The epidemiology of malaria considers a complex set of local interactions amongst host, vector, and environment. A history of reemergence, epidemic transition, and ensuing endemic transmission in Iquitos, Peru reveals an interesting case used to model and explore such interactions. In this region of the Peruvian Amazon, climate change, development initiatives and landscape fragmentation are amongst a unique set of local spatial variables underlying the endemicity of malaria. Traditional population-based approaches lack the ability to resolve the spatial influences of these variables. Presented is a framework for spatially explicit, agent-based modeling of malaria transmission dynamics in Iquitos and surrounding areas. The use of an agent-based model presents a new opportunity to spatially define causal factors and influences of transmission between mosquito vectors and human hosts. In addition to spatial considerations, the ability to model individual decisions of humans can define socio-economic and human-environment interactions related to malaria transmission. Three interacting sub-models representing human decisions, vector dynamics, and environmental factors comprise the model. Feedbacks between the interacting sub-models define individual decisions and ultimately the flexibility that will allow the model to function in a diagnostic capacity. Sensitivity analysis and simulated interactions are used to discuss this diagnostic capability and to build understanding of the physical systems driving local transmission of malaria.

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The epidemiology of malaria considers a complex set of local interactions amongst host, vector, and environment. A history of reemergence, epidemic transition, and ensuing endemic transmission in Iquitos, Peru reveals an interesting case used to model and explore such interactions. In this region of the Peruvian Amazon, climate change, development initiatives and landscape fragmentation are amongst a unique set of local spatial variables underlying the endemicity of malaria. Traditional population-based approaches lack the ability to resolve the spatial influences of these variables. Presented is a framework for spatially explicit, agent-based modeling of malaria transmission dynamics in Iquitos and surrounding areas. The use of an agent-based model presents a new opportunity to spatially define causal factors and influences of transmission between mosquito vectors and human hosts. In addition to spatial considerations, the ability to model individual decisions of humans can define socio-economic and human-environment interactions related to malaria transmission. Three interacting sub-models representing human decisions, vector dynamics, and environmental factors comprise the model. Feedbacks between the interacting sub-models define individual decisions and ultimately the flexibility that will allow the model to function in a diagnostic capacity. Sensitivity analysis and simulated interactions are used to discuss this diagnostic capability and to build understanding of the physical systems driving local transmission of malaria.

Malaria and tuberculosis constitute two of the world’s deadliest infectious diseases. Together, they afflict over one third of the world’s population. Once thought of as one of a group of nearly vanquished diseases only 50 years ago, malaria and tuberculosis have experienced renewed prominence due to issues such as multi-drug resistance and a lack of responsiveness by the global community. Fatty acid biosynthesis has been shown to be an essential pathway to the causative organisms of malaria and tuberculosis. One integral component of the fatty acid biosynthesis pathway, enoyl acyl-carrier-protein (ACP) reductase, has repeatedly been validated as an appropriate drug target in other organisms. The 2.4 Å crystal structure of the enoyl-ACP reductase from the human parasite Plasmodium falciparum (PfENR) reveals a nucleotide-binding Rossmann fold, as well as the identity of several active site residues important for catalysis. The 2.43 Å crystal structure of PfENR bound with triclosan, a widely utilized anti-bacterial compound, provides new information concerning key elements of inhibitor binding. Applying knowledge attained from these initial crystal structures, several triclosan derivatives were synthesized, and subsequently PfENR:inhibitor co-crystal structures were determined to extend our knowledge of protein:inhibitor interactions within the active site. Additionally, the crystal structures of the enoyl-ACP reductase from the mouse parasite Plasmodium berghei (PbENR), in apo-form and in complex with triclosan, were refined to 2.9 Å and 2.5 Å resolution, respectively. These structures confirm the structural and active site conservation between the human and mouse parasite enoyl-ACP reductases, suggesting that utilizing a murine model for in vivo testing of promising inhibitors is viable. The 2.6 Å crystal structure of the enoyl-ACP reductase from Mycobacterium tuberculosis (InhA) in complex with triclosan reveals a novel configuration of triclosan binding, where two molecules of triclosan are accommodated within the InhA active site. Finally, high-throughput screening approaches using enoyl acyl-carrier-protein reductases as the targets were utilized to identify new lead compounds for future generations of drugs. The 2.7 Å crystal structure of InhA bound with Genz-10850 confirms the value of this technique.

Malaria is a disease that causes more than 1 million deaths per year world wide and more than 400 million clinical cases. Due to the acquired resistance of Plasmodium falciparum to the drugs used to control the infection, searching for new anti-malaria drugs is necessary in modern days. Recent studies have shown that the parasite synthesizes fatty acids using a fatty acid synthase type II (FAS-II) instead of a type-I fatty acid synthase (FAS-I) that is present in other eukaryotes. Plasmodium falciparum enoyl reductase (PfENR) is responsible for the last step of fatty acid biosynthesis in the parasite. This enzyme is located within the apicoplast, a plastid-like organelle that is responsible for several important metabolic pathways, including fatty acid biosynthesis. It is known that triclosan is an inhibitor of ENR in bacteria and we and others have shown that it is also effective against ENR in apicomplexan organisms such as P. falciparum. However triclosan cannot be used to treat malaria in humans because it has metabolic liability (glucoronidation) which limits its inhibitory potency. We have used X-ray crystallography and a Structural Activity Relationship (SAR) strategy to design and cocrystallize a tertiary complex of PfENR with NAD+ and triclosan derivatives to improve their properties as drugs to treat malaria. More than five hundred triclosan derivatives were synthesized, and their in vitro and in vivo inhibitory activity evaluated. Furthermore, structural studies were made of their affinity to interact with residues in PfENR active sites, as well as with the cofactor NAD+. A total of six PfENR-NAD+-triclosan analog/complexes structures were determined. Analogs which had replacements of chloride groups at position 5 of ring A and 4' of ring B were determined, allowing the structural analysis of the binding of these triclosan analogs to PfENR. In addition, the urea derivatives (modification at position 1) as well as phenylsulphonamides (modification at position 2') have shown to be more potent inhibitors than triclosan in the in vivo assay. The analysis of the inhibitory properties and the structure of these analogs bound to PfENR will provide novel compounds in the search for new anti-malarial drugs.

