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1
Casals-Pascual, Climent. "Ineffective erythropoiesis in P. falciparum malarial anaemia." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409709.
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Marques, João Pedro Nogueira. "Identificação de determinantes de resistência em P. falciparum." Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10904.
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Mestrado em Bioquímica<br>O presente estudo teve como objetivo a análise de possíveis determinantes de resistência por parte do Plasmodium falciparum ao fármaco antimalarico mefloquina. Para tal foi utilizada a estirpe W2, resistente à cloroquina e sensível à mefloquina, e uma estirpe isogénica W2mef, derivada de W2 e obtida por pressão seletiva em meio rico em mefloquina. Procedeu-se a um fracionamento subcelular e analisaram-se os extractos obtidos, com recurso a marcação com isótopos, O18 e iTRAQ, seguida de LC MS/MS MALDI, tendo sido identificadas 248 proteínas, sendo 76 de P. falciparum e 172 de Homo sapiens. Verificaram-se alterações na expressão proteómica de 10 proteínas de P. falciparum e 7 de Homo sapiens.
A análise da atividade proteolítica por zimografia, revelou a diferenças relevantes de atividade proteásica nas amostras de W2mef, tendo sido identificada a aminopeptidase, “M1 family aminopeptidase”.
Através dos resultados a atividade proteolítica em conjugação com análise bioinformática verificou-se que a protease identificada, tem um papel relevante na via de degradação da hemoglobina, estabelecendo interações indiretas com proteínas que se sabe estarem envolvidas no processo de obtenção de a.a., fundamental para a sobrevivência e desenvolvimento parasitário.
Em suma as significativas diferenças de atividade proteolítica das amostras com a estirpe resistente e o facto da “M1 family aminopeptidase” estar associada a um processo vital para o desenvolvimento do parasita, faz com que esta protease possa ser apontada como o novo determinante para o desenvolvimento de novos fármacos, nomeadamente baseados em inibidores da PfA-M1.<br>The aim of the present study was to analyze resistance determinants of Plasmodium falciparum to the mefloquine antimalarial drug. With this propose was used a W2 strain, known to be chloroquine resistant and mefloquine sensitive, and a isogenic W2mef strain, derived from W2 and obtained by selective pressure on a mefloquine rich medium. Parasatic proteins were extracted with a optimized and aggressive extraction buffer, follow of cellular fractionation and ultracentrifuge. The protein profile of the samples was analyzed using labeling with O18 and iTRAQ, followed by LC MS/MS MALDI. Were identified 248 proteins, 76 of P. falciparum and 172 of Homo sapiens and has been identifying changes in the expression of 10 parasitic and 7 human proteins.
The proteolytic activity analysis by zimography reveals significant differences in protease activity in the samples of W2mef, and has been identified an aminopeptidase, the “M1 family aminopeptidase”. Through the results of the proteolytic activity in conjuction with bioinformatics analysis reveals that the identified protease, plays a central role in the hemoglobin degradation pathway, establishing indirect interactions with proteins known to be involved in the obtaining of a.a., which is fundamental to parasite survival and development.
In conclusion, the significant proteolytic activity differences of resistant strain samples and the fact that “M1 family aminopeptidase” is being associated with a vital process to the parasite development, makes this protease, the new possible determinant for the development of new drugs, in particular, based in PfA-M1 inhibitors.
3
Jaurigue, Jonnel Anthony [Verfasser]. "Antibodies against P. falciparum glycosylphosphatidylinositol epitopes / Jonnel Anthony Jaurigue." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1202463886/34.
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Seidlein, Lorenz von. "Transmission reduction of P. Falciparum by targeted drug intervention." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270781.
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Noble, Robert John. "Antigenic variation and its evolution in P. falciparum malaria." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:271b8ef9-4e14-42e3-80e6-5584119e20ca.
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This thesis investigates antigenic variation and its evolution in Plasmodium falciparum, the cause of the most deadly form of human malaria. Antigenic variation is a strategy for evading immunity by switching between antigenic variants during infection. In P. falciparum, such variable antigens confer different binding phenotypes that may affect parasite survival and have also been linked to pathology. Here, a new statistical method is described for determining the switching patterns that underlie antigenic variation. This method is then applied to experimental data to yield a full description of an antigenic switching network in P. falciparum. In light of the findings, theoretical modelling is used to show how immune selection and binding phenotypes may have contributed to the evolution of antigenic repertoire structure, expression order and virulence. Related models are also used to investigate parasite population diversity, providing possible explanations for observations reported here and elsewhere, with implications for vaccine design. Together, these chapters advance understanding of P. falciparum immune evasion and how it relates to pathology. This work further reinforces the role of host immunity in shaping pathogen population diversity at multiple levels.
6
Amrane, Dyhia. "Pharmacomodulation d'hétérocycles α-trichlorométhylés ciblant l'apicoplaste chez P. falciparum". Electronic Thesis or Diss., Aix-Marseille, 2021. http://www.theses.fr/2021AIXM0379.
