Estudo qualitativo que tem como objetivo compreender os significados socioculturais relacionados à saúde, doença e morte de crianças de 0 a 5 anos na comunidade de Mopeia tendo por objeto as campanhas sanitárias governamentais em Moçambique, particularmente, vacinação de crianças, utilização de redes mosquiteiras e amamentação exclusiva até os 6 meses de idade. Através do método etnográfico e particularmente da observação participante, do uso de diário de campo e entrevistas semidiretivas, no sentido de captar as vinculações das práticas e saberes socioculturais com os elementos do contexto de vida da comunidade, realizou-se o trabalho de campo entre os meses de Julho e Setembro de 2010. Os resultados apontam que certas praticas socioculturais relacionadas à falta de higiene e saneamento do meio, à não-amamentação exclusiva até os 6 meses, bem como ao uso incorreto das redes mosquiteiras, associadas às limitações na efetividade das intervenções sanitárias, podem estar contribuindo para a mortalidade de crianças menores de 5 anos por doenças preveníveis. Observou-se também que há falta de consonância entre os programas de intervenção de saúde pública, particularmente as medidas mecânicas para o controle de certas doenças preveníveis, como a malária e a diarréia, através de campanhas sanitárias e a realidade de vida das populações. Neste contexto, há necessidade de se articular as campanhas sanitárias com as práticas socioculturais da região, concomitantemente com a disponibilidade e expansão de infra-estruturas básicas, para que haja mais eficácia na intervenção das políticas de saúde pública na luta contra a redução da mortalidade de menores de 5 anos por doenças preveníveis / This qualitative study seeks to understand the socio-cultural meanings about health, disease and death of children aged between 0-5 at Mopeia community. Its object is the government run health campaigns in Mozambique, particularly children vaccination, mosquito nets use, exclusive breast feeding up to six years of age. By applying the ethnographic method, particularly through participative observation, field diary and interviews to capture the relationship between the practices, the socio-cultural knowledge and the individuals of the community, a field work was carried out between July and September 2010. The results show that some socio-cultural practices like lack of hygienic practices and community sanitation, non exclusive breast feeding up to six years of age, the improper use of mosquito nets, associated to the shortage of health care assisance can be contributing to the mortality of children under five by preventable diseases. It was also observed that there is a mismatch between public health programs, particularly those addressed to preventable diseases like malaria and diarrhea and the reality of the community. Thus, there is the need to match the campaigns to the socio-cultural practices in the region, make available and expand infrastructure for primary health care to boost the efficacy of the intervention in public health policies aimed at fighting and reducing the death rates by preventable diseases of children under five years of age

Nos últimos anos, estudamos vários aspectos da resposta imune naturalmente adquirida em indivíduos de diferentes áreas endêmicas da Região Amazônica expostos à malária. Para isso, utilizamos proteínas recombinantes baseadas em antígenos de formas sanguíneas de P. vivax, os quais têm sido considerados candidatos à vacina contra a malária vivax. No presente trabalho, nossos estudos imunoepidemiológicos concentraram-se em 396 indivíduos de uma comunidade rural da Amazônia ocidental brasileira, localizada no Estado do Acre, com o objetivo de realizar um estudo transversal e longitudinal da resposta de anticorpos contra um painel de proteínas recombinantes derivadas de merozoítos de P. vivax (MSP119, AMA-1, MSP3α e MSP3β). Para isso, os soros desses indivíduos foram testados por ELISA quanto ao reconhecimento das quatro proteínas recombinantes. As proporções de indivíduos na linha de base com anticorpos IgG contra MSP119, AMA- 1, MSP3α e MSP3β foram de 59,8%, 50,0%, 23,5% e 26,5%, respectivamente. Dentre esses indivíduos, apenas 10,9% tinham infecções por P. vivax, P. falciparum ou malária mista. No grupo de infectados por P. vivax, a proporção de respondedores foi maior para as proteínas recombinantes MSP119 e AMA-1, atingindo 78,6%, em ambos os casos. A proporção de indivíduos com anticorpos para cada uma das proteínas associou-se com o maior tempo de exposição à malária, exceto para a MSP3β. Além disso, a positividade foi mais alta nas áreas de maior risco de transmissão. Não observamos associações relevantes entre o genótipo do antígeno Duffy dos indivíduos e presença de anticorpos para as proteínas estudadas. No estudo