Première des maladies infectieuses jugées comme prioritaire en Guyane, la dengue fait l’objet d’une forte mobilisation des pouvoirs publics. L’amélioration des connaissances relatives aux facteurs climatiques et environnementaux qui influencent la dengue est un préalable indispensable pour le développement de modèles de prédiction nécessaires pour anticiper et adapter les mesures de gestion aux différentes échelles du département. Cette thèse poursuit un double objectif : i) analyser aux différentes échelles de la Guyane (département, territoires, communes), l’effet des facteurs climatiques et environnementaux sur la dynamique des épidémies de dengue et ii) développer des modèles de prédiction des épidémies. A cet égard, des outils statistiques, de fouille de données et de modélisation complémentaires on été utilisés pour étudier l’influence des facteurs climatiques et environnementaux sur la dynamique de la dengue. Un modèle de prévision climatique des épidémies à l'échelle du départeent, présentant une bonne valeur prédictive a été développé. Ce modèle prédit une épidémie pour 2016. / Dengue is the most prioritized infectious disease in French Guiana with an intense mobilization of public health authorities. In this context, the improvement of knowledge on the climatic, environmental and demographic determinants of dengue transmission is a necessary condition to the development of epidemic prediction model for the planning of control activities at each level of organization of the territory. This thesis had two objectives: i) assess the effect of climatic and environmental factors on dengue spread; ii) develop prediction models of epidemic to anticipate and plan prevention and control activities. We used complementary statistical, data mining and modeling tools to show that climatic and environmental factors interplay with dengue incidence differently at different territory scales. A predictive model with a good performance was developped considering the whole territory of French Guiana. This model indicates that a dengue epidemic is likely to occur in 2016.

Genetic control strategies are a novel method for reducing populations of pest insects such as the yellow fever mosquito Aedes aegypti, a major vector of several important arboviral diseases. This thesis describes efforts to develop new tools to engineer the Ae. aegypti genome and to better understand existing tools, and furthermore to use these to engineer a gene drive system in Ae. aegypti. The piggyBac transposon was found to be extremely stable in the germline of Ae. aegypti, and transposons engineered into the germline could not be remobilized with either an endogenous or exogenous source of piggyBac transposase. Conversely, somatic remobilization of piggyBac transposons was found to be readily detectable in the presence of a source of active transposase, the first report of such remobilization in Ae. aegypti. Toward new tools for genome engineering, the site-specific integrase from the phage φC31 was successfully used to promote exchange between a transgene cassette inserted into the genome of Ae. aegypti and a cassette in a plasmid vector, in the first demonstration of recombinase mediated cassette exchange technology in a pest insect species. The integrases from phages φRV1 and Bxb1 were not found to be active in the germline of the mosquito. Finally, development of a gene drive system in Ae. aegypti using an RNAi-mediated killer-rescue mechanism was attempted. Tissue-specific expression of tTAV-regulated-toxic effectors genes, using the promoter regions of the blood meal induced genes Carboxypeptidase A-1, 30Kb and Vitellogenin A, was possible, but sex-specificity was not achieved. A blood meal inducible lethal phenotype was not possible using the chosen promoters, with expression of the effectors either leading to death in early development or to a sublethal phenotype. RNAi against tTAV fused to the Mnp fragment of the dengue virus’ genome was tissue specific, but was found to be highly effective in the fat body suggesting that the Vitellogenin A was the best candidate for the engineering of killer-rescue systems in the mosquito.