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Le paludisme est la première parasitose en termes de mortalité à l’échelle mondiale. Les thérapies combinées à base d'artémisinine, traitement de première ligne du paludisme à Plasmodium falciparum, font face à des échecs dûs à l’apparition de résistances. Il est donc nécessaire de développer de nouvelles molécules antiplasmodiales possédant un mécanisme d’action novateur. Dans cet objectif, notre laboratoire a précédemment décrit la synthèse et les activités biologiques d'une chimiothèque de molécules azahétérocycliques α-trichlorométhylées, dont une molécule hit en série quinazoline qui présente le meilleur profil biologique.Une première partie de ce travail s’est intéressée à la pharmacomodulation en série 4-carboxamidoquinazoline. Afin de compléter l’étude RSA, la stratégie de scaffold hopping a permis l’obtention de nouvelles molécules en séries quinoxaline et phtalazine. Par simplification structurale, de nouveaux composés en séries pyrimidine, pyridazine et pyrazine ont été obtenus. Enfin, dans le but de moduler la partie benzénique des noyaux quinazoline et quinoxaline, des dérivés en série thiénopyrimidine et pyrido[2,3-b]pyrazine ont été synthétisés. Parmi plus de 110 nouvelles molécules originales synthétisées, plusieurs nouvelles molécules hit ont pu être identifiées. Leurs propriétés physicochimiques et pharmacocinétiques in vitro ont été déterminées en vue d’identifier une molécule candidate pour l’évaluation in vivo. De plus, afin d’élucider le mécanisme d’action de ces composés qui diffère de ceux des antipaludiques commerciaux, nous avons récemment identifié par immunofluorescence que ces molécules possèdent une action sur l’apicoplaste de P. falciparum<br>Malaria remains the leading cause of death among parasitic infections worldwide. Currently, there are major concerns about the spread of resistance to artemisinin derivatives that are the basis of first-line antimalarial treatment. Therefore, there is an urgent need to develop new antiplasmodial molecules with a novel mechanism of action. For this purpose, our laboratory has previously described the synthesis and biological activities of a chemical library of α-trichloromethylated azaheterocycles including a hit molecule in the quinazoline series which presents the best biological profile.The first part of this work focused on 4-carboxamide quinazoline pharmacomodulation. In order to complete the SARs, scaffold hopping strategies allowed us to obtain new compounds in the quinoxaline and phthalazine series. By structural simplification, new compounds in the pyrimidine, pyridazine and pyrazine series were obtained. Finally, in order to explore the benzene part of the quinazoline and quinoxaline rings, new thienopyrimidine and pyrido[2,3-b]pyrazine derivatives were also synthesized. More than 110 new original molecules were obtained, among them several new hit molecules were obtained. The physicochemical and in vitro pharmacokinetic properties were determined in order to initiate the study of their in vivo activity on Plasmodium berghei. In addition, in order to elucidate the mechanism of action of these compounds, which differs from those of commercial antimalarials, we have recently identified by immunofluorescence that these molecules target the apicoplast of P. falciparum, an organelle essential to parasite survival
7
Pugh, Kathryn Maria. "Developing chemical biological tools to probe phosphorylation in P. falciparum." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/28933.
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In 2010 there were an estimated 219 million cases of malaria worldwide, accounting for approximately 0.66 million deaths. With growing resistance to current antimalarial agents a challenge is placed on the scientific community to provide efficacious and cost effective methods for the diagnosis and treatment of malaria. As protein phosphorylation regulates most aspects of cell life, understanding the function of protein kinases in malaria parasites has the potential to uncover novel drug targets. To this end, this work focused on the study of three essential Plasmodium falciparum kinases using two different chemical genetic approaches: γ-modified ATP analogues for the investigation of PfCK2; and covalent complementarity for the study of PfCLK1 and PfCLK3. The work presented here highlights the instability of the P-N bond of ATP phosphoramidates during the acidic conditions required for analysis by MALDI-TOF MS and seeks to overcome this through the development of alternative linkers to the γ-phosphate of ATP. Apparent IC[subscript 50] values recorded provide evidence of PfCK2α tolerating modification of the γ-phosphoryl group of ATP; however, no evidence was found to support GTP serving as an alternative co-substrate of PfCK2α. The gatekeeper mutant kinases PfCLK1F630C and PfCLK3F444C were successfully produced. It was found that this mutation rendered PfCLK3 inactive and was detrimental to the activity of PfCLK1. Under the conditions used PfCLK1F630C was not inhibited by a panel of 23 electrophilic inhibitors.
8
Lemieux, Jacob E. "Gene expression in P. falciparum : statistical patterns and molecular determinants." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:f6827b50-ca5f-4fe2-a52c-1947fef224ab.
