Durante os anos de 1889 e 1890 uma forte epidemia se abateu sobre Campinas. Alguns médicos diziam ser a temida febre amarela, outros, no entanto, não concordavam com o diagnóstico e supunham ser alguma outra das tantas febres que reinavam na cidade. E a doença voltaria a se manifestar em 1890, colocando na pauta do dia antigas discussões. Mesmo considerando que as epidemias que se abateram em Campinas foram realmente de febre amarela, as discórdias entre os médicos evidenciavam o quanto alguns aspectos da doença ainda eram desconhecidos da comunidade médica; essas desavenças sugerem também que, ao contrário do que indica a bibliografia sobre a história da cidade de Campinas, nem sempre a classe médica daquela cidade superou suas discórdias particulares em favor da erradicação da doença na cidade. O tema da febre amarela em Campinas é pouco comentado na bibliografia sobre a história daquela cidade, e, em tais exceções, a perspectiva das narrações sempre recaia sobre os esforços de médicos e sanitaristas em vencer a doença e livrar Campinas dos infortúnios da febre amarela, prevalecendo sempre a figura de determinados personagens. Dessa maneira, ao invés de seguir essa linha costumeira e considerar apenas os esforços considerados efetivamente válidos no combate à febre amarela, interessa-nos mais observar, no próprio contexto, quais eram as percepções que aqueles clínicos possuíam sobre a doença e como essas percepções ditavam suas práticas médicas. / During the Years of 1889 and 1890, a swift epidemic outbrake stroke the city of Campinas. Even though some physicians argued that it was in fact the \"dreaded\" Yellow Fever, many doctors disagreed, assuming it was just one of the many other illnesses that had previously hunted the town. By the year of 1890, the disease was back in the hospitals and in the medical agenda. Even considering that the epidemics that fell upon Campinas in the course of those years were endeed Yellow Fever outbrakes, these opposing diagnostics clearly show that some aspects of this condition were still unknown to the medical community. They also suggest that, contrary to what the majority of the bibliography concearning Campinas\'s history states, the medical community of that area wasn\'t always able to overcome personal issues in favor of the erradication of this disease. The topic of the Yellow fever outbrake in Campinas has never been sufficiently explored by historians. In the few cases where that happened, the narratives exlusively focus on the medical and hygienical efforts to overcome the epidemic burst of the fever in the city, prevailing the image and accomplishes of some specific characters. Therefore, instead of seeing this through tradicional angles, considering just the approved measures taken back then to fight the disease, it\'s more in our interest to explore what perceptions these physicians had about this particular ilness and, more importantly, how these perceptions defined their medical practice.

INTRODUÇÃO: A vacina contra febre amarela é a principal forma de prevenção da doença, e é raramente associada a eventos adversos graves, para os quais pessoas que vivem com o vírus da imunodeficiência humana (HIV) teoricamente possuem risco aumentado. Nessa população, estudos sugerem que a imunogenicidade da vacina é inferior, e fatores associados à resposta vacinal são pouco conhecidos. Neste estudo, avaliamos a imunogenicidade e reatogenicidade da vacina contra febre amarela em pessoas infectadas por HIV e controles, comparando os títulos de anticorpos neutralizantes, ocorrência de viremia pelo vírus vacinal e eventos adversos após a vacinação, e investigamos potenciais preditores da resposta vacinal. Avaliamos ainda o grau de conhecimento a respeito da febre amarela e a adesão às recomendações de vacinação entre pessoas que vivem com HIV. MÉTODOS: No Estudo 1, indivíduos com infecção por HIV e controles com indicação de receber a vacina foram incluídos em uma coorte prospectiva com um ano de acompanhamento, com avaliação periódica de eventos adversos, viremia pelo vírus vacinal e títulos de anticorpos neutralizantes específicos contra febre amarela após a vacinação. No Estudo 2, indivíduos com infecção por HIV sob tratamento antirretroviral e controles com uma única dose da vacina contra febre amarela no passado foram incluídos em um estudo de corte transversal para avaliação dos títulos de anticorpos neutralizantes contra febre amarela. Finalmente, no Estudo 3 pessoas infectadas por HIV foram convidadas a completar um questionário avaliando o grau de conhecimento a respeito da febre amarela e a adesão às recomendações de prevenção. RESULTADOS: Não observamos entre pessoas infectadas por HIV maior risco de viremia pelo vírus vacinal, ocorrência de eventos adversos ou diferença estatisticamente significante nos títulos de anticorpos nos primeiros três meses após a vacinação. Entretanto a persistência de anticorpos foi significantemente inferior entre indivíduos infectados por HIV, e associou-se inversamente à relação CD4+/CD8+, um marcador de ativação imune e inflamação de importância crescente. Nas respostas ao questionário, embora os participantes tenham demonstrado conhecimento a respeito da febre amarela e sua prevenção, a prevalência de discrepância entre as recomendações e o uso da vacina foi de 19%. CONCLUSÕES: Nossos resultados enfatizam a necessidade de novos estudos e intervenções entre pessoas infectadas por HIV a fim de melhorar a adesão às recomendações de uso da vacina, reduzir a