longitudinal, observamos um aumento da prevalência de respondedores durante a parasitemia patente, sendo de 81,9%, 80,9%, 31,9% e 48,9% para a MSP119, AMA-1, MSP3α e MSP3β, respectivamente. Em conclusão, nossos resultados confirmam a alta antigenicidade dessas proteínas, o que pode ser de grande importância para futuros ensaios clínicos na região. / In recent years we studied various aspects of the naturally acquired immune response in individuals from different endemic areas of the Amazon region exposed to malaria. For this purpose we used recombinant proteins based on P. vivax blood stage antigens considered candidates for a vaccine against vivax malaria. In the present study, we focused on 396 individuals from a rural community in western Brazilian Amazon located at the state of Acre. We conducted a transversal and longitudinal study of the antibody response to a panel of recombinant proteins representing P. vivax merozoites surface antigens (MSP119, AMA-1, MSP3α and MSP3β). The sera of these individuals were tested by ELISA for the recognition of the four antigens mentioned above. The proportions of individuals at the baseline with IgG antibodies to MSP119, AMA-1, MSP3α and MSP3β were 59.8%, 50.0%, 23.5% and 26.5%, respectively. Among these individuals, 10.9% had patent malaria infections with either P. vivax or P. falciparum or both. Among individuals with patent P. vivax infection, the frequency of responders was high for MSP119 and AMA-1, (78.6% in both cases). Except in the case of MSP3β, the proportion of individuals with antibodies to each protein correlated with the time of malaria exposure. Also, the positivity was higher in areas of higher transmission levels. No relevant association was found between the Duffy genotypes and presence of antibodies to the different antigen. In longitudinal study, we observed an increased prevalence of responders during patent parasitemia, 81.9% 80.9% 31.9% and 48.9% to MSP119, AMA-1, MSP3α and MSP3β, respectively. In conclusion, our results confirm the high antigenicity of these proteins, which can be of great importance for future clinical trials in the region.

Entre cepas diferentes de P. falciparum existe uma grande variação entre as sequências das famílias de genes variantes. Um motivo para esta grande variedade é o fato que a maioria dos genes variantes se encontra em regiões subteloméricas e que o parasita é capaz de recombinar telômeros heterólogos durante a meiose (recombinação ectópica), levando a uma nova distribuição e a criação de novos genes variantes. Além desse fenômeno que ocorre durante a fase sexual do parasita, foi considerado que recombinações também podem ocorrer durante a fase mitótica na fase assexuada sanguínea. Neste estudo, procuramos monitorar a importância desta recombinação ectópica na geração de novos genes var em amostras de campo da Amazônia brasileira. Em experimentos paralelos elucidamos se existe recombinação ectópica também durante divisões puramente mitóticas. Observamos que muitos genes var que são compartilhados entre isolados mudam raramente ou não mudam de posição cromossômica. Observamos que no caso de mudança de posição cromossômica muitas vezes ocorreu duplicação do lócus. Muitos dos genes var compartilhados se encontraram em cromossomos 5-6 e 9-7. Por monitoramento de clones de 3D7 após 180 gerações não observamos nenhuma translocação de genes var subtelomérico ou telomérico indicando que a recombinação ectópica em mitoses é de fato um evento raro. / Different strains of the causative agent of malaria, Plasmodium falciparum, possess greatly varying repertoires of variant antigen encoding gene families. One reason for this variety lies in the fact that most of the variant gene families are found in subtelomeric regions. The parasite is able to recombine heterologous telomers during meiosis through a process coined ectopic recombination, potentially leading to a new distribution and creation of variant genes. Due to morphological similarities of chromosome end clustering in sexual as well as in asexual forms, it was hypothesized that ectopic recombination may also occur in mitotic asexual blood stage parasites. Herein we monitor the occurrence of ectopic recombination in field samples from the Brazilian Amazon. In parallel, we elucidated whether ectopic recombination also takes place in purely mitotic divisions. We observed that many var genes which are shared among isolates rarely change their chromosomal position. When a change occurred, we often observed chromosomal locus duplication and many of the shared genes were found on chromosomes 5-9 or 5-10. After outgrowth of the 3D7 strain for 200 generations with intermittent cloning we did not observe any translocation of telomeric or subtelomeric var genes, indicating that ectopic recombination in mitosis is a rare event.