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This thesis investigates patterns and mechanisms of gene expression in P. falciparum. The rapidly cycling patterns of genes during the asexual stages confounds the analysis of gene expression in culture and in patients. In order to overcome this problem, we develop statistical models to estimate the temporal progression of malaria parasites by using the observed gene expression values and known reference sets. We extend this framework to account for lineage commitment, and show that, similar to asexual development, it is also possible to recover information about parasite sexual differentiation given observed gene expression values. Using datasets from our own lab as well as those available in the literature, we establish that the patterns of expression in patients are similar to those observed in culture but in additive mixtures whose proportions can vary between patients. We then investigate epigenetic and spatial factors that are important in regulating gene expression. Using second-generation DNA sequencing, we generate genomic maps of chromatin state and chromosome interactions. These maps provide the first global view of chromosome folding and locus-specific affinities in malaria. They also highlight the importance of epigenetic modifications in imposing structure on the spatial organization of the genome. After generating an initial set of genomic maps, we apply these tools to study chromatin reconfigurations during var gene switching. We show that when the active var gene changes, reconfigurations can be seen in the local three-dimensional chromatin structure of the activated locus. Overall, our results contribute new methods for analyzing malaria microarray data, highlight the importance of lineage mixtures in patient infections, generate an atlas of spatial interactions in the nucleus at a resolution of approximately 5 kilobases, and establish a link in malaria between the spatial configuration of active loci and the local chromatin environment.
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Sussmann, Rodrigo Antonio Ceschini. "Biossíntese de vitamina E nos estágios intraeritrocitários de P. falciparum." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-05082011-105023/.
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O estudo da biossíntese de isoprenóides em P. falciparum por meio da via 2C-metil-D-eritritol-4-fosfato (MEP) é apontado como possível alvo terapêutico, visto a via ser ausente em humanos. Foi descrito que nos estágios intraeritrocitários de P. falciparum a via essencial de biossíntese de isoprenóides é a via MEP. As vias do Chiquimato e MEP são precursoras da biossíntese de vitamina E e ambas já foram descritas em P. falciparum. É sugerido que a biossíntese de vitamina E possa ocorrer no parasita, representando um possível alvo para o desenvolvimento de novas drogas antimaláricas. Empregando marcações metabólicas com precursores radioativos, três diferentes métodos de RP-HPLC e análises por espectrometria de massas confirmamos a biossíntese de vitamina E nos três estágios intraeritrocíticos do parasita. O tratamento com ácido úsnico, mostrou inibição dessa biossíntese no estágio esquizonte e do crescimento do parasita. Demonstramos por meio de uma sonda fluorescente, ácido Parinárico, que a vitamina E atua como antioxidante lipofílico, protegendo a lipoperoxidação. Esses resultados não só contribuem para a compreensão da biologia de P. falciparum, mas também elucidam partes das vias MEP e do Chiquimato que podem servir como alvos terapêuticos.<br>The study of isoprenoid biosynthesis in Plasmodium falciparum by 2C-methyl-D-erythritol-4-phosphate pathway (MEP) it is presented as a therapeutic target once that it is absent in humans. It was found in intraerythrocytic stages of P. falciparum the biosynthesis of isoprenoids by the MEP pathway. The shikimate and MEP pathways are the precursors of biosynthesis of vitamin E and both pathways have already been described in P. falciparum. It is suggested that the biosynthesis of vitamin E might occur in the parasite, representing a possible target for developing new antimalarial drugs. Using metabolic labelling with radiolabelled precursors, three different methods of RP-HPLC and mass spectrometry analyses confirmed the biosynthesis of vitamin E in the three intraerythrocytic stages of parasite. The treatment with usnic acid showed an inhibition of this biosynthesis and of the growth of parasite. We demonstrated by means of a fluorescent probe, the acid Parinaric, that vitamin E acts as a lipophilic antioxidant protecting the membrane of lipoperoxidation. These findings not only contribute to the current understanding of P. falciparum biology but shed light on a pathway that could serve as a chemotherapeutic target.
10
Saif, A. M. "Pharmacology and pharmacodynamics of selected antimalarials against P. falciparum gametocytes." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3005700/.
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Malaria is a vector-borne disease that is still responsible for high human morbidity and mortality. Of the five Plasmodium species that can cause malaria in humans, Plasmodium falciparum is regarded the most virulent species. The most fundamental component of sustained control and eradication efforts is the development of effective drugs for malaria treatment and prophylaxis. Plasmodium falciparum’s sexual stages (gametocytes) are not associated with malarial pathogenesis or the clinical symptoms, but they are responsible for the transmission of the disease from human hosts to mosquitos. As such, the development of gametocytocidal interventions that targets the transmission stage to break the disease’s lifecycle forms the basis of efforts towards malaria elimination and eradication. However, despite the importance of this developmental stage, the biology and pharmacology of gametocytes are still very poorly understood. This thesis has set out to gain a better understanding of the identity of gametocyte-active antimalarials and a deeper understanding of the mechanisms underpinning the activity. Using a newly generated luciferase-reporting transgenic line, pharmacodynamic gametocyte studies could be performed to help characterise the activity of selected known reference antimalarials, new potential gametocyte inhibitors in pre-clinical development as well as newly developed fully synthetic compounds designed against the sexual stages. This novel assay revealed that the efficacy of active tested compounds is highly stage-specific. Of all the tested reference antimalarial drugs, MB and DHA were the most potent antimalarial across all gametocyte stages and importantly they were active at clinically relevant levels. These observations were progressed further, developing a time- dependent killing assay that was performed with different concentrations of targeted drug over discrete time intervals to determine the drug’s kill rate. These parameters were then used to simulate the PK/PD relationship of the drug in order to estimate gametocyte clearance profiles during the human treatment period (Chapter 3 and 4). A main focus of the thesis was conducted to better understand the mechanism of drug activity of the 8-aminoquinolines against gametocytes. The ability of a series of 8-aminoquinolines (primaquine as the parent drug, synthesised metabolites in chapter 5, three novel analogues and tafenoquine in (chapter 6) to interact with CYP2D6 was tested by measuring their ability to specifically inhibit the metabolism of fluorescently-tagged tracer substrate by recombinant human CYP 2D6. Reaction products from the CYP metabolites and HLM were then used to test firstly their ability to kill gametocytes, and then to establish their ability to generate hydrogen peroxides and finally measure their haemolytic toxicity. At 10 µM, primaquine CYP metabolites showed activity against the gametocytes that was higher than that of the parent drugs, with the exception of tafenoquine which, interestingly, demonstrated good activity and haemolytic toxicity as a parent drug. These analyses are presented and discussed in the context of strategies that aim at the discovery and development of new transmission-reducing antimalarial drugs.