ativação imune excessiva associada à pior resposta vacinal, e determinar o intervalo de tempo ideal para administração de reforço vacinal nessa população / INTRODUCTION: The yellow fever vaccine is the main prevention strategy against the disease, and is rarely associated with severe adverse events for which HIV-infected persons present theoretical increased risk. Studies suggest that the immune response to the vaccine is reduced in this population, but predictors of the vaccine immunogenicity are not well known. In this study, we assessed yellow fever vaccine immunogenicity and reactogenicity among HIV-infected persons and controls by comparing yellow fever-specific neutralizing antibody titers, detection of viremia by the vaccine virus and adverse events following vaccination. We also investigated potential predictors of vaccine response. Furthermore, we assessed knowledge and perceptions about yellow fever, and adherence to yellow fever vaccine recommendations among HIV-infected individuals. METHODS: In Study 1, HIV-infected participants and controls with indication to receive yellow fever vaccine were enrolled in a prospective cohort study and followed for one year with serial assessments of adverse events, viremia by the vaccine virus and yellow fever-specific neutralizing antibody titers after vaccination. In study 2, HIV-infected individuals under antiretroviral therapy and controls with a history of a single dose of yellow fever vaccine in the past were enrolled in a cross sectional study to evaluate yellow fever-specific neutralizing antibody titers after vaccination. Finally, in Study 3, HIV-infected persons under clinical follow up were invited to complete a survey assessing knowledge and perceptions about yellow fever and adherence to yellow fever prevention recommendations. RESULTS: We found no increased risk for the occurrence of viremia by the vaccine virus or adverse events, and no significant difference in yellow fever-specific antibody titers among HIVinfected participants in the first three months after vaccination. However, the duration of antibody response was reduced in HIV-infected persons, and was inversely associated to CD4+/CD8+ ratio, a biomarker of immune activation and inflammation of increasing importance. In the survey responses, although participants demonstrated awareness about yellow fever and yellow fever prevention, the prevalence of discrepancy between vaccine recommendation and actual compliance was 19%. CONCLUSIONS: Our results reinforce the need for new studies and interventions among HIVinfected persons to improve adherence to yellow fever vaccine recommendations, reduce excessive immune activation associated with impaired vaccine response, and to determine the ideal interval for a booster vaccination in this population

INTRODUÇÃO: A Faringotonsilite é doença comum nos consultórios e prontosocorros de pediatria. OBJETIVOS: Avaliar o impacto da realização rotineira da prova rápida para pesquisa de estreptococo do grupo A (PRE) no diagnóstico e tratamento da faringotonsilite aguda em crianças e adolescentes atendidos em um Hospital Geral. MÉTODOS: Trata-se de um estudo prospectivo, observacional, de protocolo de atendimento, instituído no Pronto-Socorro do Hospital Universitário da Universidade de São Paulo para o atendimento de crianças e adolescentes com diagnóstico de faringotonsilite aguda. RESULTADOS: Foram estudadas 1039 crianças e adolescentes. Com base no quadro clínico, antibiótico seria prescrito em 530 pacientes (51%), e com o uso da PRE e/ou cultura de orofaringe foi prescrito em 268 (25,8%) pacientes. Das 509 crianças que não receberiam antibiótico pelo quadro clínico, 157 tiveram PRE e/ou cultura de orofaringe positiva. O diagnóstico baseado no quadro clínico apresentou sensibilidade de 63,06% (IC-95%:62,95-63,17%); especificidade de 57,33% (IC-95%:57,25-57,41%); valor preditivo positivo de 50,57% (IC-95%:50,47-50,66%) e valor preditivo negativo de 69,16% (IC-95%: 50,47-50,66%). CONCLUSÕES: Neste estudo o diagnóstico clínico da faringotonsilite estreptocócica mostrou baixa sensibilidade e especificidade. O uso rotineiro da prova rápida para pesquisa de estreptococo permitiu uma redução do uso de antibiótico e a identificação de crianças e adolescentes com faringotonsilite estreptocócicas que não receberiam antibiótico e estariam sob o risco das complicações da infecção estreptocócica / BACKGROUND: Sore throat is a common disease in the pediatric emergency room. OBJECTIVES: The objective of this study was to evaluate the impact of routine performance of rapid antigen detection test (RADT) in the diagnosis and treatment of acute pharyngitis in children treated at an academic hospital. METHODS: This is a prospective, observational, protocol compliance, established at the Emergency of Hospital Universitário - Universidade de São Paulo for the care of children and adolescents diagnosed with acute pharyngitis. RESULTS: We studied 1039 children and adolescents. Based on clinical findings, antibiotic would be prescribed in 530 patients (51%) and using the RADT or sore throat culture was prescribed in 268 patients. Of the 509 children who did not receive antibiotics for the clinical, 157 had positive RADT or sore throat culture. The diagnosis based on clinical sensitivity was 63,06% (IC 95% 62,95- 63,17%), specificity 57,3% (IC 95% 57,25-57,41%), positive predictive value of 50,57% (IC 95% 50,47-50,66%) and negative predictive value of 69,16% (IC 95% 50,47-50,66%). CONCLUSIONS: In this study the clinical diagnosis of streptococcal pharyngitis had low sensitivity and specificity. The routine use of rapid test for streptococcal research led to a reduction of antibiotic use and the identification of a risk group for complication of streptococcal infection