Submitted by Tereza Risi (tereza.risi@icict.fiocruz.br) on 2013-10-11T19:29:13Z No. of bitstreams: 1 Isabel Levy.pdf: 2081227 bytes, checksum: d87790882fbeedaf43096403d4e742be (MD5) / Made available in DSpace on 2013-10-11T19:29:13Z (GMT). No. of bitstreams: 1 Isabel Levy.pdf: 2081227 bytes, checksum: d87790882fbeedaf43096403d4e742be (MD5) Previous issue date: 2013 / Fundação Oswaldo Cruz. Instituto de Comunicação e Informação Científica e Tecnológica em Saúde. Rio de Janeiro, RJ, Brasil / O advento e a popularização das tecnologias da informação e da comunicação ± dentre elas, a internet e as redes sociais on - lin e ± têm modificado profundamente as formas como pessoas e instituições se relacionam. No campo da Comunicação e Saúde, diversas experiências contemporâneas apontam a concorrência entre forças centrípetas e centrífugas no ciberespaço e levantam a questão: o investimento das instituições públicas de saúde em atividades desenvolvidas na internet, por meio das redes sociais on - line, é de fato uma inovação em suas práticas discursivas ou corresponde a uma inovação relativa ao suporte, mas não ao modo de relação com os seus interlocutores? Por meio da abordagem da netnografia, a pesquisa buscou mapear, descrever e analisar práticas de comunicação do Ministério da Saúde no ciberespaço, tendo como objeto específico a Campanha Nacional de Combate à Dengue 2011/2012. O estudo aponta que, a o assumir algumas características que tradicionalmente são observadas na forma como a mídia hegemônica aborda os temas de saúde, os espaços virtuais do Ministério da Saúde constituem - se mais como mídias digitais e menos como redes soc iais on - line. Os resultados nos levam a concluir que, apesar da inovação no uso de suportes digitais e no investimento em recursos criativos como as narrativas transmídia, as práticas de Comunicação e Saúde desenvolvidas pelo Ministério da Saúde no ciberes paço durante a Campanha estudada repetem as dinâmicas que caracterizam o modelo hegemônico de comunicação de natureza transferencista, bipolar, linear unidirecional e centralizado no emissor, e consolidam o discurso campanhista de saúde / The information and communication technologies ± especially the internet and online social networks - have profoundly changed the relationshi p between people and institutions. In the field of Communication and Health, various contemporary experiences indicates the competition between centripetal and centrifugal forces in cyberspace and raise the question about the public institutions investmen t in online activities. Is it is indeed an innovation in their discursive practices or represents an innovation on the devices , but not on the mode of relationship with their interlocutors? Through netnography approach, the research sought to identify, des cribe and analyze communication practices of the Ministry of Health in cyberspace, with the specific object of the National Campaign to Combat Dengue 2011/2012. The study shows that by taking a few features that are traditionally found in how the hegemonic media covers WKH WRSLFV RI KHDOWK 0LQLVWU\ RI +HDOWK¶V YLUWXDO VSDFHV DUH PRUH OLNH GLJLWDO PHGLD DQG less like online social networking. The results lead us to conclude that, despite the innovative use of digital media and creative resources as transmed ia narratives, Communication and Health practices developed by the Ministry of Health in cyberspace during the Campaign repeat the dynamics that characterize the hegemonic model of communication - bipolar, linear and unidirectional, centralized in an emit ter polo - and consolidate the health's prescriptive speech

Contexte : La dengue est une fièvre ayant pris davantage d’ampleur dans plusieurs régions du monde à climat tropical, dont le département Méta en Colombie, un lieu endémique dans la dernière décennie. Sachant que la propagation de cette maladie est entièrement dépendante des sites de reproduction du vecteur de transmission Aedes, l’investigation de prédicteurs environnementaux les affectant nous semblait pertinente d’un point de vue épidémiologique. Notre étude vise des retombées sur un plan de surveillance de santé publique et l’élaboration de programmes basés sur des observations temporelles et spatiales. Objectifs : Décrire la distribution spatio-temporelle de la dengue dans les 29 municipalités de Méta selon des prédicteurs environnementaux, soit les précipitations, la température ambiante, la température du point de rosée et la pression au niveau de la mer dans le cadre d’une étude écologique. Méthodes : Des données de surveillance SIVIGILA, de télédétection ainsi que de recensement DANE des 29 municipalités du département de Méta entre 2011 et 2019 ont été utilisées pour étudier l’association entre la dengue et les prédicteurs environnementaux. La modélisation de ces associations a été effectuée à l’aide d’un modèle de Markov cachés à changement de régime. Résultats : Des associations positives importantes ont été détectées entre les précipitations et l’incidence de la dengue atteignant des risques relatifs élevés (RR=1.97 à El Calvario à un décalage de 5 semaines ; RR=1.61 à San Juanito à un décalage de 20 semaines). La température ambiante et la température du point de rosée ont suivi en matière de pertinence n’excédant pas des RR de 1.11 pour la maladie. Or, la pression au niveau de la mer n’a pas présenté des