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Liu, Lixuan. "MMV008138 and analogs: potential novel antimalarial agents for P. falciparum." Thesis, Virginia Tech, 2018. http://hdl.handle.net/10919/95315.
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Malaria is a severe and deadly mosquito-borne disease. Although treatable, the continuous emergence of multi-drug resistant parasite strains urgently calls for the development of novel antimalarial agents. P. falciparum parasites synthesize essential isoprenoid precursors, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), via a non-mevalonate pathway: the methylerythritol phosphate (MEP) pathway. This pathway is not utilized by humans. Thus, compounds that target the MEP pathway and disrupt isoprenoid biosynthesis in P. falciparum hold promise as potent and safe new antimalarial agents, that engage new targets.
Previously, we and others identified MMV008138 from the Malaria Box as a MEP pathway targeting compound. Later work revealed that it targets the IspD enzyme within the MEP pathway. Work in the Carlier group has established preliminary structure-activity relationship (SAR) of MMV008138: 1) (1R,3S)-configuration is required; 2) 2', 4'-disubstitution of the D-ring with small, electronegative substituents; 3) functional importance of carboxylate acid at C3.
In this work, I aim to gain further insight into the C3 SAR and A-ring SAR of lead compound MMV008138. Synthesized acid bioisosteres and A-ring analogs of MMV008138 were evaluated in their ability to inhibit P. falciparum parasite growth. We showed that the C3 substituent of MMV008138 has a very tight SAR, and likely interacts with a very constricted pocket within the PfIspD enzyme. A-ring modifications are limited to certain positions of MMV001838 and need to be sterically small. However, we have yet to identify a modification that significantly improves drug lead potency.
Future work will continue towards understanding the A-ring SAR of MMV008138, as well as D-ring SAR and C1-SAR. Efforts will also be directed towards finding analogs with improved potency, transport and metabolic stability.<br>MS
12
Tchioffo, Tsapi Majoline. "Interactions génomes - environnement dans le système vectoriel Anopheles gambiae / P. falciparum : rôle de la flore microbienne du moustique dans la modulation du développement de P. falciparum." Thesis, Montpellier 2, 2013. http://www.theses.fr/2013MON20167/document.
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Le parasite Plasmodium falciparum, responsable des formes graves du paludisme chez l'homme, est transmis par Anopheles gambiae, son principal vecteur en Afrique sub-saharienne. Les nouvelles stratégies de lutte contre la maladie visent à limiter ou à interrompre le développement du parasite chez le moustique vecteur, et il est donc nécessaire d'améliorer notre compréhension des interactions entre le vecteur, son environnement et le parasite. L'objectif de ce projet de thèse a été de caractériser la flore microbienne du vecteur An. gambiae en conditions naturelles de transmission, d'étudier le rôle des principales espèces bactériennes colonisant l'estomac du moustique sur le développement de P. falciparum et de mesurer l'influence des bactéries sur la réponse immunitaire des moustiques femelles et leur capacité à transmettre le parasite. Pour mener à bien ce projet, nous avons collecté des populations de moustiques sauvages au Cameroun pour la caractérisation de la flore microbienne, nous avons ensuite exposé des moustiques de la colonie de laboratoire Ngousso à des cultures bactériennes puis infecté ces moustiques avec des isolats naturels de P. falciparum. Notre étude a montré que les souches bactériennes naturelles de l'intestin du moustique Serratia, Pseudomonas et Escherichia réduisaient la prévalence et l'intensité de l'infection et que le degré d'inhibition variait selon les taxons bactériens et les porteurs de gamétocytes. L'analyse des flores bactériennes des différents épithéliums de l'insecte par pyroséquençage a révélé des similarités entre la flore intestinale et celles retrouvées dans les ovaires et les glandes salivaires pour un même moustique. Les analyses d'expression suggèrent que la régulation de l'expression des gènes l'immunité par les bactéries intestinales pourrait participer à la modulation de la réponse antiplasmodiale. Les mécanismes impliqués dans les interactions bactéries-Plasmodium-vecteur sont complexes et multifactorielle et la modélisation de l'ensemble des interactions qui permettent à P. falciparum d'accomplir son cycle chez le moustique vecteur sera nécessaire pour envisager de nouvelles méthodes de lutte efficaces et durables<br>Plasmodium falciparum, the parasite responsible for the severe form of malaria, is transmitted by Anopheles gambiae, its major vector in sub-Saharan Africa. Novel strategies for malaria control envision interrupting the sporogonic development in An. gambiae, then it is important to better understand vector*environment*parasite interactions that underlie parasite transmission. The aim of this project was to characterize the microbial flora of An. gambiae in natural conditions, to study the role of the main bacterial strains on sporogonic development