Trata-se de um estudo desenvolvido numa Unidade de Conservação de São Paulo o Parque Estadual Alberto Lofgrën - PEAL, situado na zona norte da cidade e conhecido como Horto Florestal. Visou identificar iniciativas sobre as diretrizes de promoção da saúde no parque, e a relevância dos determinantes sociais, ambientais e de saúde frente à Febre Maculosa Brasileira - FMB. A área de visitação pública do parque tornou-se importante área de estudo por possuir características epidemiológicas, consideradas pelo programa de controle desta doença, como área de alerta e, portanto, potencial para transmissão. Buscou-se identificar também as ações pedagógicas oferecidas pelo Núcleo de Educação Ambiental para entender a atuação dos monitores ambientais e foi efetuado um levantamento da infraestrutura e funcionamento do PEAL. Foram elaboradas oficinas pedagógicas com os monitores e outros profissionais que mantinham uma atuação de interface com a população para abordagem de temas norteadores do estudo como: educação em saúde e ambiental, promoção da saúde, Febre Maculosa Brasileira, planejamento de ações educativas e controle de carrapatos. Para garantir um processo pedagógico participativo nas oficinas, foram discutidos temas de interesse do grupo e utilizadas uma diversidade de estratégias para estimular nos participantes sentimentos de co-responsabilidade e pertencimento ao processo. Um espaço de reflexão sobre promoção da saúde, qualidade de vida, o ambiente do parque, estratégias pedagógicas e ações de cuidados com a FMB, foi criado, com o objetivo de integrar ações de educação ambiental e de saúde, que articuladas poderiam amplificar a atuação dos profissionais. A coleta de dados foi feita por meio de análise documental, observação de campo, entrevista com a gestora e encontros pedagógicos com os monitores. A análise dos resultados foi construída a partir da triangulação dos dados obtidos das técnicas de pesquisa citadas. Os produtos deste estudo foram: um plano de mobilização intersetorial para o controle de carrapatos de importância médica e da FMB no PEAL, produzido pelos monitores; a inclusão do tema sobre cuidados com carrapatos e a FMB na orientação do professor utilizada pelos educadores ambientais; a participação de profissionais de saúde no Plano de Manejo do Parque garantindo um capítulo específico sobre zoonoses no documento oficial de gestão da unidade; um artigo técnico publicado em revista especializada sobre as principais zoonoses do PEAL; a qualificação profissional dos envolvidos nas oficinas pedagógicas; e a contribuição para as discussões sobre as temáticas de saúde e o cuidado ambiental numa área de lazer, porém de risco para zoonoses como pode vir a ser uma Unidade de Conservação com elevado número de visitação e próximo a áreas urbanas. / This is a study developed a Conservation Unit of the São Paulo State Park Alberto Lofgren - PEAL, located in the north of the city and known as \"Horto Florestal\". This research sought to identify initiatives on guidelines for health promotion in the park, and the relevance of social determinants, environmental and health problem facing the Brazilian Spotted Fever - FMB. The area of public visitation to the park has become important for the study of epidemiological characteristics have, as the program of control of FMB as the alert area and, therefore, potential for transmission of the disease. We tried to identify the educational activities offered by the Center for Environmental Education to understand the performance of monitors and has done a survey of infrastructure and operation of PEAL. Educational workshops were developed with tutors and others who had a role to interface with the population approach to guiding the study of topics such as education and environmental health, health promotion, spotted fever, educational planning and control of the FMB. To ensure a participatory process were discussed issues of interest and used a variety of pedagogical strategies in encouraging participants feelings of co-responsibility and belonging to the process. A space of reflection on health promotion, quality of life, the environment of the park, and care strategies for action with the FMB was established with the objective of integrating environmental education activities and health, which could amplify the coordinated action of professionals. Data collection was done by means of documentary analysis, observation of field, interview with the management and educational meetings with the monitors. The analysis was constructed from the triangulation of data and techniques of research cited. The products of this study, are: the plan to mobilize to control the inter FMB in PEAL, produced by monitors and the inclusion of the issue with FMB care about the teacher\'s book used by environmental educators and the participation of the health team in the Management Plan of the Park to a specific chapter on zoonoses in document management unit, a technical paper published in the magazine, on major zoonoses of Peale and the professional growth of those involved in educational workshops, and contribution to the discussions on issues of health and environmental care in an area of leisure but at risk for zoonoses to be of conservation unit.