Estudos conduzidos por vários grupos demonstraram que é possível direcionar antígenos para diferentes subtipos células de dendríticas (DCs) utilizando anticorpos monoclonais (mAbs). Neste trabalho, fusionamos o mAb αDEC205 a dois fragmentos de massa molecular aproximada de 42 e 19 kDa derivados da proteína 1 de superfície do merozoíto (MSP1) do Plasmodium vivax, um importante candidato para o desenvolvimento de uma vacina contra a malária. Para estudar a resposta induzida pelo direcionamento da proteína MSP142 e MSP119 para o subtipo de DCs DEC205+CD8α+, administramos duas doses dos mAbs na presença de poly (I:C), que é um agonista de TLR3 e MDA5. Nossos resultados indicam que o direcionamento da MSP142 para o subtipo de DCs DEC205+CD8α+ é capaz de induzir uma potente resposta celular contra o fragmento de 33 kDa e elevados títulos de anticorpos contra a porção de 19 kDa nas duas linhagens de camundongos. / Studies conducted by several groups have shown that it is possible to target antigens to different subtypes dendritic cell (DC) using monoclonal antibodies (mAbs). Our group has been using a mAb that is able to direct the antigen to subtype of DCs DEC205+CD8α+ . In this work, we fused the αDEC205 mAb with a 42 and 19 kDa fragment derived from the Plasmodium vivax merozoite surface protein 1 (MSP1), a major candidate for the development of a malaria vaccine. In order to study the response induced by the MSP142 targeting to the DEC205+CD8α+ DC subtype, we administered two doses of the mAbs in the presence of poly (I: C), a TLR3 and MDA5 agonist. Our results indicate that MSP142 targeting to the DEC205+CD8α+ DC subtype is able to induce strong cellular response against the 33 kDa fragment, and high antibody titers against the 19 kDa portion in two strains of mice.

Poucos estudos descrevem os aspectos histopatológicos da malária placentária em áreas de transmissão instável para Plasmodium vivax. Pretendemos identificar as alterações histopatológicas e suas intensidades, avaliar o impacto de fatores clínicos e epidemiológicos e a associação dos níveis de citocinas e anafilatoxinas relacionadas à malária placentária causada por Plasmodium vivax. Um estudo longitudinal foi realizado em Cruzeiro do Sul (Acre), com seleção de gestantes não infectadas e infectadas. A prevalência de malária placentária detectada por histologia foi de 13,5%. Não foram encontradas evidências microscópicas da adesão por P. vivax no sinciciotrofoblasto, porém esta espécie ocasionou danos placentários semelhantes aos observados na malária gestacional por P. falciparum, porém com intensidade menor do que a observada em áreas de alta transmissão. As alterações ocasionadas podem ser decorrentes de distúrbios locais e sistêmicos que contribuem para um desfecho desfavorável durante a malária gestacional e placentária ocasionadas por P. vivax. / Few studies describe histopathological aspects of placental malaria in unstable transmission areas for Plasmodium vivax. The objectives of the present work were to identify histopathological alterations and their intensities by assessing the impact of clinical and epidemiologic factors and the association of cytokines and anaphylatoxin levels related to gestational and placental malaria caused by the Plasmodium vivax. A longitudinal study was performed in Cruzeiro do Sul (Acre) by selecting non-infected and infected pregnant. No microscopic evidence of adhesion were found for that species in the syncytiotrophoblast, but this species cause similar placental damage to those seen in P. falciparum malaria, but with lower intensity than that observed in high transmission areas. Finally, the alterations caused in the placental environment can concomitantly result from local and systemic disturbances that jointly contribute to an unfavorable outcome upon the gestational and placental malaria caused by the P. vivax.

