Every year three million deaths are attributed to malaria, of which one-third are of children. Malaria is a vector-borne disease, where a mosquito acts as the vector that transmits the disease. In the last few years, computer simulation based models have been used effectively to study the vector population dynamics and control strategies of vector-borne diseases. Typically, these models use ordinary differential equations to simulate the spread of malaria. Although these models provide a powerful mechanism to study the spread of malaria, they have several shortcomings. The research in this thesis focuses on creating a simulation model based on the framework of cellular automata, which addresses many shortcomings of previous models. Cellular automata are dynamical systems, which are discrete in time and space. The implementation of the model proposed can easily be integrated with EpiSims/TRANSIMS. EpiSims is an epidemiological modeling tool for studying the spread of infectious diseases; it uses social contact network from TRANSIMS (A Transport Analysis and Simulation System). Simulation results from the prototype implementation showed qualitatively correct results for vector densities, diffusion and epidemiological curves. / Master of Science

Parasitic infections are ubiquitous, but the consequences to hosts can vary substantially. Variation in the consequences of infection can be related to individual differences in the use of two parasite defense strategies, resistance and tolerance. Resistance entails reducing parasite burden by removing parasites or restricting parasite reproduction. Tolerance involves minimizing the costs associated with a given parasite burden. Genetic variation, environmental conditions, and life history stage can contribute to variation in resistance and tolerance, but the physiological mechanisms that underlie investment in each strategy are not well understood. I proposed that glucocorticoid hormones, which mediate responses to challenges in the physical and social environment in vertebrates, might alter host investment in resistance and tolerance (Chapter I). Glucocorticoids influence a suite of physiological processes including immune function, resource allocation, and tissue growth, all which could alter resistance and tolerance. Using a combination of observational and experimental studies, I test the hypothesis that glucocorticoids mediate resistance and tolerance to infection in red-winged blackbirds (Agelaius phoeniceus) infected with Haemosporidians, including malaria (Plasmodium) and malaria-like (Haemoproteus and Leucocytozoon) parasites. I performed a medication experiment (Chapter II) to identify the physiological consequences of Haemosporidian infection and explored the relationships between glucocorticoids and parasite resistance and tolerance in both an observational field study and a hormone manipulation experiment (Chapters III and IV). Medication treatment effectively reduced Plasmodium burden, increased hematocrit and hemoglobin, and reduced the rate of red blood cell production (Chapter II). In an observational field study (Chapter III), red-winged blackbirds with higher plasma glucocorticoid concentrations maintained higher hematocrit than expected for their parasite burdens, suggesting a positive association between glucocorticoids and tolerance. In this study, I found no support for a relationship between glucocorticoids and resistance. However, experimental elevation of glucocorticoids (Chapter IV) yielded nearly opposite results: the higher of two doses of glucocorticoids increased Plasmodium burdens and caused a decrease in body mass with increasing parasite burden, indicative of a decrease in tolerance. I discuss possible causes of the differences in our observational and experimental studies and the implications of my work for future studies of individual variation in parasite tolerance (Chapter V). / Ph. D. / Why does a cold leave some people bed-ridden, while others can go about their day with only a few sniffles? We can easily see that people react differently when they encounter an infection, but it is not clear why. When faced with an infection, there are two main defense strategies: resistance and tolerance. Resisting infection means reducing the number of parasites or pathogens in the body. Tolerance, on the other hand, refers to reducing the damage or costs that occur during infection. For example, an individual could resist a cold by using the immune system to kill off viruses. If someone tolerates a cold, they might not feel very sick, despite the presence of viruses. Individuals that are more tolerant could be suppressing their own immune response, which can cause the inflammation that leads to a stuffy nose, or these individuals might be repairing damage caused by the virus. Individuals can vary in the extent to which they resist or tolerate infection, but we do not know why this variation exists. In this dissertation, I investigate how the hormones associated with physiological stress might influence resistance and tolerance to malaria and malaria-like parasite infections in red-winged blackbirds. First, I performed a study in which I treated birds infected with a blood-borne parasite with anti-malarial medication to identify the costs of chronic infection. Then I observed the relationships between glucocorticoids (the hormones associated with physiological stress) and estimates of resistance and tolerance in wild red-winged blackbirds. Finally, I used hormone implants to increase stress hormone concentrations in birds held in aviaries, and assessed whether the implants caused changes in resistance and/or tolerance. My results suggest that chronic malaria infection can 5 damage or destroy red blood cells and birds compensate by increasing the rate of blood cell production. In wild red-winged blackbirds, birds with higher concentrations of stress hormones were able to maintain a higher proportion of red blood cells in the blood for a given parasite burden, suggesting they were more tolerant. Stress hormone levels were not associated with the total number of parasites, and thus, we have no evidence for a relationship between the hormones and resistance. When we increased the hormone levels in the aviary experiment, we found nearly opposite results. A high dose of stress hormones caused an increase in the number of parasites and increased the cost of infection. In this dissertation, I discuss possible explanations for the different results in the observational study and the experiment and suggest avenues for future studies.