using natural isolates of parasites and to measure the influence of bacterial exposure on the mosquito immunity and its successive ability to transmit P. falciparum. To carry out this project, we used wild mosquito populations from Cameroon to characterize the mosquito microbial flora, next we challenged female mosquitoes of the Ngousso colony to bacterial strains and then infected the mosquitoes with natural isolates of P. falciparum. Our study showed that Serratia, Pseudomonas and Escherichia isolated from the mosquito midgut reduced infection prevalence and intensity and that the effect of the bacterial exposure on parasite infection levels varied between bacterial strains and gametocyte carriers. The analysis of the 454 sequencing of the different mosquito epithelia revealed intriguing similarities between bacterial communities in the midgut, ovaries and salivary glands of a single mosquito. Expression analyses suggested that immune gene regulation by midgut bacteria could help the mosquitoes to mount an effective antiplasmodial response. Mechanisms involved bacteria-Plasmodium-vector interactions are complex and rely on multiple factors. Deeper investigations on these interactions that allow P. falciparum to complete its cycle in the mosquito vector will be necessary for modeling parasite transmission in the field and for developing new methods for effective malaria control
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Krebs, Johann Hendrik. "Dihydroartemisinin esters as prodrugs against resistant P. falciparum strains / Krebs J.H." Thesis, North-West University, 2011. http://hdl.handle.net/10394/7352.
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Malaria is caused by the Plasmodium sp. parasite that infects the red blood cells. Of the four
types of malaria, the most serious type is transmitted by Plasmodium falciparum species. It
can be life threatening. The other types of malaria (P. vivale, P. ovale and P. malariae) are
generally less serious and are not life threatening. The existence of malaria as an enemy of
humankind certainly predates written history. For thousands of years malaria has been a
deadly scourge, and it remains one today. From American president John Adams who nearly
succumbed to malaria in Amsterdam while on a diplomatic mission, back down to the
timeline to the early Chinese, Indians, Greeks and Romans, malaria has not spared its
victims, rich or poor.
It wasn’t until the 19th Century that information about the true cause of malaria became
known. Yet despite this knowledge, malaria still ravages Sub–Saharan Africa, South–East
Asia and Latin America, taking as its victim’s mainly young children and pregnant women.
However, without certain discoveries leading to a better understanding of malaria, new
groundbreaking work wouldn’t be possible.
Artemisinin and its derivatives are developing into a very important new class of antimalarial
and their usage is becoming more common in the fight against malaria. The most commonly
used and applied of these derivatives are artesunate, artemether, arteether and
dihydroartemisinin. The discovery of artemisinin as the pharmacological active ingredient in
an age old Chinese herb, Artemisia annua, was a major breakthrough in malaria
chemotherapy. Discovery of qinghaosu in the 1970s sparked a new age for chemotherapy of
malaria, and greatly inspired further research on organic peroxides. This generated
widespread interest and led to the design and synthesis of organic peroxides into a highly
active area of organic chemistry.
The artemisinin derivatives act quickly and are eliminated quickly. Their rapid onset makes
them especially effective against severe malaria. Their rapid disappearance may be a key
reason why artemisinin resistance has been so slow to develop, and may be the reason why
recrudences are so common when these drugs are used in monotherapy. Since their
isolation, artemisinins have had a substantial impact on the treatment of malaria. Although
very potent, the use of artemisinins as prophylactic antimalarials is not recommended.
The aim of this study was to synthesise ester derivatives of artemisinin, determine certain
physicochemical properties such as aqueous solubility and partition coefficient, and to
evaluate their antimalarial activity in comparison to dihydroartemisinin and chloroquine.
In this study eight esters of dihydroartemisinin (DHA) were synthesised by substitution at C–
10. The structures of the prepared derivatives were confirmed by nuclear magnetic
resonance spectroscopy (NMR) and mass spectrometry (MS).
The new artemisinin esters were tested in vitro against the chloroquine sensitive strain of
Plasmodium falciparum (D10). All the compounds tested showed activity against the D10
strain. All of the esters showed potency significantly better than chloroquine, except the octyl
and decyl esters which were less active. The reason for the low activity could be ascribed to
the fact that these two esters are both water immiscible oils, leading to solubility problems.
The ethyl, butyl, phenyl and p–nitrophenyl esters all had similar IC50 values making their
activity similar. The lowest IC50 value was displayed by the butyl ester with a value of 3.2 x 10–
3 uM.