Cette thèse a permis la mise en place d’un système d’alerte précoce des épidémies de paludisme basé sur le système de surveillance sentinelle proposant différents seuils épidémiques et un modèle de prédiction. Les données collectées quotidiennement par SMS sont automatiquement stockées sur un serveur dédié. Concomitamment, le système acquiert systématiquement et de manière automatique des données satellitaires météorologiques sur chaque site sentinelle en lien avec les changements de prévalence du paludisme, tels que la température, les précipitations et l'indice de végétation (eng. NDVI). Une base de données des interventions contre le paludisme a également été créée. Ce système a déjà démontré sa capacité à détecter une épidémie de paludisme dans le sud-est du pays en 2014. Deuxièmement, nous avons réalisé une étude pour évaluer la relation entre la durée de l'efficacité de la campagne de masse des moustiquaires imprégnées d'insecticide à effet longue durée (MILD) et les épidémies de paludisme identifiées à Madagascar de 2009 à 2015 par le système de surveillance sentinelle. Cette étude a montré que la différence entre l'efficacité théorique et l’efficacité réelle peut entraîner des lacunes dans la couverture des services pendant les années suivantes, contribuant au rebond du paludisme et souligne la nécessité de mise en place de mécanisme de distribution continue de moustiquaires. Ce travail vise à maximiser l'utilité d'un système de surveillance sentinelle dans des milieux à ressources limitées, guider les changements dans l'orientation des programmes de lutte et fournir des exemples pratiques pour son utilisation dans d'autres systèmes ou contextes. / We describe a Malaria Early Warning System (MEWS) using various epidemic thresholds and a forecasting component with the support of recent technologies to improve the performance of a sentinel MEWS. Malaria-related data from sentinel sites collected by Short Message Service are automatically stored in a database hosted on a server at Institut Pasteur de Madagascar. Concomitantly our system routinely and automatically acquires site specific satellite weather data related to changes in malaria prevalence such as temperature, rainfall and Normalized Difference Vegetation Index (NDVI). A Malaria Control Intervention data base has also been. This system has already demonstrated its ability to detect a malaria outbreak in southeastern part of Madagascar in 2014. In a second time, we conducted a study to assess the relationship between the effectiveness of mass campaign of long-lasting insecticidal nets (LLIN) over time and malaria outbreaks identified in Madagascar from 2009 to 2015 through the Sentinel surveillance system. This study showed that the difference between efficacy and effectiveness may result in gaps in service coverage during the subsequent years contributing to malaria rebound well before the replacement of the LLINs and highlights the need of continuous distribution mechanism of LLINs.This work aims to maximize the usefulness of a sentinel surveillance system to predict and detect epidemics in limited-resource environments, to guide any changes in the orientation of malaria control programs and to provide practical examples and suggestions for use in other systems or settings.

A malária causa complicações envolvendo diversos órgãos, inclusive o fígado, onde se sabe que ocorrem inflamação e dano hepáticos, os quais contribuem para a severidade da doença. A interleucina (IL)-1 α é uma citocina pró-inflamatória que pertence à família da IL-1 e que pode ser produzida e liberada tanto por células não-hematopoiéticas, como hematopoiéticas em contextos como dano tecidual, infecção e doenças autoimunes em diversos órgãos. O presente estudo tem como objetivo avaliar a produção e o papel da IL-1 na imunopatogênese e na proteção durante a malária experimental. A produção da IL-1 foi investigada durante a inflamação e necrose no fígado em camundongos C57BL/6 infectados com o estágio eritrocítico do Plasmodium chabaudi. A fonte de IL-1 no fígado dos camundongos infectados foi determinada por imunofluorescência e citometria de fluxo. Camundongos IL1A-/- foram utilizados para avaliar o papel da IL-1 neste contexto. Durante a infecção aguda com o P. chabaudi, a inflamação hepática e o desenvolvimento das lesões necróticas são acompanhados pelo aumento nos níveis de IL-1 no fígado, que ocorre de forma independente do inflamassoma NLRP3 (Nod-like receptor protein 3). Os neutrófilos foram identificados como sendo a fonte de IL-1 α no fígado dos camundongos C57BL/6 infectados. De forma sistêmica, a deficiência em IL-1 α resultou numa diminuição da perda de peso e da hipotermia causados pela malária, mas teve um efeito menos significativo no controle da parasitemia. No fígado, a ausência de IL-1 reduziu o número de células TUNEL+, atenuando a necrose induzida pela infecção. A melhora no dano hepático nos camundongos IL1A-/- infectados está associada com uma menor resposta inflamatória em comparação aos camundongos C57BL/6 infectados, incluindo uma menor produção do TNF- α (Tumor necrosis factor alpha), citocina associada à apoptose de hepatócitos e, consequentemente, à necrose do tecido hepático durante a malária causada pelo P. chabaudi. Apesar de exercer um importante papel na imunopatogênese do dano e inflamação do fígado durante a fase eritrocítica da infecção pelo P. chabaudi, a ausência da IL-1 α não impediu a proteção conferida pela presença das formas eritrocíticas contra a reinfecção com esporozoítos. Em conclusão, neutrófilos produzem IL-1 α no