schistosomiasis is a millennial disease and constitutes a public health problem worldwide. According to the World Health Organization - WHO (2009), there is 235 million cases of schistosomiasis, with 732 million people at risk of infection in areas worldwide. In Brazil, the disease is found mainly in the Northeast and the state of Minas Gerais. According to the Health s Ministry - MS (2009), the state of Sergipe has the highest prevalence and incidence of disease in the Federation. Being identified areas of high endemicity, such as the city of Ilha das Flores, the subject of this research, which showed about 46.5% of the infected population analyzed in 2007. It is known that the study area is highlighted as a major producer of rice in the Northeast. This activity has a significant economic and strategic value to the city. However, the areas of extenseis type irrigation are recognized worldwide as major sources of transmission of schistosomiasis, because they have conditions conducive to the creation of shellfish and dissemination of S. mansoni infection. Based on this hypothesis, the objective of this study is to analyze the spatial dynamics of the factors that make the city studied endemic for this infection. In order to achieve the proposed objective, initially was to the prevalence of the disease in the municipality through an epidemiological survey of 500 residents between 2009 and 2010. Then, from the diagnosis of environmental conditions, socioeconomic and cultural, through field work, geostatistical and spatial analysis, and preparation of thematic maps, and map the vulnerability to the disease. Of the 500 individuals who participated in this study, 120 were positive for schistosomiasis, which corresponds to 24% of the sampling universe (BCA (Bootstrap) 95% [20.4 to 27.6]). From the positive individuals, the multinomial model of spatial analysis, Kernel density estimator, specialized areas more vulnerable to disease occurrence, and punctuated areas in which quality of life is precarious. By combining the results of geology, pedology and geomorphology and the characterize land use, it was noted that the incidence of the disease occurred in the area of the plain fluviolagunar, predominantly agricultural areas, where urban areas are located in the city. Thus it was possible to associate the occurrence of disease in the city to work in irrigated farming, and the existence of favorable ecological characteristics of the proliferation of snails (intermediate hosts of S. mansoni). The geostatistical analyzes ratified the information cited to establish standards that identify populations most susceptible to infection. What associations were identified between S.mansoni and: being male, 65.2% of positive (PR = 2.0, 95% CI 1.27 to 3.26, p = 0.003), have low education level (PR = 7.1, 95% CI 2.41 to 20.93, p <0.001), having low income (family income < U.S 273,00) (PR = 1.8, 95% CI 1.28 to 2.60, p = 0.0005), have any level of contact with natural water sources (PR = 1.9, 95% CI 1.36 to 2.59, p <0.001), time of contact with natural water sources (more than 6 hours per week) ( PR 3.6 95% CI 1.05 to 12.32, p = 0.04), be a farmer (PR = 2.7, 95% CI, 1.29 to 5.40, p <0.001) and / or be a fisherman (PR = 3.3, 95% CI 1.39 to 7.69, p <0.001). It was concluded that the population of the city of Ilha das Flores-SE is highly vulnerable to the occurrence of schistosomiasis and needs the attention of government to reverse this situation, trying to solve the problems, that are associated to schistosomiais transmission of this population. / A esquistossomose é uma doença milenar e se constitui em um problema mundial de Saúde Pública. Segundo a Organização Mundial de Saúde OMS (2009) estima-se haver 235 milhões de casos de esquistossomose, com 732 milhões de pessoas em risco de infecção em áreas de transmissão conhecida em todo o mundo. No Brasil, a doença é encontrada, principalmente na região nordeste e no estado de Minas Gerais. De acordo com dados do Ministério da Saúde MS (2009), o estado de Sergipe apresenta uma das maiores prevalência e incidência da doença na Federação. São detectadas áreas de alta endemicidade, á exemplo do município de Ilha das Flores, objeto de estudo desta dissertação, o qual apresentou cerca de 46,5% de infectados da população analisada no ano de 2007. Sabe-se que a área em estudo destaca-se como grande produtora de arroz irrigado no Nordeste, sendo esta atividade de grande expressão econômica e de amplo valor estratégico para o município. Entretanto, devemos