résultats concluants. Selon les différents aspects étudiés dans les nombreuses cartes de ce mémoire, nous avons observé une dépendance géographique répétée à l’ouest du département. Conclusion : Nos conclusions recommandent qu’une attention particulière de la santé publique doit s’imposer quant à la prévention de la dengue en saison pluvieuse dans le Meta. Les hausses des valeurs de température ambiante et de la température du point de rosée peuvent expliquer certaines augmentations de l’incidence et incitent donc à la surveillance de ces paramètres également. À noter que nos résultats ont possiblement pu être influencés par un biais d’information et un biais de confusion. / Context: Dengue is a type of fever that has significantly spread in several regions of the world characterized by a tropical climate, including the Meta department in Colombia, which seemed to be an endemic place in the last decade. Knowing that the spread of this disease is entirely dependent on the reproduction sites of the Aedes transmission vector, the study of environmental predictors affecting those sites seemed relevant from an epidemiological point of view. Our study aims to add to the knowledge that can be used for public health surveillance and program elaboration based on temporal and spatial observations of dengue patterns within the region. Objectives: To describe the spatiotemporal distribution of dengue fever in the 29 municipalities of Meta according to its environmental predictors (i.e. precipitation, ambient temperature, dew point temperature and pressure at sea level) within the framework of an ecological study. Methods: SIVIGILA surveillance, remote sensing and DANE census data from 29 municipalities in the Meta department between 2011 and 2019 were used to study the association between dengue fever and environmental predictors. These associations were modeled using a regime-switching hidden Markov model. Results: Significant positive associations were detected between rainfall and dengue incidence reaching high relative risks (RR=1.97 in El Calvario at a 5-week lag; RR=1.61 in San Juanito at a 20-week lag). Ambient temperature and dew point temperature followed in terms of relevance not exceeding RRs of 1.11 for disease. However, pressure at sea level did not show conclusive results. According to the different aspects studied in the many geographical maps of this thesis, we observed a repeated geographical dependence in the west of the department. Conclusion: We recommend that special public health attention should be given to the prevention of dengue fever in the rainy season in Meta. Increases in ambient temperature values and dew point temperature may explain some increases in incidence and therefore prompt monitoring of these parameters as well. It should be noted that our results may have been influenced by an information bias and confusion bias.

In under 6 decades dengue has emerged from South East Asia to become the most widespread arbovirus affecting human populations. Recent dramatic increases in epidemic dengue fever have mainly been attributed to factors such as vector expansion and ongoing ecological, climate and socio-demographic changes. The failure to control the virus in endemic regions and prevent global spread of its mosquito vectors and genetic variants, underlines the urgency to reassess previous research methods, hypotheses and empirical observations. This thesis comprises a set of studies that integrate currently neglected and emerging epidemiological, ecological and evolutionary factors into unified mathematical frameworks, in order to better understand the contemporary population biology of the dengue virus. The observed epidemiological dynamics of dengue are believed to be driven by selective forces emerging from within-host cross-immune reactions during sequential, heterologous infections. However, this hypothesis is mainly supported by modelling approaches that presume all hosts to contribute equally and significantly to the selective effects of cross-immunity both in time and space. In the research presented in this thesis it is shown that the previously proposed effects of cross-immunological reactions are weakened in agent-based modelling approaches, which relax the common deterministic and homogeneous mixing assumptions in host-host and host-pathogen interactions. Crucially, it is shown that within these more detailed models, previously reported universal signatures of dengue's epidemiology and population genetics can be reproduced by demographic and natural stochastic processes alone. While this contrasts with the proposed role of cross-immunity, it presents demographic stochasticity as a parsimonious mechanism that integrates, for the first time, multi-scale features of dengue's population biology. The implications of this research are applicable to many other pathogens, involving challenging new ways of determining the underlying causes of the complex phylodynamics of antigenically diverse pathogens.