fígado durante a fase aguda da malária causada pelo P. chabaudi. Esta citocina amplifica a resposta inflamatória à infecção e promove a necrose hepática, assim como exacerba a perda de peso e a hipotermia. / Malaria causes complications involving several organs, including the liver, where there are inflammation and damage that contribute to the disease severity. Interleukin (IL)-1 is a pro-inflammatory cytokine from the IL-1 family that can be released by non-hematopoietic or hematopoietic cells during tissue damage, infection and autoimmune diseases in different organs. The present study aims to evaluate the production and the role of IL-1 in the immunopathogenesis and in the protection during experimental malaria. IL-1 production was assessed during hepatic inflammation and necrosis in C57BL/6 mice infected with blood stages of Plasmodium chabaudi. The source of IL-1 in the liver of infected mice was determined by immunofluorescence and flow cytometry analyses. IL1A-/- mice were used to assess the role of IL-1 in this context. During acute P. chabaudi infection, hepatic inflammation and development of necrotic lesions were accompanied by an increase in IL-1 levels in the liver, which occurred independently of the Nod-like receptor protein 3 (NLRP3) inflammasome. Neutrophils were identified as the source of IL-1 α in the liver of infected C57BL/6 mice. Systemically, IL-1 deficiency resulted in reduction of weight loss and hypothermia caused by P. chabaudi malaria, but had minor effect on parasitemia control. In the liver, the absence of IL-1 reduced the number of TUNEL+ cells and attenuated the necrotic process induced by infection. The amelioration of liver damage in infected IL1A-/- mice was associated with lower inflammatory response compared to infected C57BL/6 mice, in particular with a decrease in tumor necrosis factor alpha (TNF- α) production, which has been directly implicated in the apoptosis of hepatocytes and, in consequence, the necrosis of the liver tissue during P. chabaudi malaria. Despite the important role in liver damage and inflammation immunopathogenesis during the blood-stage P. chabaudi infection, the absence of IL-1 α did not impair the protection conferred by blood stages against sporozoite reinfection. This study shows that neutrophils produce IL-1 α in the liver during acute P. chabaudi malaria. This cytokine amplifies the inflammatory response to infection and promotes liver necrosis, as well as exacerbates the weight loss and hypothermia.

Malaria is one of the oldest parasitic diseases known to man, and the disease has played a role in shaping civilizations and the success of human populations over many centuries. While the malaria is well studied, it still remains a worldwide killer--claiming about 600,000 lives annually with children under the age of five representing a disproportionate population of those lethally infected. Malaria is caused by the protozoan parasite Plasmodium, which is introduced to the human body through the bite of a female Anopheles mosquito. The most lethal form of the disease is carried by the parasite Plasmodium falciparum, while the most widespread form of malaria is caused by Plasmodium vivax, the latter of which has a specific mode of entry and life cycle that makes it difficult to eradicate. The entry of P. vivax into human reticulocytes is based on the presence of the Duffy antigen chemokine receptor (DARC), which is uniquely absent in two-thirds of the Black population and populations of immediate African descent making it rare in the African region while endemic in Western and Asian countries. Inability to culture the parasite P. vivax in vitro and exhaustible tissue samples makes an accurate model of P. vivax malaria difficult to maintain ex vivo. The current study focuses on overcoming those limitations by modeling the mode of entry of P. vivax into patient-specific, induced pluripotent stem cell (iPSC)-derived erythrocyte-lineage cells by showing firstly that DARC is a measurable marker of susceptibility in vitro via FACS analysis, and that secondly, P. vivax cell culture limitations can be bypassed by creating a lentivirus designed to specifically infect DARC-expressing cells. To demonstrate the potency of this system, we show that a virus expressing the conserved region of the Duffy binding ligand, Duffy binding protein II (DBPII), can selectively infect peripheral blood mononuclear cells (PBMCs) that express DARC. Moreover, our current study focuses on the development of an iPSC-based disease model using patient samples derived from DARC expressing patients (DARC+) and DARC negative Sickle Cell Disease (SCD) patients (DARC-). We show that DARC+ iPSC-derived erythroid lineage cells express a transient population of DARC-expressing cells via FACS analysis, and we explore different protocols to stabilize this unique population. We hypothesize that DARC is a stage-specific marker for erythrocyte maturation, and we believe that any subset of cells expressing DARC consists of more mature erythrocyte-lineage cells. This study then, provides a novel platform by which to study malaria infection in a patient-specific manner while bypassing the limitations of culturing P. vivax in an in vitro culture system, as well as introducing a new way to measure erythrocyte maturation. Successful establishment of such a disease model has great implications for in-depth drug screenings for novel therapeutics that target the blood stage of the parasitic disease that were previously difficult to validate due to the limitations of currently existing models.