considerar que as áreas de irrigação são mundialmente reconhecidas como importantes focos de transmissão da esquistossomose, pois, estas apresentam condições propícias à criação dos moluscos e de disseminação da infecção pelo S. mansoni. Partindo desta hipótese, o estudo objetiva analisar o dinamismo espacial dos fatores que, somados à irrigação, potencializam para tornar o referido município endêmico. Visando a alcançar o objetivo proposto, inicialmente, identificou-se a prevalência da doença no município através de inquérito epidemiológico com 500 munícipes no período de 2009 á 2010. Em seguida, a partir do diagnóstico dos condicionantes ambientais, socioeconômicos e culturais, por intermédio de trabalhos de campo, de análises geoestatísticas e espaciais, e da confecção dos mapas temáticos, obteve-se a vulnerabilidade à ocorrência da doença. Dos 500 indivíduos que fizeram parte deste estudo, 120 foram positivos para esquistossomose, o que corresponde a 24% do universo amostral. A partir dos individuos positivos, o modelo multinominal de análise espacial, estimador de densidade Kernel, espacializou as áreas mais vulneráveis a ocorrência da doença, sendo pontuadas áreas em que a qualidade de vida é precária. Ao sobrepor os resultados da geologia, pedologia e geomorfologia à caracterização de uso da terra, notou-se que a incidência da doença da-se na zona da planície fluviolagunar, área predominantemente agrícola e onde se localizam as áreas urbanas do município. Sendo possível associar a ocorrência da doença no município ao trabalho na lavoura irrigada e a existência de características ecológicas favoráveis à proliferação dos caramujos (hospedeiros intermediários do S. mansoni). As análises geoestatísticas ratificaram as informações supracitadas ao estabelecerem padrões que identificaram populações mais suscetíveis à infecção, em que foram identificadas associações entre S. mansoni e: ser do sexo masculino, 65,2% dos positivos; ter baixo nível de escolaridade; ter baixa renda (renda familiar < R$545,00); ter qualquer nível de contato com fontes naturais de água; tempo de contato com fontes naturais de água (mais de 6 horas por semana); ser agricultor e/ou ser pescador. Concluindo-se que a população do município de Ilha das Flores-SE esta extremamente vulnerável a ocorrência da esquistossomose e necessita da atenção do poder público para reverter esse triste quadro.

Neste estudo avaliou-se o efeito in vitro de 4 compostos isolados de espécies vegetais, as amidas piplartina e piperina, a lignana grandisina e o alcaloide epiisopiloturina; 1 composto isolado da pele de anfíbio, o peptídeo antimicrobiano dermaseptina 01; e de 6 extratos etanólicos obtidos de vegetais, Piper tuberculatum, P. crassinervium, P. diospyrifolium, P. fuligineum, P. gaudichaudianum e Pothomorphe umbellata em adultos (machos e fêmeas com 49 dias) e esquistossômulos (recém-transformados, 1, 3, 5 e 7 dias) de Schistosoma mansoni linhagem BH. O estudo avaliou: 1) a viabilidade de vermes adultos; 2) a capacidade reprodutiva, avaliada pelo acasalamento e oviposição; 3) o efeito no tegumento em parasitas adultos; 4) a viabilidade e o efeito no tegumento em esquistossômulos; 5) a citotoxicidade de compostos e extratos em células de mamífero (célula Vero). Além disso, com microscopia confocal, neste estudo é proposto um novo modelo experimental que avalia, quantitativamente, o efeito de esquistossomicidas no tegumento dos esquistossomos. / In this study, the in vitro effect of 4 compounds isolated from plant species, amides piplartine and piperine, the lignin grandisin and alkaloid epiisopiloturine; 1 compound isolated from amphibian skin, the antimicrobial peptide dermaseptin 01; and 6 ethanolic extracts of plants, Piper tuberculatum, P. crassinervium, P. diospyrifolium, P. fuligineum, P. gaudichaudianum and Pothomorphe umbellata was evaluated in adults worm pairs (49-day-old) and schistosomula (newly-transformed, 1-, 3-, 5-, and 7-day-old) of Schistosoma mansoni BH strain. The effect of compounds and extracts against schistosomes was examined regarding: 1) adult worms survival, 2) the reproductive fitness as assessed by mating and oviposition; 3) alterations on adult worms tegumental surface; 4) viability and morphological alterations on schistosomula; 5) the cytotoxicity of compounds and extracts in mammalian cells (Vero cells) In addition, this study shows a new experimental model to evaluate quantitatively the effect of schistosomicidal drugs on the tegument of the schistosomes.