The poorest activity was recorded by the two oils, the octyl and decyl esters, with IC50 values
of 38 x 10–3 uM and 90.2 x 10–3 uM respectively. All other compounds showed less antimalarial
potency against the D10 strain compared with the other reference drug dihydroartemisinin,
except the butyl ester. The butyl ester 12 displayed activity comparable to that of DHA (IC50;
3.2 x 10–3 uM versus 3.8 x 10–3 uM), and is thus worthwhile being further investigated in terms
of pharmacokinetics in order to determine its half–life. Statistically it is impossible to make
structure–activity relationship (SAR) deductions from the data received as the number of
compounds in the series is too small.
The butyl (12) (IC50 = 3.2 uM), 4–nitrobenzyl (16) (IC50 =15 uM), 2–(acetyloxy) acetyl (17) (IC50
= 8.6 uM), and 2–phenylacetyl (18) (IC50 = 12.4 uM) esters showed on a 0.05 level
statistically significantly better activity against the chloroquine sensitive D10 strain of
Plasmodium falciparum than chloroquine itself while the decyl ester (14) (IC50 = 90.2 uM) was
statistically significantly less potent. The activity of the octyl (13) (IC50 = 38.0 uM) and benzyl
(15) (IC50 = 25.7 uM) esters did not differ from that of chloroquine. In comparison to
dihydroartemisinin the propyl (11) (IC50 = 24.1 uM), octyl (13) (IC50 = 38.0 uM), decyl (14)
(IC50 = 90.0 uM), and benzyl (15) (IC50 = 25.7 uM) esters proved to be statistically
significantly less potent than DHA while the activity of the butyl (12) (IC50 = 3.2 uM), 4–
nitrobenzyl (16) (IC50 =15.3 uM), 2–(acetyloxy) acetyl (17) (IC50 = 8.6 uM), and 2–phenylacetyl
(18) (IC50 = 12.4 uM) esters did not differ from that of DHA.<br>Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2012.
14
Banfield, Mark James. "Structural studies of antibody engineering and lactate dehydrogenase from P. falciparum." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389341.
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Heincke, Dorothee [Verfasser]. "Charakterisierung des Inneren Membrankomplexes in P. falciparum (Welch, 1897) / Dorothee Heincke." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1225041872/34.
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Zapata, Monica. "Identification of binding partners of a novel P. falciparum exported protein." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1694.
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Plasmodium falciparum is the causative agent of the most severe form of malaria. This parasite drastically modifies its host cell, the erythrocyte, to create a hospitable environment for its growth and reproduction. In order for these modifications to occur, the parasite secretes proteins into the erythrocyte. While the secretion machinery is still unknown, many secreted proteins have been found to have a hydrophobic signal sequence and a novel host-targeting signal downstream of the hydrophobic sequence. A novel P. falciparum protein has been shown to be secreted from the parasitophorous vacuole, yet it lacks both a hydrophobic signal sequence and a host-targeting signal. It was hypothesized that this protein, Pfl2110c, must interact with other proteins as it migrates into the erythrocyte. Using immunofluorescence assays and co-immunoprecipitation experiments, I found that Pfl2110c interacts with several parasite proteins as well as with the erythrocyte cytoskeleton. Therefore, Pfl2110c was renamed skeleton-binding protein 2 (SBP-2).
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Hammam, Elie. "DNA methylation in P. falciparum : a novel epigenetic target for new antimalarial discoveries." Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS141.
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La méthylation de la cytosine de l’ADN (5mC) est une marque épigénétique très bien établie chez les eucaryotes supérieurs contrôlant l'expression des gènes et jouant un rôle clé dans un large éventail de processus biologiques tels que l'empreinte génomique et l'inactivation du chromosme X. L’hydroxyméthylation de l’ADN (5hmC) a récemment attiré beaucoup d’attention dans le domaine de l’épigénétique et a été validée en tant que marque distincte de 5mC, ayant différentes fonctions et impact sur l’expression des gènes. Chez le parasite humain du paludisme P. falciparum, la présence de méthylation de l’ADN est depuis longtemps sujet à controverse dans la littérature jusqu’à ce qu’on ait récemment démontré que l’ADN 5mC est présent à des niveaux relativement élevés dans le génome du parasite. Au cours de cette thèse, nous avons utilisé des technologies de pointe, notamment l'immunoprécipitation de l'ADN hydroxymétylée couplée au séquençage et le « oxidative-bisulfite/biuslfite-sequencing » (oxBS / BS-seq) pour étudier la présence d'hydroxyméthylation de l'ADN dans le parasite. Nous avons montré pour la première fois que la modification de l’ADN la plus abondante chez P. falciparum n’est pas 5mC mais plutôt une modification de type 5hmC, présente principalement dans le corps des gènes activement transcrits, alors que 5mC est présente à des niveaux très bas. D'autre part, nous avons utilisé l'édition du génome CRISPR-Cas9 pour générer des parasites mutants dépourvus de Pf.DNMT2 et avons montré que l'enzyme n'était pas nécessaire pour l'activité de la DNMT dans les extraits nucléaires de parasites. Cela indique que le parasite code pour d'autres DNMT non identifiés bioinformatiquement. Fait intéressant, le taux d'engagement sexuel des