Modelagem e simulação estocástica para o estudo da dinâmica de Rickettsia rickettsii em populações de Hydrochoerus hydrochaeris e de Amblyomma sculptum no estado de São Paulo

There are a huge number of pathogens with multi-component transmission cycles, involving ampli_er hosts, vectors, complex pathogen life cycles and particular environmental conditions. These complex systems present challenges in terms of modeling and policy development. The deadliest tick-borne infectious disease in the world, the Brazilian Spotted Fever (BSF), is a relevant example of that. The current increase of human cases of BSF has been associated with the presence and expansion of capybaras Hydrochoerus hydrochaeris, amplifer host for the agent Rickettsia rickettsii and primary host for the tick vector Amblyomma sculptum. The objective of this thesis was to analyze the dynamics of the FMB with the purpose of providing bases for the planning of strategies focused on the prevention of human cases. We proposed diferent approaches to evaluating: i) the contribution of hosts and vectors in the transmission of BSF, ii) potential risk areas and anthropogenic parameters associated with the occurrence of human cases, iii) the pattern and the spatial propagation velocity of BSF, and iv) climatic and landscape factors that could be related to the distribution of the vector. The proposed approaches elucidated how BSF control and prevention strategies can be focused on the management of amplifier hosts populations. We found that geographical barriers generated, for example, by areas of riparian reforestation, could prevent the spatial spread of BSF, since a positive association between the occurrence of human cases and the increment of sugarcane crop was determined, as well as a higher propagation velocity of BSF in places with higher carrying capacity. This thesis was interdisciplinary and required, on one hand, expertise in biology, computational epidemiology, mathematics and statistics and on the other hand, a datarich environment such as the Laboratory of Parasitology of the VPS/FMVZ/USP. The results of this thesis can be usefulness in the planning of public health policies related to the prevention of BSF. Furthermore, this work will open the path to further mathematical and computational studies focused on the dynamics and prevention of other vector-borne infectious diseases.Existe um grande número de agentes patogênicos com ciclos de transmissão complexos, envolvendo hospedeiros amplificadores, vetores e condições ambientais particulares. Esses sistemas complexos apresentam desafios quanto a modelagem e desenvolvimento de políticas públicas. A Febre Maculosa Brasileira (FMB) é a doença transmitida por carrapatos mais letal do mundo e é um claro exemplo de um sistema complexo. O aumento atual de casos humanos de BSF tem sido associado à presença e expansão de capivaras Hydrochoerus hydrochaeris, hospedeiros amplificadores do agente Rickettsia rickettsii e hospedeiros primários do carrapato vetor Amblyomma sculptum. O objetivo desta tese foi analisar a dinâmica da FMB com o propósito de fornecer bases para o delineamento de estratégias de prevenção de casos em humanos. Diferentes abordagens foram propostas para avaliar: i) a contribuição específica de hospedeiros e vetores na transmissão da FMB, ii) os parâmetros antropogênicos associados com a ocorrência dos casos e potenciais áreas de risco, iii) o padrão e a velocidade de propagação espacial e da doença, e iv) os fatores climáticos e paisagísticos que poderiam estar relacionados à distribuição do vetor. Os modelos propostos elucidaram que as estratégias de controle e prevenção da FMB podem estar focadas em práticas de manejo das populações de hospedeiros amplificadores. Uma vez que uma associação positiva entre ocorrência de casos humanos e o incremento de cultura de cana-de-açúcar foi determinada, assim como uma maior velocidade de propagação da FMB em locais com alta quantidade desta cultura, barreiras geográficas geradas, por exemplo, por zonas de reflorestamento ciliar, poderiam impedir a disseminação da FMB. Esta tese foi interdisciplinar e exigiu, por um lado, conhecimentos em biologia, epidemiologia computacional, matemática e estatística e, em contrapartida, um ambiente rico em dados biológicos como o Laboratório de Parasitologia do VPS/USP. Os resultados desta tese poderão ser utilizados na planificação de políticas de saúde pública enfocadas à prevenção da FMB. Complementarmente, este trabalho abrirá o caminho para futuros estudos matemáticos e computacionais orientados no estudo da dinâmica e prevenção de outras doenças infecciosas transmitidas por vetores

Accessibility model for the spatial planning of public health actions: The case of rabies vaccination and sterilization programs for dogs and cats in Bogota, Colombia