Malaria, a disease caused by members of the Plasmodium genus, remains a threat to global health. Despite the availability of therapeutics, Plasmodium's propensity for generating resistance-conferring mutations threatens the efficacy of these drugs. Therefore, it is essential to develop novel therapeutics, and one approach to discover such compounds is to repurpose current drugs as antimalarials. Human kinase inhibitors, most of which are developed as antineoplastics, are a valuable source of such novel compounds. Human kinase inhibitor research spans over twenty years, generating a wellspring of knowledge regarding compound design, mechanism, and tolerability that can be leveraged in the quest to develop new antiplasmodial drugs. Furthermore, the plasmodial kinome differs substantially from the human kinome, providing opportunities for selectivity and minimization of off-target effects in the host. To this end, we sought to identify and characterize compounds within human kinase inhibitor collections that have antiplasmodial effects. One library yielded a potent polo-like kinase 1 (PLK1) kinase inhibitor, BI-2536, which possessed potent antiplasmodial activity in both the asexual blood stage and liver stage and likely acts through involvement of amino acid starvation. Another library comprised exclusively of type II kinase inhibitors, designed to target kinases in the inactive conformation, produced several interesting lead compounds – TL5-135, YLIU-06-026-1, and the analog pair XMD13-99 and WZ9-034-2. These compounds were highly active against asexual blood stage parasites, killing rapidly while also possessing favorable selectivity and liver stage activity. In vivo, TL5-135 and YLIU-06-026-1 acted prophylactically by preventing infection, and therapeutically by resolving an established infection. Currently, investigations are underway to determine the mechanism of action of the lead compounds and to improve their druglike properties. In whole, this effort has not only yielded promising antiplasmodial compounds, but it also underscores the value of the repurposing approach in the quest for novel antimalarial drugs.

No / The structure of 2,7-dibromocryptolepine acetic acid solvate, C16H11N2Br2 [1.5(C2H4O2)][C2H3O2 -] [0.5H2O], Mr = 460.17, has been determined from X-ray diffraction data. The crystals are monoclinic, space group P21/c with Z = 4 molecules per unit cell and a = 7.3243(3), b = 18.7804(6), c = 15.8306(7) A ° , b = 94.279(1) , Vc = 2171.5(2) A ° , crystal density Dc = 1.667 g/cm3. The structure was determined using direct methods and refined by full-matrix least-squares to a conventional R-index of 0.0496 for 4,908 reflections and 258 parameters. The cryptolepine nucleus of the 2,7-dibromocryptolepine molecule is highly planar and the two Br atoms are in this plane within 0.06 and 0.01 A ° , respectively. The crystal structure is maintained via hydrogen bonding between N(10) in the cryptolepine nucleus and the oxygen of one of the three solvated acetic acid molecules. The acetic acid molecules also form hydrogen bonded chains. Acetic acid B is deprotonated and its two C¿O bond lengths are equivalent, unlike those in A and C. Acetic acid C lies very close to a crystallographic centre of symmetry. To avoid overlap the two repeats cannot exist together and are subject to 50% statistical disorder. O(1C) of this methanol is furthest from the two-fold axis and its occupancy refines to a value of 1.0 and is assumed to exist alternately as a water oxygen hydrogen bonding to methanol O(1C) across the two-fold axis at a distance of 2.775 A ° .

No / This paper reports 35 medicinal plants belonging to 25 families used in the treatment of malaria by the people inhabiting the forests located near to Bhubaneswar, the capital city of Orissa, a south-eastern state in India. The methods adopted for the preparation of plant parts are discussed along with their family and local name(s). The majority of the herbal preparations were made in the form of juices or by using water as the medium in the form of decoctions or infusions. Various plant parts, such as leaves, flowers, fruits, barks, stems, roots, and in some cases the whole plants are used to prepare these remedies each of which contains a single species.