nÃo hà / O dengue permanece como problema de saÃde pÃblica no Brasil. No nordeste brasileiro, os grandes depÃsitos domiciliares utilizados para acumular Ãgua sÃo importantes criadouros para reproduÃÃo do Aedes aegypti, o principal transmissor do dengue. O uso de alternativas ao controle quÃmico desse vetor vem sendo incentivado. Os objetivos desse trabalho foram avaliar se a presenÃa de peixes larvÃfagos altera o padrÃo de postura do A. aegypti, identificar a sobrevivÃncia de peixes larvÃfagos ao cloro e descrever a eficÃcia do peixe Betta splendens em condiÃÃes de campo. O padrÃo de postura foi avaliado em uma gaiola com 6 m3. Os peixes avaliados foram Poecilia reticulata e B. splendens. Na gaiola foram inseridos oito depÃsitos, sendo quatro com peixes, quatro sem peixes (controle) e 100 mosquitos. Em cada depÃsito tinha Ãgua e uma palheta de eucatex para postura dos ovos. Ao final de cada semana os ovos postos nessas palhetas foram contados. Os ensaios foram replicados por sete semanas consecutivas para cada espÃcie. A sobrevivÃncia do B. splendens e P. reticulata, ao cloro, foi avaliada para trÃs concentraÃÃes (1,0; 1,5 e 2,0 mg/L) utilizando tambores com 35 litros de Ãgua. Foram utilizados 105, 140 e 175 peixes para cada concentraÃÃo testada, na proporÃÃo de 6 depÃsitos com cloro para cada controle (sem cloro). A eficÃcia foi avaliada a partir de dados gerados pelo Programa Municipal de Controle do Dengue, na cidade de Fortaleza. Foi avaliada a permanÃncia dos peixes em depÃsitos domiciliares e a infestaÃÃo nesses depÃsitos com B. splendens e o larvicida Bacillus thuringiensis israelensis. A presenÃa do B. splendens inibiu a postura de ovos pelas fÃmeas de Aedes aegypti com um Ãndice de Atividade de OviposiÃÃo (IAO) de -0,627. O nÃmero mÃdio de ovos postos em depÃsitos com B. splendens (32,5/semana) foi menor que nos depÃsitos com o P. reticulata (200,5/semana) e os controles (186,5/semana; p < 0,0001). Todos os B. splendens sobreviveram a concentraÃÃo de cloro de 1,0 mg/L; 72,5 e 39,3% sobreviveram as concentraÃÃes de 1,5 e 2,0 mg/L. Por outro lado, apenas 4,4% do P. reticulata sobreviveram a concentraÃÃo mÃnima de 1,0 mg/L. Em campo foram encontrados trÃs depÃsitos com a presenÃa do B. splendens e larvas de mosquitos (1,6%), infestaÃÃo significativamente menor que nos depÃsitos com o Bti, onde essa infestaÃÃo foi de 10,9% (p < 0,001). Nos depÃsitos onde o peixe nÃo permaneceu a infestaÃÃo foi de 27,8%, maior que nos depÃsitos com Bti (p < 0,010). Nos depÃsitos onde o peixe permaneceu ele foi 85% mais eficaz que o larvicida. A permanÃncia dos peixes foi maior nos tanques de alvenaria (48,5%), localizados no peridomicÃlio (47,5%) e ao nÃvel do solo (53,3%). ConcluÃmos que o B. splendens pode ser apropriado para controle biolÃgico de larvas de Ae. aegypti em grandes reservatÃrios domiciliares, desde que possa ser atestada sua permanÃncia nesses depÃsitos. / Dengue fever remains an important public health problem in northeast Brazil. Large domestic containers used to store water are important breeding sites of Aedes aegypti, the main vector. The use of alternatives to chemical vector control has increased in the last years. The objectives of this study were: to evaluate the inhibition of oviposition by female Ae. aegypti in domestic containers with larvivorous fish; to describe the survival of larvivorous fish to different chlorine concentrations; and to describe the efficacy of Betta splendens fish under field conditions. Oviposition was assessed in a cage of 6 m3 of size. The fish species Poecilia reticulata and B. splendens were used in the laboratory assays. In the cage, eight water containers were placed - four with fish, four without fish (control), and 100 mosquitoes. In each container with 15 l water eucatex strips were placed to facilitate oviposition. At the end of each week, eggs laid on these strips were counted. For each species, the assays were repeated for seven consecutive weeks. Survival of B. splendens and P. reticulata to different concentrations of chlorine (1.0, 1.5 and 2.0 mg / L) was assessed in drums with 35 liters of water. We used 105, 140 and 175 fish for each concentration: six test containers with chlorine for each control without chlorine. Secondary data of the Municipal Dengue Control Program of the city of Fortaleza were analyzed to assess the efficacy of B. splendens under field conditions. The presence of fish in household containers was verified after several weeks. Infestation of containers with mosquito larvae was compared to containers with the larvicide Bacillus thuringiensis israelensis. The presence of B. splendens inhibited oviposition by Ae. aegypti with an activity oviposition index of -0.627. The mean number of eggs laid in deposits with B. splendens (32.5 / week) was lower than in deposits with P. reticulata (200.5 / week) and controls (186.5 / week, p <0.0001). All B. splendens specimens survived a chlorine concentration of 1.0 mg / L, and 72.5% and 39.3% survived concentrations of 1.5 and 2.0 mg / L, respectively. On the other hand, only 4.4% of P. reticulata survived a concentration of 1.0 mg / L. Under field conditions, three containers were encountered with B. splendens and mosquito larvae (1.6%), significantly less than infested deposits with Bti (10.9%; p <0.001). In containers where the fish died or disappeared, infestation was 27.8% higher than in deposits with Bti (p <0.010). In deposits where the fish remained, efficacy was 85% better than Bti. The permanence of fish was higher in concrete tanks (48.5%), located outside the house (47.5%) and at ground level (53.3%). We conclude that B. splendens may be suitable for biological control of Ae. aegypti larvae in large domestic water containers.