Parmi les nombreuses pathologies infectieuses dignes d’intérêt en Guyane, deux d’entre elles, deux zoonoses, ont connu récemment un regain d’intérêt conduisant en quelques années à améliorer nettement leur connaissance, mais également découvrir des particularités épidémiologiques inattendues qui nous ont amené à nous poser la question de leur caractère émergent ou réémergent. Bien que cosmopolite et à tropisme tropical, la leptospirose n’a que peu été décrite en Guyane et sur le bouclier des Guyanes. La littérature repose sur des cas cliniques ou série de cas anciens, la dernière publication remontant à 1995. Sont présentées ici plusieurs études qui ont permis d’en savoir un peu plus sur cette infection bactérienne : revue exhaustive de la littérature, étude rétrospective des rapports du CNR, étude rétrospective multicentrique sur les leptospiroses prises en charge en Guyane entre 2007 et 2014, avec analyse de ses déterminants, démographiques, écologiques, cliniques, séro-épidémiologique, comparaison de ses formes graves à celles d’Afrique du Nord. Bien que sa présence ait été identifiée dès les années 50 en Guyane, la fièvre Q ou infection à Coxiella burnetii, n’avait suscité localement aucun intérêt jusqu’à la fin des années 1990. Le travail ici présente la progression des connaissances sur cette infection bactérienne, également cosmopolite, mais avec des spécificités locales tout à fait inédites. Au fil des découvertes sur cette bactérie à la sauce guyanaise, nous présenterons la contribution de notre équipe à la progression du savoir sur cette pathologie et l’apport de réponses amenant tout autant de nouvelles. Ainsi les réflexions portent autour de ce génotype si particulier, le MST17, trouvé exclusivement en Guyane, qui entraine l’incidence la plus élevée au monde de la fièvre Q, une prévalence élevée parmi les pneumopathies retrouvée nulle ailleurs. En outre, le cycle épidémiologique de la bactérie, habituellement fondé sur le bétail, semble ici suivre un tout autre chemin et trouver son réservoir dans la faune sauvage. L’on s’interroge également sur le contraste entre le problème de santé publique majeur que cette maladie représente en Guyane et le caractère tout juste anecdotique dans le reste de l’Amérique latine.Finalement, bien que ces deux zoonoses puissent être qualifiées de « maladies nouvelles » en Guyane, il s’agit probablement pour la leptospirose d’une augmentation récente du nombre de cas lié à l’amélioration des techniques diagnostiques et à la sensibilisation des médecins à cette maladie, tandis que la fièvre Q semble présenter un véritable profil émergent, avec augmentation récente de son incidence, et de nombreuses inconnues lié à un génotype très particulier.Plusieurs questions concernant ces deux infections restent encore sans réponse, et le travail est immense pour mieux comprendre les enjeux de ces deux maladies, tant à l’échelle de la Guyane qu’à celle du continent latino-américain. / Among the numerous infectious diseases of interest in French Guiana (FG), two of them, two zoonoses, have recently experienced a revival of interest leading in a few years to a marked improvement in their knowledge. Several studies allowed as well discovering unexpected epidemiological features that have led us to question their emerging or reemerging character.Although cosmopolitan and with tropical a tropism, leptospirosis has been barely described in FG and on the Guiana Shield. The literature is old and reports only clinical cases or series, the most recent publication dating back to 1995. Several studies are presented in this work which have allowed to know a little more about this bacterial infection: exhaustive review of the literature, retrospective study of the reference national center reports, a retrospective multicenter study on leptos-piroses managed in FG between 2007 and 2014, with analysis of its determinants, demographic, ecological, clinical, sero-epidemiological, and a study comparing Guianese severe forms to those of North Africa.Although its presence had been suspected as early as the 1950s in FG, Q fever or Coxiella burnetii infection had not aroused interest locally until the late 1990s. The work here presents the progression of the knowledge of this bacterial infection, also cosmopolitan, but with unusual local specificities. In the course of the discoveries around this Guianese outbreak, we will present the contribution of our team to the progression of knowledge on this pathology and the contribution of answers bringing as much new questions. Thus the discussion will focus on this particular genotype, MST17, found exclusively in FG, which results in the highest incidence of Q fever in the world, a prevalence among pneumonias never found elsewhere. Moreover, the epidemiological cycle of the bacterium, usually based on livestock, seems to follow a completely different path and find its reservoir in wildlife. We also wonder about the contrast between the major public health problems that this disease represents in FG and the anecdotal character in the rest of Latin America.Finally, although these two zoonotic diseases may be described as "new diseases" in FG, it is likely that leptospirosis presents a recent increase in the number of cases related to the improvement of diagnostic techniques and the sensitization of physicians to this disease, but without real emergence, while Q fever seems to present a true emergent profile, with a recent increase in its incidence, and many unknowns linked to a very particular genotype.Many questions concerning these two infections remain unanswered, and the work is immense to better understand the stakes of these two diseases, both on the scale of FG and that of the Amazonian region and the Latin American continent.