No

Thesis (Mcur)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: The researcher has identified several problems in the North West Health Directorate community of Namibia regarding malaria and malaria related deaths. Against this background the study was undertaken to: • Identify the attitude(s) of the community towards malaria. • Determine the community's knowledge of malaria. • Determine the prevention strategies the community employed to guard against malaria. • Make recommendations. Methodological triangulation was used to obtain data and the findings reflected the following: • Lack of knowledge about malaria, its causes, management and prevention due to lack of adequate health information. • Socio-cultural factors have an influence on the community's knowledge of malaria, their attitudes towards malaria and on strategies employed by the community to prevent malaria. Recommendations included provision of proper and adequate health information to the community by health workers, increasing community participation in order to enhance attitude change and co-ordination and collaboration between traditional healers and the Ministry of Health and Social Services. Keywords: malaria I community I prevention I knowledge I attitudes / AFRIKAANSE OPSOMMING: Die navorser het verskeie probleme rakende malaria en malaria verwante sterftes in die gemeenskap van die Noordwes Gesondheidsdirektoraat van Namibië geïdentifiseer. Teen hierdie agtergrond is die studie gedoen om: • Die houding van die gemeenskap teenoor malaria te identifiseer. • Die gemeenskap se kennis omtrent malaria te bepaal. • Die voorkomende strategieë wat die gemeenskap toepas om malaria te voorkom te bepaal. • Aanbevelings te maak. Metodologiese triangulasie is gebruik om data te verkry en die bevindinge het die volgende gereflekteer: • Gebrek aan kennis aangaande malaria, die oorsake, hantering en voorkoming van malaria as gevolg van 'n gebrek aan voldoende gesondheidsinligting. • Sosio-kulturele faktore beïnvloed die gemeenskap se kennis van malaria, hul houding teenoor malaria en die strategieë wat hul toepas om malaria te voorkom. Aanbevelings sluit in die voorsiening van korrekte en voldoende gesondheidsinligting aan die gemeenskap deur gesondheidswerkers, verhoging van gemeenskapsdeelname om houdingsveranderinge teweeg te bring asook om die koërdinasie en samewerking tussen tradisionele helers in die Ministerie van Gesondheid en Welsyn te verbeter. Sleutelwoorde: malaria I gemeenskap I voorkoming I kennis I houding.

Thesis (PhD)--Stellenbosch University, 2012. / Please refer to full text for abstract.

Malaria is a disease of global importance, causing hundreds of thousand of deaths a year. The majority or deaths are caused by Plasmodium falciparum, a parasite transmitted by the mosquito Anopheles. Its pathogenicity largely results from an ability to transform infected erythrocytes by creating knob-like structures that result in endothelial adhesion. Two major components of these knob structures have been identified as P. falciparum erythrocyte membrane protein 1 (PfEMP1) and knob-associated histidine rich protein (KAHRP). The extracellular fragment of PfEMP1 is responsible for antigenic variability and cytoadherence while its intracellular domain (ATS) connects to the cytoskeleton via interactions with other plasmodium-encoded proteins. In addition, perforin-like proteins (PLPs) with a MACPF domain have been identified in the genome of Plasmodium. PLPs are highly conserved and are expressed in various life-cycle stages of the parasite. They are believed to form pores in membranes of the host cell but their structure is yet unknown. The aim of the work in this thesis was to obtain new information about the structure and role of malaria proteins, thus giving a better understanding of the disease and its possible treatment. Studies of numerous designed constructs of the ATS family were carried out using biophysical methods including high resolution NMR and CD. These revealed that ATS domains are mainly unstructured with a relatively small folded core, consisting of a bundle of α-helices. Surprisingly, no evidence could be found for ATS binding to KAHRP in solution conditions although previous pull-down data had indicated an interaction. Bioinformatics analysis and yeast-two-hybrid data suggested, however, that there is a conserved protein interaction epitope on the central flexible part of ATS. It was shown, using fluorescence anisotropy measurements, that this part of ATS associates with a parasite protein containing a PHIST (Plasmodium helical interspersed sub-telomeric) domain. Expression constructs of the PLP protein family were designed and manufactured, with the aim of enabling structural studies of this putative pore protein.