parasites dépourvus de DNMT2 a été multiplié par 8 par rapport aux parasites 3D7 de type sauvage. Nos données indiquent que Pf.DNMT2 est lié au contrôle de l'engagement sexuel chez Plasmodium. Enfin, nous avons criblé des inhibiteurs de l’ADN méthylatransférase humaine dérivés de la famille des quinazolines-quinoléines et avons montré que ces inihibiteurs sont très efficaces et tuent les parasites en moins de 6 heures. De plus, nous avons utilisé des tests d'activité in vitro de DNMT et avons montré que les hDNMTi réduisaient de manière significative l'activité DNMT dans les extraits nucléaires de P. falciparum. Fait intéressant, les inhibiteurs de DNMT sélectionnés étaient également actifs contre les isolats cliniques résistants à l'artémisinine. Dans l’ensemble, nos données valident fortement la voie de la méthylation de l’ADN chez P. falciparum en tant que nouvelle cible thérapeutique potentielle pour de nouvelles découvertes antipaludiques<br>DNA cytosine methylation (5mC) is a very well established epigenetic mark in higher eukaryotes controlling gene expression and playing a key role in a wide range of biological processes such as genomic imprinting and X chromosme inactivation. Recently, DNA hydroxymethylation (5hmC) has gained a lot of attention in the epigenetics field and has been validated as a separate mark from 5mC having different functions and impact on gene expression. In the human protozoan malaria parasite Plasmodium falciparum, the presence of DNA 5mC has long been a subject of controversy in the litterature. During the course of this Ph.D we revisited this topic using state-of-the-art technologies including hydroxymetylated DNA immunoprecipitation coupled to sequencing and oxidative bisulfite/bisulfite sequencing (oxBS/BS-seq) to investigate the presence of DNA cytosine methylation in this human pathogen. We showed for the first time that the most abundant DNA modification in P. falciparum is not 5mC but a novel type of cytosine modification we call here 5hmC-like modification. This modification is enriched in the gene body of actively transcribed genes. In P. falciparum, only one of the three canonical DNA methyltransferase type of genes have been detected. We used CRISPR-Cas9 genome editing to generate mutant parasites lacking the predicted cytosine DNA methyltransferase gene Pf.DNMT2. We show that the enzyme is not essential for parasite proliferation and is not required for DNMT activity in parasite nuclear extracts. This points to the existence of noncanonical DNMTs gene(s) in this pathogen. Importantly, parasites lacking DNMT2 showed an 8-10 fold increase in their sexual commitment rate when compared to wild-type 3D7 parasites. Linking Pf.DNMT2 to the control of malaria sexual commitment is an unprecedented finding. Although DNMT2 has been shown to methylate tRNA in other organism and in P. falciparum, it remains unclear how this function contributes to the activation of gametocyte development. Finally, we show that a new generation of human DNA methyltransferase inhibitors is highly efficient in killing multidrug resistant parasite and significantly reduces DNMT activity in P. falciparum nuclear extracts. Taken together, our data validate the existence of atypical DNA methylation pathways in P. falciparum that can be targeted for the development of novel antimalarial drugs
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Coura, Kelly Dias. "Estudo das subclasses de IgG anti-P. falciparum durante a evolução de malária não complicada." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/5/5160/tde-13102014-102157/.
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O desenvolvimento de imunidade naturalmente adquirida na malária é lento e depende de fatores como o número de malárias prévias, intervalo entre cada malária, exposição a variantes antigênicas múltiplas e idade do indivíduo. Mecanismos imunes efetores dependentes de anticorpos são importantes no desenvolvimento dessa imunidade. Vários estudos têm mostrado que as subclasses IgG1 e IgG3 anti-P. falciparum, conhecidas por sua ação citofílica, são anticorpos protetores, enquanto anticorpos não citofílicos como IgG4 reconhecendo os mesmos epítopos seriam bloqueadores dos mecanismos protetores. Dados recentes sugerem que sob determinadas condições, IgG2 também pode ter ação citoíflica e participar da proteção na malária. Neste trabalho, nós estudamos pela primeira vez, a evolução das subclasses de IgG contra formas eritrocitárias de P. falciparum de pacientes com malária falciparum não complicada internados em hospital por até 42 dias, sob tratamento com mefloquina. As subclasses de IgG foram avaliadas por ELISA em 48 pacientes (7 amostras de soro de cada um colhidas nos tempos 0h, 48h, 7, 14, 28, 35 e 42 dias), quanto à quantidade (concentração, ug/ml; índices de reatividade, IR; ou em freqüência, %) e quanto à avidez dos anticorpos (índice de avidez, IA). Amostras de soro de 14 pacientes (tempos: 0, 48h, 7, 21 e 28 dias) também foram avaliadas quanto à especificidade e a avidez de reconhecimento das diferentes bandas protéicas do antígeno de P. falciparum por Immunoblotting. As subclasses IgG1, IgG2, IgG3 e IgG4 anti-P. falciparum, na maioria de alta avidez, estavam presentes no início do tratamento, respectivamente, em 100%, 39,5%, 80,6% e 28,4% dos pacientes e com concentrações médias de 20, 2; 3,8; 1,5 e 0,05 ?g/mL. As concentrações máximas das subclasses de IgG foram alcançadas no 7o dia, e os IAs máximos de IgG1 e