O estudo tem por objetivo compreender o movimento entre sentir-se saudável e sentir-se doente nos diferentes modos de andar a vida de crianças e adolescentes com febre reumática e cardiopatia reumática. O recorte do objeto foi elaborado a partir das discussões sobre: a doença crônica e condição crônica, febre reumática e cardiopatia como doenças crônicas específicas e particularidades da condição crônica gerada pela febre reumática e pela cardiopatia reumática em crianças e adolescentes. O quadro teórico teve como base a discussão teórico-epistemológica do processo saúde-doença para a aproximação de uma outra discussão central, a fronteira entre o normal e o patológico. Os participantes foram crianças e adolescentes com febre reumática e cardiopatia reumática atendidos no Ambulatório de Cardiologia Pediátrica de um hospital universitário de Cuiabá- MT e suas mães. A coleta de dados ocorreu por meio da análise de documentos e da entrevista aberta que se efetivou no hospital, na residência e no local de trabalho. Os resultados e discussão deram origem a cinco temas: 1. Apresentação dos participantes: uma breve história, no qual se descreve como se conformou o curso da febre reumática e da cardiopatia reumática; 2. Contexto da assistência à criança e ao adolescente, no qual se evidenciou a produção de cuidados baseada no modelo clínico especializado e a fragmentação da assistência; 3. Noções sobre a febre reumática e a cardiopatia reumática segundo os participantes, no qual surge um saber fragmentado, com noções ora do modelo etiológico endógeno ora do modelo etiológico ontológico. 4. Repercussão da condição crônica gerada pela febre reumática e pela cardiopatia reumática na vida de crianças e adolescentes, no qual se discorre sobre a trajetória e as repercussões dessa condição crônica mostrando as dificuldades relacionadas aos sintomas, à hospitalização, à escola, às limitações, aos amigos, às brincadeiras, aos jogos e às particularidades da adolescência. 5. O movimento entre sentir-se saudável e sentir-se doente, no qual surgem situações que impõem normas de tratamento e evidencia que o modo de andar a vida dos participantes se baseia em diferentes normalidades, que influenciam, ou não, a adesão ao tratamento. A partir dessas situações surgem conflitos entre sentir-se saudável e ser classificado como doente. Nas considerações finais sugere-se a discussão junto aos profissionais de saúde e nas instituições formadoras sobre os princípios do SUS nos diferentes níveis da atenção à saúde, como forma de amenizar a fragmentação da assistência; a necessidade de trabalhar com o gerenciamento da condição crônica, sempre buscando conhecer as diferentes normalidades que fundamentam o modo de andar a vida de crianças e adolescente, considerando que as normas ditadas pelos profissionais de saúde não são as únicas que permeiam suas vidas e, por fim, a busca de estratégias para o fortalecimento de crianças, adolescentes em condição crônica e suas famílias, como maneira de ampliar a compreensão delas sobre a própria condição crônica para que as normas ditadas pelos profissionais de saúde sejam aceitas não por crença, mas por compreensão de que podem ampliar o leque de possibilidades de ser feliz. / This study aims at knowing the idea between feeling healthy and feeling ill in the different ways of children and teenager’s lives, with rheumatic fever and rheumatic heart disease. This study issue was made based on the discussions about: the chronic disease and the chronic condition, rheumatic fever and heart disease as chronic and specific diseases and particularities of the chronic condition generated by the rheumatic fever and by the rheumatic heart disease in the children and teenagers’ lives. The theoretical chart was based on a theoretical-epistemological discussion of the heath-disease process to get to another central discussion, the frontier between the normal and the pathological. The participants were children and teenagers who had rheumatic fever and rheumatic heart disease cared in the Policlinic of the Pediatric Cardiology of a university hospital in Cuiabá-MT and their mothers. The data were collected through the analysis of documents and open interviews which happened in the hospital, in the households and in their work. The results and discussion gave rise to five themes: 1. Presentation of the participants: a brief historical part in which it is described how the rheumatic fever and the rheumatic heart disease were confirmed in their lives; 2. The context of assistance to the children and the teenagers, in which the production of care based on the specialized clinical model and the fragmentation of the assistance was shown. 3. Notions about rheumatic fever and the rheumatic heart disease, in which a fragmented knowledge appears, sometimes with notions of the endogenous etiologic model and sometimes with notions of the ontological etiologic model. 4. Effects of the chronic condition brought by the rheumatic fever and by the rheumatic heart disease in the children and teenagers’ way of living, in which the trajectory and the effects of this chronic condition is discussed, showing the problems related to the symptoms, hospitalization, school classes, limitations, friends, children’s play, games and the particularities of the adolescence period. 5. The idea between feeling healthy and feeling ill, when there are situations that impose rules for treatment and highlights that the way the participants live, is based on a different kind of normality, which influence or not, the adhesionto the treatment. From these situations, other conflicts arise between feeling healthy and being classified as ill. In the final considerations, the discussion with the health professionals and in the institutions that teach about the principles of SUS in the different levels of the health care is suggested as a way of easing the assistance fragmentation; the need of working with the chronic condition, always trying to know the different kinds of normality which explain the children and teenagers’ way of living considering that the rules set up by the health professionals are not the only ones that permeate their lives and, finally, the search for strategies for the children and teenagers’ strengthening with a chronic condition and their families, as a way of widening their understanding about their chronic condition so that the rules established by the health professionals are accepted not by belief but by understanding that they can enlarge the possibilities of being happy.