Les interactions hôtes-parasites sont classiquement vues comme un équilibre dynamique entre seulement deux partenaires ; cependant, ce paradigme a progressivement changé ces dernières années avec la découverte de nombreux hôtes naturellement co-infectés par de multiples parasites. L'étude des co-infections s'avère particulièrement pertinente lorsque l'hôte est un vecteur de maladies, dans la mesure où les infections multiples peuvent avoir d'importantes conséquences sur la transmission d'un parasite, à la fois à des échelles écologiques et évolutives. Wolbachia pipientis est la bactérie endosymbiotique la plus commune chez les insectes, et de fait, suscite un intérêt particulier pour comprendre le rôle des co-infections sur l'issue des infections parasitaires. Afin de déterminer si l'infection naturelle par Wolbachia affecte la capacité des moustiques à transmettre la malaria, nous avons étudié une triade qui partage une histoire évolutive commune : le parasite de la malaria aviaire P. relictum SGS1, son vecteur naturel Cx. pipiens, et un ensemble de souches wPip de Wolbachia naturellement présentes chez ce moustique. Nous nous sommes tout d'abord intéressé à l'impact de différents types de wPip sur la prévalence et la diversité des parasites responsables de la malaria aviaires dans les populations naturelles de Cx. pipiens de la région de Montpellier. Puis, par l'utilisation de différentes lignées isogéniques de moustiques, infectés ou non par Wolbachia, nous avons étudiés l'impact de la présence du symbiote sur différents traits d'histoire de vie du moustique essentiels pour la transmission de Plasmodium. Nous montrons ainsi que Wolbachia profite à Cx. pipiens, mais également à Plasmodium: elle améliore plusieurs traits d'histoire de vie des moustiques, tels que leur longévité et leur fécondité, leur tolérance à l'infection par P. relictum, et facilite l'infection par ce parasite à la fois qualitativement et quantitativement (i.e. elle augmente à la fois la prévalence et l'intensité de l'infection). Bien que les mécanismes impliqués dans cette interaction tripartite restent encore inconnus, ces résultats suggèrent que Wolbachia peut avoir d'importantes implications sur la transmission de la malaria dans la nature. De plus, ces résultats suggèrent la nécessité de réévaluer l'utilisation de Wolbachia comme moyen de lutte contre les pathogènes et soulignent la nécessité de mieux comprendre les interactions multipartites. / In recent years, there has been a shift in the one host one parasite paradigm with the realization that, in the field, most hosts are co-infected with multiple parasites. Coinfections are particularly relevant when the host is a vector of diseases, because multiple infections can have drastic consequences for parasite transmission at both the ecological and evolutionary time scales. Wolbachia pipientis is the most common parasitic microorganism in insects and as such it is of special interest for understanding the role of coinfections in the outcome of parasite infections. This thesis investigates whether a natural Wolbachia infection can alter the quality of mosquitoes as vectors of malaria. To address this issue, we used a Wolbachia-mosquito-Plasmodium triad with a common evolutionary history. Our experimental system consists in the avian malaria parasite P. relictum SGS1 and its natural vector, the mosquito Cx. pipiens, which naturally harbours several wPip Wolbachia strains. First, we investigated the impact of different wPip groups on the prevalence and diversity on avian malaria in natural populations of Cx. pipiens mosquitoes in the Montpellier region. Second, using different isogenic laboratory mosquito strains harboring or not Wolbachia, we investigated the impact of the presence of Wolbachia on several mosquito and Plasmodium life history traits relevant for malaria transmission. We show that Wolbachia benefits both Cx. pipiens and Plasmodium: it enhances several mosquito life history traits, such as longevity and fecundity, increases their tolerance to P. relictum (i.e. compensates for a Plasmodium-induced mortality) and facilitates P. relictum infection both qualitatively (increases infection prevalence) and quantitatively (increases infection intensity). Although the mechanisms involved in the mosquito-Wolbachia-Plasmodium interaction remain elusive, these results suggest that Wolbachia may have important implications on the transmission of malaria in nature. This is consistent with the high prevalence and diversity of avian malaria parasites found in natural populations of Cx. pipiens. Further, these results suggest the need to reassess the use of Wolbachia as a way to fight pathogens and highlight the need to better understand parasite multipartite interactions.