Les modèles de Markov cachés (MMC) par exemple ceux de la librairie Pfam sont des outils très populaires pour l'annotation des domaines protéiques. Cependant, ils ne sont pas toujours adaptés aux protéines les plus divergentes. C'est notamment le cas avec Plasmodium falciparum (principal agent du paludisme chez l'Homme), où les MMC de Pfam identifient peu de familles distinctes de domaines, et couvrent moins de 50% des protéines de l'organisme. L'objectif de cette thèse est d'apporter des méthodes nouvelles pour affiner la détection de domaines dans les protéines divergentes.Le premier axe développé est une approche d'identification de domaines utilisant leurs propriétés de co-occurrence. Différentes études ont montré que la majorité des domaines apparaissent dans les protéines avec un ensemble très réduits d'autres domaines favoris. Notre méthode exploite cette propriété pour détecter des domaines trop divergents pour être identifiés par l'approche classique. Cette détection s'accompagne d'une estimation du taux d'erreur par une procédure de ré-échantillonnage. Chez P. falciparum, elle permet d'identifier, avec un taux d'erreur estimé inférieur à 20%, 585 nouveaux domaines dont 159 familles étaient inédites dans cet organisme ce qui représente 16% du nombre de domaines connus.Le second axe de mes recherches présente plusieurs méthodes de corrections statistiques et évolutives des MMC pour l'annotation d'organismes divergents. Deux types d'approches ont été proposées. D'un côté, nous intégrons aux alignements d'apprentissage des MMC, les séquences précédemment identifiés dans l'organisme cible ou ses proches relatifs. La limitation de cette solution est que seules des familles de domaines déjà connues dans le taxon peuvent ainsi être identifiées. Le deuxième type d'approche contourne cette limitation en corrigeant tous les modèles par une prise en compte de l'évolution des séquences d'apprentissage. Pour cela, nous faisons appel à des techniques classiques de la bioinformatique et de l'apprentissage statistique. Les résultats obtenus offrent un ensemble de prédictions complémentaires totalisant 663 nouveaux domaines supplémentaires dont 504 familles inédites soit une augmentation de 18% à ajouter aux précédents résultats. / Hidden Markov Models (HMMs) from Pfam database for example are popular tools for protein domain annotation. However, they are not well suited for studying highly divergent proteins. This is notably the case with Plasmodium falciparum (main causal agent of human malaria), where Pfam HMMs identify few distinct domain families and cover less than 50% of its proteins. This thesis aims at providing new methods to enhance domain detection in divergent proteins.The first axis of this work is an approach of domain identification based on domain co-occurrence. Several studies shown that a majority of domains appear in proteins with a small set of other favourite domains. Our method exploits this tendency to detect domains escaping to the classical procedure because of their divergence. Detected domains come along with an false discovery rate (FDR) estimation computed with a shuffling procedure. In P. falciparum proteins, this approach allows us identify, with an FDR below 20%, 585 new domains with 159 families that were previously unseen in this organism which account for 16% of the known domains.The second axis of my researches involves the development of statistical and evolutionary methods of HMM correction to improve the annotation of divergent organisms. Two kind of approaches are proposed. On the one hand, the sequences previously identified in the target organism and its close relatives are integrated in the learning alignments. An obvious limitation of this solution is that only new occurrences of previously known families in the taxon can be discovered. On the other hand, we evade this limitation by adjusting HMM parameters by simulating the evolution of the learning sequences. To this end, classical techniques from bioinformatics and statistical learning were used. Alternative libraries offer a complementary set of predictions summing 663 new domains with 504 previously unseen families corresponding to an improvement of 18% to add to the previous results.