Los genotipos de Plasmodium vivax, junto con la densidad parasitaria pueden estar relacionados al grado de severidad de la malaria. El conocimiento de esta relación puede ayudar a un mejor manejo de la enfermedad, tratamiento con drogas y elaboración de posibles vacunas. El objetivo del trabajo fue determinar el número de genotipos de Plasmodium vivax presentes en la Amazonía Peruana. Para la genotipificación se usó el gen que codifica la proteína de superficie del merozoito (MSP3 alfa) y el polimorfismo generado por secuencias repetitivas de nucleótidos (TR) encontrado en un segmento de 100 Kilobases (Kb) de Plamodium vivax “sinténico” al cromosoma 3 de Plasmodium falciparum. Se trabajó con 302 muestras de sangre de pacientes, a todas ellas se les realizó el examen de la gota gruesa y frotis para el diagnóstico y conocimiento de la densidad parasitaria, dicho diagnóstico fue confirmado por Nested PCR. A las muestras confirmadas se les realizó la genotipificación. Con el marcador MSP3 alfa se identificaron 9 genotipos, de los cuales uno de ellos se encontró asociado a severidad de la enfermedad (P7) (P<0.05, OR>1), y otro relacionado con infecciones mixtas (P9), 1/9 (11%). Para los TR se seleccionaron 9 pares de “primers” de un total de 33. Encontrándose 102 genotipos diferentes de los cuales 24/102 (24%) fueron infecciones por genotipos mixtos. El hecho que exista una inserción en el tamaño de su ADN originalmente reportado, aumenta la posibilidad que se dé la enfermedad en forma más severa. Estos resultados indicarían que poblaciones de Plasmodium vivax son altamente diversos y que infecciones por múltiples clonas se darían en la región hipoendémica de la Amazonía Peruana, las cuales podrían representar un desafío para evaluación posterior de drogas y vacunas. / Genotypes of Plasmodium vivax along with parasite density may be associated with the severity level of malaria, and knowledge of this relation can help to better understand the disease, drug treatments and the development of new vaccines. The object of this project was to determine the number of Plasmodium vivax genotypes present in the Peruvian Amazon. This genotyping utilized the gene encoding a merozoite surface protein (MSP3 alpha) and the polymorphism generated by a sequence of nucleotide repeats (TR) found in a 100 kilobases (Kb) de Plasmodium vivax syntenic chromosome 3 of Plasmodium falciparum. In this project we used 302 blood samples from patients. A blood droplet and droplet smear were obtained for the diagnostic and observation of parasite density; these results were later confirmed through Nested PCR. All samples were submitted for genotyping. Using the marker MSP3 alpha, 9 genotypes were identified, one was found associated with disease severity (P7) (P<0.05, OR>1) and other with mixed infections (P9) 1/9 (11%). For the TR, 9 pairs of primers were selected from a pool of 33 describing 102 different genotypes of which 24 (24 %) were mixed infections. Observation supported by the existence of a DNA insertion that increases the original size of the sequence, increasing the possibility that the disease become more severe. These results would indicate that populations of Plasmodium vivax are highly diverse and can result in multiple infections by different clones in hypoendemic regions such as the Peruvian Amazon, making later evaluation of drugs and vaccines more challenging.

Thesis (Ph.D.)(Biochemistry)--University of Pretoria, 2002. / Includes bibliographical references.

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<p>The broad aim of the study is to understand the process and identify the factors associated with presumptive diagnosis and home management of childhood malaria among nomadic Fulani in Demsa, Adamawa State of Nigeria during the immediate past malaria season.</p>

<p>Malaria is a health, social and economic burden in Nigeria and consistently ranks amongst the four most common causes of childhood deaths. Treatment of malaria is usually started at home / care is only sought from the health facility when the treatment is ineffective (McCombie, 1996). Patent medicine vendors (PMVs) have been identified as a widely patronized source for drugs used in the home treatment of malaria (Breiger et al, 2001 / Goodman, et al, 2007 / Salako et al, 2001). Inadequate or poor knowledge and practices in the use of anti-malaria drugs (AMDs) increases morbidity and mortality, undermines therapeutic efficacy, and promotes the emergence and spread of drugresistant malaria. Aim: The aim of the study was to describe and quantify the knowledge and self-reported practices of PMVs in the use of antimalarials, particularly artemisinin-based combination therapies (ACTs), in a poor urban community in Lagos state, Nigeria.</p>