Os objetivos deste trabalho foram: verificar a ocorrência de esquistossomose e a distribuição dos focos de transmissão em dois municípios, Aparecida e Roseira, com características sócioambientais distintas, localizados no Vale do Paraíba, Estado de São Paulo, e comparar os dados entre si e com os obtidos nos últimos dez anos. Fatores ambientais, climáticos, demográficos e sociais foram identificados e associados ao perfil da doença. Dados epidemiológicos relativos à esquistossomose foram obtidos a partir dos relatórios da Superintendência de Controle de Endemias (SUCEN) e índices pluviométricos e de temperatura foram organizados a partir da plataforma de coleta de dados da Escola de Especialistas de Aeronáutica. A análise dos coeficientes de prevalência, entre 1995 e 2004, mostrou queda do número de casos nos dois municípios. Intensa pressão de urbanização foi observada, tendo sido identificados como urbanos 100% dos casos de Aparecida, e 74% dos casos em Roseira. Os indivíduos na faixa etária de 21 a 25 anos foram os mais atingidos e quanto ao sexo, a predominância foi entre os do sexo masculino. Com relação ao contato com águas naturais, os locais mais citados foram: áreas de várzeas, rio Paraíba do Sul, valetas. Foram identificadas e comparadas, em dois momentos no decorrer do estudo, 1995 e 2004, as áreas consideradas de risco para transmissão da esquistossomose, analisando-as quanto às alterações ambientais ocorridas e verificando-se potenciais focos ainda existentes. Associação entre prevalência da doença e índices pluviométricos e de temperatura não foi significativa. A redução dos casos de esquistossomose podem estar associados a: mudança de hábitos da população, mecanização da cultura de arroz, mudança no tipo de lavoura e substituição da lavoura por pastagens. Apesar da melhoria das condições de saneamento básico, ambos os municípios continuam com potencial de transmissão da esquistossomose. / This study had as objectives: to verify the occurrence of schistosomiasis and the distribution of the transmission foci in two cities, with distinct social and environmental characteristics, Aparecida and Roseira, located in the Valley of the Paraíba river, Sao Paulo State, Brazil, and to compare the data between them and with the ones obtained in the last ten years. Environmental, climatic, demographic and social factors were identified and associated to the profile of the disease. Epidemiological data related to schistosomiasis were obtained from the reports of the Superintendence for the Control of Endemic Diseases (SUCEN) and the meteorological conditions, related to rain fall and temperature, were organized from the data collection platform of the of School for Aeronautic Specialists. The analysis of the prevalence coefficients, between 1995 and 2004, showed fall in the number of cases in both municipalities. Intense urbanization pressure is observed, having been identified as urban 100% of the cases from Aparecida, and 74% of the cases from Roseira. The male group was more infected than female, and the age group of 21 to 25 years old was the most infected one. With relation to the contact with natural waters, the most cited places were: holm and drains areas and the Paraíba do Sul river. Some risk areas were identified and compared at two moments during the study, 1995 and 2004, and than analyzed according to environmental alterations. The occurrence of schistosomiasis does not seem to be associated to the rain fall nor temperature variations. The reduction of schistosomiasis cases can be associated to: changing on population habits, mechanization of the rice culture, changing on the type of farming or substitution for pasture areas. Despite the improvement of the basic sanitation conditions, both cities continue to have potential for schistosomiasis transmission.

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PhD (Mathematics) / Department of Mathematics and Applied Mathematics / In this study, we developed multiscale models of vector-borne diseases. In general, the transmission of vector-borne diseases can be considered as falling into two categories, i.e. direct transmission and environmental transmission. Two representative vector-borne diseases, namely; malaria which represents all directly transmitted vector-borne diseases and schistosomiasis which represents all environmentally transmitted vector-borne diseases were studied. Based on existing mathematical modelling science base, we established a new multiscale modelling framework that can be used to evaluate the effectiveness of vector-borne diseases treatment and preventive interventions. The multiscale models consisted of systems of nonlinear ordinary differential equations which were studied for the provision of solutions to the underlying problem of the disease transmission dynamics. Relying on the fact that there is still serious lack of knowledge pertaining to mathematical techniques for the representation and construction of multiscale models of vector-bone diseases, we have developed some grand ideas to placate this gap. The central idea in multiscale modelling is to divide a modelling problem such as a vector-bone disease system into a family of sub-models that exist at different scales and then attempt to study the problem at these scales while simultaneously linking the sub-models across these scales. For malaria, we formulated the multiscale models by integrating four submodels which are: (i) a sub-model for the mosquito-to-human transmission of malaria parasite, (ii) a sub-model for the human-to-mosquito transmission of malaria parasite, (iii) a within-mosquito malaria parasite population dynamics sub-model and (iv) a within-human malaria parasite population dynamics sub-model. For schistosomiasis, we integrated the two subsystems (within-host and between-host sub-models) by identifying the within-host and between-host variables and parameters associated with the environmental dynamics of the pathogen and then designed a feedback of the variables and parameters across the within-host and between-host sub-models. Using a combination of analytical and computational tools we adequately accounted for the influence of the sub-models in the different multiscale models. The multiscale models were then used to evaluate the effectiveness of the control and prevention interventions that operate at different scales of a vector-bone disease system. Although the results obtained in this study are specific to malaria and schistosomiasis, the multiscale modelling frameworks developed are robust enough to be applicable to other vector-borne diseases. / NRF