Le paludisme a sévi dans l’archipel des Comores depuis 1925 où une grande épidémie s’est déclenchée à la Grande Comore. Ces îles ont offert des conditions favorables au développement des vecteurs responsables de la transmission du paludisme (Anopheles gambiae et Anopheles funestus) avec un climat tropical humide, une forte densité hydrographique, un environnement forestier et marécageux et la construction de citernes de collecte d’eau de pluie dans les habitations. Cette maladie est devenue endémique stable depuis les années 70 et un problème de santé publique majeur jusqu’aux années 2000. Dès la fin des années 90, le gouvernement comorien a décidé de mettre en place une stratégie de lutte contre le paludisme par la lutte anti-vectorielle et la protection de la population contre les piqûres des moustiques. Ces vingt dernières années, ces actions de lutte contre le paludisme se sont intensifiées et, pour la première fois, un traitement de masse à base d’Artequick a été réalisé à Mohéli (2007-2009), à Anjouan (2012-2013) et à la Grande Comore (2013). Depuis, un recul spectaculaire du paludisme a été observé sur l’ensemble des îles, car Mohéli et Anjouan sont entrées en phase de pré-élimination et la Grande Comore en phase de contrôle. Cette thèse décrit, dans la première partie, l’évolution spatiale et temporelle du paludisme avant et après le traitement de masse pour appréhender l’impact des différentes actions de lutte. Une cartographie de la prévalence en milieu hospitalier et de l’incidence du paludisme à l’échelle des districts sanitaires et des villages montre son recul à Anjouan et Mohéli et son maintien à la Grande Comore. Les tests d’autocorrélation spatiale ont révélé une similitude de la transmission du paludisme entre des localités proches, qui forment des clusters à la Grande Comore. Nous avons démontré, dans la deuxième partie, qu’il existe bel et bien une influence des facteurs environnementaux sur la transmission du paludisme bien que les actions de lutte ont plus de poids. À l’échelle des districts sanitaires, des modèles de régressions linéaires simple et multiple ont été établis entre l’incidence du paludisme et les caractéristiques de l’occupation du sol des îles et les indicateurs paysagers à l’échelle des villages de la Grande Comore. Une enquête sur les connaissances, les pratiques et les vulnérabilités des populations a été menée sur 1288 ménages de l’Union des Comores pour appréhender les facteurs de vulnérabilité favorables à la transmission du paludisme. Au-delà de la présence des citernes dans les ménages, le lieu de dépôt de déchets ménagers favoriserait son maintien à la Grande Comore. L’enquête a révélé que plusieurs ménages de la grande île n’avaient pas pris le traitement de masse de 2013. Cette thèse permet de mieux comprendre les aspects humains et environnementaux du maintien du paludisme et vise ainsi à mieux cibler les futures actions de lutte. / Malaria has been present in the Comoros archipelago since 1925, when a major epidemic was first recorded in Grande Comore. The islands have been favourable to the development of vectors causing malaria transmission (Anopheles gambiae and Anopheles funestus) due to the high tropical rainfall, high hydrographic density, the suitable environment with forests and wetlands, as well as the construction of water reservoirs in households. This disease has been endemic since the 1970s and a major public health problem until the 2000s. From the end of the 1990s, the Comorian government has decided to implement a strategy to control malaria by anti-malaria vector control and population protection against mosquito bites. In the last twenty years, malaria control efforts have been intensified and for a first time, mass treatment with Artequick has been carried out in Mohéli (2007-2009), Anjouan (2012-2013) and Grande Comore (2013). There has since been a dramatic decline in malaria on all the islands, as Mohéli and Anjouan have entered a pre-elimination phase and Grande Comore is in the control phase. In the first part, this thesis describes the spatial and temporal dynamics of malaria before and after mass treatment in order to understand the impact of different control actions. A mapping of hospital prevalence and incidence of malaria at the district and village levels shows its decline in Anjouan and Mohéli and its persistence in Grande Comore. Spatial autocorrelation tests have revealed a similarity in malaria transmission between neighbouring localities that are forming clusters in Grande Comore. In the second part, it was demonstrated that environmental factors have an influence on malaria transmission, despite the greater importance of control actions. At the district level, simple and multiple linear regression models have been established between the incidence of malaria and land cover / land use patterns of islands and landscape indicators at the village level in Grande Comore. A survey on people's knowledge, practices and vulnerabilities was conducted among 1,288 households in the Union of the Comoros to assess factors of vulnerability that contribute to malaria transmission. Beyond having water reservoirs in households, the waste disposal location would also have an impact on malaria in Grande Comore. The survey revealed that several households on the large island did not take the 2013 mass treatment. This thesis provides a better understanding of the human and environmental aspects of malaria maintenance and thus aims to better target future control actions.