Les formes sévères de l’infection par les virus de la fièvre jaune (YFV) et de la dengue (DENV) sont caractérisées par une atteinte du foie, plus sévère lors d’une infection YFV. L’objectif de cette thèse est de comparer les infections de YFV et DENV dans un modèle d’hépatocytes humains dérivés de cellules souches (iHeps) afin d’identifier des facteurs à l’origine de cette différence de pathogenèse. Dans un premier temps, nous avons comparé le tropisme de YFV aux 4 sérotypes de DENV dans notre modèle hépatique établi en monocouche cellulaire. Nous avons observé une faible propagation de DENV dans les iHeps par rapport YFV. Les mêmes observations ont été faites dans des hépatocytes primaires. L’utilisation de souches chimériques 17D/DENV a permis de mettre en évidence que cette faible propagation serait liée à une faible efficacité d’entrée de DENV dans les hépatocytes. Nous avons également étudié l’infection dans des sphéroïdes iHeps, métaboliquement plus actifs que les iHeps 2D. Une infection productive a été observée uniquement avec YFV. Ce résultat pourrait s’expliquer par la faible accessibilité des cellules à l’intérieur des sphéroïdes. Dans un 2ème temps, nous avons étudié les réponses cellulaires induites dans les iHeps 2D après infection par les différents virus en utilisant une approche RNAseq. Les résultats préliminaires suggèrent un lien entre le taux de réplication et le nombre de gènes activés. La réponse interféron est plus précocement détectée dans le cas de YFV, mais l’infection par DENV induit un plus grand nombre de gènes. De plus, DENV-1 et DENV-4 induisent une augmentation d’expression de certains gènes impliqués dans la présentation d’antigène comme HLA-E et TAP-2, alors que YFV diminue l’expression de certains gènes de chimiokines et molécules d’adhésion. L’analyse préliminaire des voies liées au métabolisme hépatique révèle une inhibition de la voie de la coagulation dans le cas de l’infection par YFV, qui n’est pas observée lors de l’infection par DENV. Des observations similaires ont été décrites in vivo, au niveau protéique, confirmant la pertinence du modèle iHeps / Severe forms of infection with yellow fever virus (YFV) and dengue virus (DENV) are characterized by liver damage, with more severe symptoms observed during YFV infection. The aim of this thesis is to compare YFV and DENV infections in a model of human hepatocytes derived from stem cells (iHeps) in order to identify factors that could explain their difference in pathogenesis.First, we compared YFV tropism to the four DENV serotypes in 2D iHeps. We observed a low spread of DENV compared to YFV in both iHeps and primary hepatocytes. By using chimeric 17D/DENV strains, we demonstrate that this low propagation is linked to a low DENV entry efficiency in hepatocytes. We also studied infection in iHeps spheroids, metabolically closer to primary cells than 2D iHeps. A productive infection was observed with YFV only. The low accessibility of cells inside the spheroids could explained this result. Second, we studied cellular responses induced following infection by different viruses in 2D iHeps using an RNAseq approach. Preliminary results suggest a link between replication rate and the number of activated genes. The interferon response is detected earlier following YFV infection, but DENV induces a greater number of genes implicated in this pathway. Moreover, DENV-1 and DENV-4 up-regulate some genes involved in antigen presentation such as HLA-E and TAP-2, while YFV down-regulates genes encoding chemokines and adhesion molecules. Preliminary analysis of hepatic metabolism pathways reveals inhibition of the coagulation pathway induced by YFV infection, which is not observed during DENV infection. Similar observations have been described in vivo, at the protein level, confirming the relevance of the iHeps model

Le Virus du Nil Occidental (VNO) et le Virus de la Fièvre de la Vallée du Rift (VFVR) sont deux arbovirus transmis par le moustique Culex pipiens comprenant deux biotypes: pipiens et molestus. Au cours de ce projet, nous avons évalué la circulation du VNO au Liban dans des populations de moustiques, des humains, des chevaux et des poulets. Nous avons aussi évalué la compétence vectorielle des populations locales de Cx. pipiens à transmettre le VNO et le VFVR.Des moustiques ont été récoltés et testés pour la présence d’un gène spécifique du VNO. En plus, des sérums humains, de chevaux et de poulets ont été analysés pour rechercher des anticorps spécifiques par ELISA puis confirmés par neutralisation. En outre, des spécimens de Cx. pipiens ont été infectés avec la lignée 1 du VNO ou la souche de VFVR Clone 13. Ensuite, les taux d’infection, de dissémination et de transmission ont été déterminés à différents jours après infection des moustiques. La compétence vectorielle a été comparée entre les différents biotypes.Les résultats entomologiques ont révélé que Cx. pipiens est dominant (87.2%). Tous les moustiques analysés étaient négatifs pour le VNO. Les taux de séroprévalence étaient de 1.01% et 1.98% parmi les humains et les chevaux respectivement. De plus, Cx. pipiens s’est révélé bien plus compétent pour transmettre le VNO que le VFVR. Le biotype molestus est capable de transmettre le VNO plus tôt que celui de pipiens. Cette étude présente des preuves sur une faible circulation du VNO au Liban. Cx. pipiens s’est révélé compétent pour assurer cette transmission. Ainsi, il est essentiel d'établir des programmes de surveillance pour prévenir les éventuelles épidémies. / West Nile virus (WNV) and Rift Valley Fever virus (RVFV) are two emerging arboviruses that have never been reported in Lebanon. They can be transmitted by Culex pipiens mosquito species including two biotypes: pipiens and molestus. During this project, we assessed the circulation of WNV among mosquitoes, human, horse and chicken populations in Lebanon. Moreover, we evaluated, under experimental conditions, the capacity of local Cx. pipiens biotypes to transmit both viruses.Adult mosquitoes were collected, identified and tested to detect WNV RNA. Besides, human, horse and chicken blood samples were collected and screened for WNV antibodies using an in-house ELISA and then confirmed by neutralization assay. Moreover, local Cx. pipiens specimens were experimentally infected with WNV lineage 1 or RVFV Clone 13 strain. The viral infection, dissemination and transmission were then estimated at different days post infection.The vector competence was compared between Cx. pipiens biotypes.Entomological results revealed that 87.2% of collected adult mosquitoes were Cx. pipiens. Screened mosquitoes were negative for WNV. Seroprevalence rates were 1.01% and 1.98% among humans and horses respectively. Besides, local Cx. pipiens were highly competent for WNV transmission and to a lesser extent to RVFV. The molestus biotype was able to transmit WNV earlier than pipiens biotype.The present study provides new evidence of a low circulation of WNV among human and horses in Lebanon. Cx. pipiens is the suspected vector and is experimentally competent to ensure transmission. Therefore, there is a need to establish surveillance program to predict and prevent potential outbreaks.