Este estudo integrou sistemas de informação geográfica e métodos analíticos geoespaciais baseados em modelos de acessibilidade espacial e de locação-alocação com o objetivo de aprimorar o planejamento espacial de diferentes programas de saúde pública em áreas urbanas. Para estimar a acessibilidade espacial foi desenvolvido o modelo de três passos de área de influência flutuante (E3SFCA - Enhancement three-step floating catchment área) baseado em uma função Gaussiana, considerando um coeficiente de atrito e distâncias ao longo de uma rede de transporte, utilizando o algoritmo de Dijkstra. A metodologia foi aplicada e validada usando os programas de vacinação contra a raiva e de esterilização para cães e gatos da cidade de Bogotá, Colômbia. A escolha do método de cálculo da distância resolveu o problema de superestimação associado com a metodologia clássica que aplica zonas buffer em torno dos locais de serviço baseado em uma distância Euclideana. Em geral, não se encontrou uma adequada acessibilidade espacial aos dois programas. As zonas norte, central e periférica da cidade revelaram baixa ou nula acessibilidade aos serviços. Para determinar a alocação e realocação efetiva dos programas foram utilizados os problemas de máxima cobertura com demanda finita e de p-mediana ou de mínima impedância. A realocação proposta pelo modelo de máxima cobertura forneceu uma melhor distribuição dos serviços nas áreas mais povoadas com cães e gatos e garantiu uma acessibilidade espacial potencial a estes programas. O desenvolvimento deste trabalho pode trazer benefícios diretos para a sociedade em geral auxiliando no planejamento estratégico e melhorando a efetividade das ações públicas em áreas urbanas da América Latina.This study integrated geographic information systems and geospatial analytical methods based on spatial accessibility and location-allocation models in order to improve the spatial planning of different public health programs in urban areas. To estimate the spatial accessibility, a Gaussian-based three-step oating catchment area (E3SFCA) method was developed, including a friction coeffcient and using distances along a street network based on Dijkstra\'s algorithm. The methodology was applied and valiated using the rabies vaccination and sterilization programs for dogs and cats in the city of Bogotá, Colombia. The choice of the distance calculation method solve the overestimation associated with the classic methodology that applies buffer zones around vaccination sites based on Euclidean (straight-line) distance. In general it was not observed an adequate spatial accessibility to both programs. The zones north, central and peripheral of the city revealed low or no access to services. To determine the effective allocation or reallocation of these programs the maximum coverage with finite demand and the p-median or minimum impedance problems were used. The relocation proposed by the maximum coverage model provided a better distribution of the services in the most populated areas and proportioned a potential spatial accessibility to these programs. The development of this work can provide direct benefits to society assisting in the strategic planning and improving the effectiveness of public policies in urban areas of Latin America

Seroprevalence of Leptospira spp infection and its risk factors among domestic dogs in Bogotá, Colombia

Different analytical tools were used to determine the seroprevalence of and risk factors associated with Leptospira spp infection in 192 domestic dogs (Canis familiaris) in Bogotá, Colombia. Using the microscopic agglutination test (MAT), a battery of 16 Leptospira serovars were tested. The seroprevalence of Leptospira spp was calculated as 36.46% (95% CI 0.30-0.43). A questionnaire was applied to the dogs’ owners at the time of sampling and the variables “Water sources near home” and “Dog hunting rodents” were identified as risk factors for leptospirosis occurrence in the urban area of Bogotá. Geographical coordinates relating to the dogs’ households were obtained in order to map out the spatial distribution of reactive and unreactive dogs. Additionally, we found that the mean annual precipitation was higher at geographical locations with reactive animals than at those with unreactive dogs (p < 0.05). Preventing exposure of dogs to rodents and waste-water bodies that could be contaminated with Leptospira might effectively reduce occurrences of leptospirosis. Moreover, promoting preventive programs and vaccination of dogs against leptospirosis in areas of higher precipitation and prior to rainy months could be an effective strategy for leptospirosis prevention. Keywords: Leptospirosis, Seroprevalence, Precipitation, Epidemiology, Dog

Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions

International audienceBacterial genome sequencing has revealed a vast number of novel biosynthetic gene clusters (BGC) with potential to produce bioactive natural products. However, the biosynthesis of secondary metabolites by bacteria is often silenced under laboratory conditions, limiting the controlled expression of natural products. Here we describe an integrated methodology for the construction and screening of an elicited and pre-fractionated library of marine bacteria. In this pilot study, chemical elicitors were evaluated to mimic the natural environment and to induce the expression of cryptic BGCs in deep-sea bacteria. By integrating high-resolution untargeted metabolomics with cheminformatics analyses, it was possible to visualize, mine, identify and map the chemical and biological space of the elicited bacterial metabolites. The results show that elicited bacterial metabolites correspond to ~45% of the compounds produced under laboratory conditions. In addition, the elicited chemical space is novel (~70% of the elicited compounds) or concentrated in the chemical space of drugs. Fractionation of the crude extracts further evidenced minor compounds (~90% of the collection) and the detection of biological activity. This pilot work pinpoints strategies for constructing and evaluating chemically diverse bacterial natural product libraries towards the identification of novel bacterial metabolites in natural product-based drug discovery pipelines