La fièvre de la Vallée du Rift (FVR) est une arbovirose zoonotique décrite pour la première fois en 1930 au Kenya. Transmise principalement entre ruminants par des moustiques des genres Aedes, Culex et Anopheles, elle peut aussi se transmettre à l'homme par contact direct avec des produits d'avortement ou des fluides corporels d'animaux virémiques. Cette maladie a été décrite dans de nombreux pays d'Afrique ainsi que sur la péninsule arabique et dans l'Océan Indien. La circulation du virus de la FVR (VFVR) a été décrite dans 3 écosystèmes distincts : (i) les zones semi-arides sud- et est-africaines, (ii) les mares temporaires des zones arides, (iii) les zones irriguées adjacentes à de grands fleuves. Au sein de chacun de ces écosystèmes, le rôle des mouvements d'animaux dans l'introduction du VFVR et des moustiques vecteurs dans sa transmission ont fortement été mis en avant. Malgré l'existence de modèles statistiques pouvant prédire l'émergence du VFVR en Afrique de l'est notamment grâce au niveau de pluviométrie, les mécanismes de transmissions en jeu dans les autres régions sont encore incertains. L'apparition de foyers dans un écosystème tempéré et montagneux de Madagascar, où les espèces et abondances vectorielles ne sont pas favorable à la persistance du VFVR, suscite des interrogations quant à ces mécanismes. L'objectif de cette thèse est d'identifier les facteurs et les processus épidémiologiques permettant la circulation récurrente du VFVR dans un écosystème tempéré de Madagascar. L'étude a pris en considération les pratiques socio-économiques ainsi que les principaux moustiques vecteurs du virus de la zone tempérée des hautes terres malgaches. Les principaux modes de diffusion du virus entre bovins ont été étudiés au cours de 3 années de suivi sérologique. Un modèle mathématique calibré sur la base de nombreuses données empiriques collectées dans cette zone est proposé. Deux pratiques commerciales ont pu être distinguées : le commerce classique et une pratique traditionnelle de troc. Les résultats de l'analyse suggèrent une implication différente de ces deux pratiques dans la circulation du VFVR. Alors que le commerce pourrait permettre l'introduction du virus, la pratique du troc serait quant à elle le support de la circulation au sein de la zone. Un modèle déterministe est construit afin de comparer quatre scénarios pouvant expliquer la circulation virale dans cet écosystème peu favorable. Les résultats suggèrent que, si la transmission vectorielle reste la principale voie de transmission dans cet écosystème inhabituel, la transmission directe lors du vêlage de vaches virémiques pourrait également jouer un rôle. La circulation du VFVR est de plus favorisée par les pratiques socio-économiques de la zone qui permettent, malgré la saison sèche, l'exposition des bovins introduits et potentiellement virémiques aux moustiques vecteurs. / Rift Valley fever (RVF) is a zoonotic disease first described in 1930 in Kenya. Primarily transmitted between ruminant by mosquitoes of Aedes, Culex and Anopheles genus, it can also be transmitted to humans by direct contact with abortion products or body fluids of viraemic animals. This disease has been described in many African countries, in the Arabian Peninsula and the Indian Ocean. The circulation of RVF virus (RVFV) has been reported in three ecosystems: (i) semi-arid areas of South and East Africa, (ii) temporary ponds in arid areas, (iii) irrigated areas near large rivers. Within each of these ecosystems, the role of animal movements in the introduction of RVFV and that of mosquitoes in virus transmission has been strongly emphasized. Despite the existence of statistical models that predict the emergence of RVFV in East Africa based on rainfall level, the transmission mechanisms involved in other areas are still uncertain. The occurrence of an outbreak in a temperate and mountainous ecosystem of Madagascar, where the species and vector abundances are unfavorable to the persistence of RVFV, raises questions about these mechanisms.The objective of this thesis is to identify the factors and the epidemiological processes that support the RVFV recurrent circulation in a temperate ecosystem of Madagascar. The study took into account the socio-economic practices as well as major mosquito vectors of the area. The main modes of virus spread between cattle were studied during a three years serological follow-up. A mathematical model was elaborated and calibrated using empirical and field data collected in the area. Two cattle exchange practices could be distinguished: the usual trade and a traditional practice of barter. The results of the analysis suggest a different impact of these two practices in RVFV circulation. While trade may allow virus introduction, the barter practice would support its spread within the area. A deterministic model was built to compare four scenarios that could explain the recurrent virus circulation in this unfavorable ecosystem. Results suggest that, if the vector-based transmission remains the main transmission mode, direct transmission from viremic cows at calving could also play a role. RVFV circulation is favored by socio-economic practices of the area that led, despite the dry season, to the exposure of introduced, and potentially viremic, cattle to vectors.

We are unceasingly exposed to potentially harmful microorganisms. The battle against threatening infectious agents includes activation of both the innate and of the adaptive immune systems. Illness responses are elicited and include inflammation, fever, decreased appetite, lethargy and increased sensitivity to painful stimuli in order to defeat invaders. While many of these signs of disease are controlled by the central nervous system, it has remained an enigma how signals from the peripheral immune system reach the brain through its blood-brain barrier, which precludes macromolecules, including cytokines, from diffusing into the brain parenchyma. Previous findings indicate the existence of a pathway across the blood-brain barrier, which includes binding of the cytokine interleukin-1 (IL-1) to its receptor in the brain vessels, thereby inducing the production of the prostaglandin E2 (PGE2) synthesizing enzymes cyclooxygenase-2 (Cox-2) and microsomal prostaglandin E synthase-1 (mPGES-1), which ultimately synthesize PGE2. PGE2 subsequently binds to any of the four prostaglandin E2 (EP) -receptors. Previous results from our laboratory have suggested that this pathway plays a critical role in the febrile response to infectious stimuli. The present thesis aims at further investigating the molecular events underlying immune-to-brain signalling, with special emphasis on fever, hypothalamic-pituitary-adrenal (HPA) -axis activation and anorexia and their connection to signalling molecules of the cytokine and prostaglandin families, respectively. In paper I, the molecular processes linking the proinflammatory cytokine interleukin-6 (IL-6) and PGE2 in the febrile response were investigated. Both IL-6 and PGE2 have been shown to be critical players in the febrile response, although the molecular connections are not known, i.e. if IL-6 exerts its effects up- or downstream of PGE2. Mice deficient in IL-6 were unable to respond to bacterial lipopolysaccharide (LPS) with a febrile response, but displayed similar induction of Cox-2 and mPGES-1, and similar concentrations of PGE2 in the cerebrospinal fluid as wild-type mice. Paradoxically, the IL-6 deficient mice responded with a dose-dependent elevation of body temperature in response to intracerebroventricularly injected PGE2. Furthermore, IL-6 per se was not pyrogenic when injected peripherally in mice, and did not cause increased levels of PGE2 in cerebrospinal fluid. IL-6 deficient mice were not refractory to the action of PGE2 because of excess production of some hypothermia-producing factor, since administration of a Cox-2 inhibitor in LPS-challenged IL-6 deficient mice did not unmask any hypothermic response, and neutralization of tumor necrosis factor α (TNFα), associated with hypothermia, did not produce fever in LPS-challenged IL-6 deficient mice. These data indicate that IL-6 rather than exerting its effects up- or down-stream of PGE2 affects some process in parallel to PGE2, perhaps by influencing the diffusion and binding of PGE2 onto its target neurons. In papers II and III, we injected the proinflammatory cytokine IL-1β in free-fed wild-type mice, in mice with a deletion of the gene encoding mPGES-1, or in mice deficient in the EP1, EP2 and EP3. Food intake was continuously measured during their active period, revealing that mPGES-1 deficient mice were almost completely resistant to anorexia induced by IL-1β. However, all of the investigated EP receptor deficient mice exhibited a normal profound anorexic response to IL-1β challenge, suggesting that the EP4 is the critical receptor that mediates IL-1β-induced anorexia. We also investigated the role of mPGES-1 in anorexia induced by lipopolysaccharide (LPS) in mPGES-1 deficient mice. The profound anorexic response after LPS-challenge was similar in mPGES-1 deficient and wild-type mice. To further investigate the anorectic behaviour after LPS injection, we pre-starved the animals for 22 hours before injecting them with LPS. In this paradigm, the anorexia was less profound in mPGES-1 knock-out mice. Our results suggest that while the inflammatory anorexia elicited by peripheral IL-1β seems largely to be dependent on mPGES-1-mediated PGE2 synthesis, similar to the febrile response, the LPS-induced anorexia is independent of this mechanism in free-fed mice but not in pre-starved animals. In papers IV and V, the role of prostanoids for the immune-induced HPA-axis response was investigated in mice after genetic deletion or pharmacological inhibition of prostanoid-synthesizing enzymes, including Cox-1, Cox-2, and mPGES-1. The immediate LPS-induced release of ACTH (adrenocorticotropic hormone and corticosteroids was critically dependent on Cox-1 derived prostanoids and occurred independently of Cox-2 and mPGES-1 derived PGE2. In contrast, the delayed HPA-axis response was critically dependent on immune-induced PGE2, synthesized by Cox-2 and mPGES-1, and occurred independently of Cox-1 derived enzymes. In addition, in the mPGES-1 deficient mice, the synthesis of CRH hnRNA and mRNA was decreased in the paraventricular nucleus of the hypothalamus after LPS-challenge, indicating that the delayed hormone secretion was mediated by PGE2-induced gene-transcription of CRH in the hypothalamus. The expression of the c-fos gene and Fos protein, an index of synaptic activation, was maintained in the paraventricular nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. This suggests that the immune-induced neuronal activation of autonomic relay nuclei occurs independently of prostanoid synthesis and that it is insufficient for eliciting stress hormone release.