IgG3 foram alcançados no 7o dia, e os de IgG2 no 14o dia e os de IgG4 no 2o dia. A concentração inicial dos anticorpos IgG3 anti-P. falciparum apresentou correlação negativa com o tempo de clareamento parasitário (TCP) e a relação das somas dos anticorpos IgG1, IgG2 e IgG3 pelos níveis de IgG4 se correlacionaram negativamente com a parasitemia inicial. No Immunoblotting, foram identificadas frações protéicas que podem estar relacionadas com o reconhecimento imune protetor, por serem reconhecidas pelas subclasses IgG1, IgG2 e IgG3 e não reconhecidas ou reconhecidas tardiamente por IgG4: 125, 96, 86, 75, 55 e 47 kDa. A resposta predominante das subclasses IgG1, IgG2 e IgG3 observada nestes pacientes, todos com malária não complicada, pode indicar que esses anticorpos estão cooperando para o controle de formas graves da doença e refletirem um certo grau de desenvolvimento de imunidade adquirida<br>The development of naturally acquired immunity to malaria is slow and depends of several factors as number of previous malaria, interval between each malaria attack, exposure to parasite multiple antigen variant and ageassociated maturation of the immune system. Antibody-dependent effector immune mechanisms are believed to be important to the protective immunity. A number of studies have showed that anti-P. falciparum IgG1 and IG3, named cytophilic antibodies, are protective, whereas the noncytophilic, IgG4, that recognize the same epitopes may block the protective mechanisms. Recent data have suggested that in certain situations, IgG2 can also act as cytophilic and to cooperate in protection. In this work, we have studied, for the first time, the evolution of the IgG subclasses against P. falciparum blood stages in uncomplicated falciparum malaria patients taken into hospital upon mefloquine treatment and followed up 42 days. These antibodies were determined by ELISA in 48 patients (7 serum samples from each patient collected in different times: 0h, 48h, 7, 14, 28, 35 and 42 days). The results were expressed in concentration (ug/ml), index of reactivity (IR) or frequency (%) and the avidity were expressed as index of avidity (IA). Serum samples 14 patients (time of collection: 0, 48h, 7, 21 and 42 days) were also evaluated by Immunoblotting as their specificity and avidity against different proteins of the P. falciparum blood stages The subclasses Anti-P. falciparum IgG1, IgG2, IgG3 and IgG4, high avidity predominantly, were present since the beginning of the treatment, respectively, in 100%, 39,5%, 80,6% and 28,4% of the patients with the following concentrations: 20, 2; 3,8; 1,5 and 0,05 ?g/mL. The highest concentrations were reached at day 7, and IgG1 and the highest IgG3 IAs were reached at day 7, and the highest IgG2 IAs at day 14 and the highest IgG4 IAs at day 2. The initial concentration of anti-P. falciparum IgG3 showed a negative correlation with the parasitemia clearance time (PCT) and the ratio between the sum of IgG1, IgG2 and IgG3 levels to IgG4 levels was negatively correlated with the initial parasitemia. Six protein fractions were identified by the Immunoblotting that can be related to protective immune recognition, because they were recognized by IgG1, IgG2 and IgG3 antibodies and not or only later recognized by IgG4 antibodies: 125, 96, 86, 75, 55 and 47 kDa. The predominant IgG1, IgG2 and IgG3 responses observed in these uncomplicated malaria patients may suggest that these antibodies are cooperating to the control of severe disease and reflecting a certain development of protective immunity
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Peyron, François. "Action cyto-inhibitrice des plaquettes humaines sur P. Falciparum cultivé in vitro." Lyon 1, 1989. http://www.theses.fr/1989LYO1H083.
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Cubillos, Eliana Fernanda Galindo. "O papel de dois fatores de transcrição ApiAP2 no controle da transcrição de genes variantes em Plasmodium falciparum." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-17082016-134208/.
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O parasita Plasmodium falciparum causa a forma mais grave da malária humana.Para evadir a resposta imune do hospedeiro, as formas assexuadas do parasita podem usar variação antigênica ou podem se diferenciar em formas sexuais como estratégia para sobreviver e garantir a sua transmissão para o mosquito.A base molecular desses processos ainda é pouco compreendida. Por manipulação genética, nos identificamos a participação de um fator de transcrição da família ApiAP2 ( PF3D7_1143100), no controle da transcrição de genes variantes e no desenvolvimento em formas sexuais na fase intraeritrocítica. Demonstramos ainda que um outro membro desta família, PF3D7_1466400, não é essencial no ciclo assexual de P. falciparum, já que seu silenciamento não afeto o normal desenvolvimento do parasita.<br>The parasite Plasmodium falciparum causes the most severe form of human malaria. To evade the host immune response, asexual parasite forms can employ antigenic variation or differentiation to gametocytes as a means to survive and secure their transmission to the mosquito. The molecular basis behind these processes is still poorly understood. By genetic manipulation, we indentified the participation of a ApiAP2 transcription factor, PF3D7_1143100, in the control of variant gene transcription as well as in the switching from asexual to sexual development in the intraerythrocytic stage. We also demonstrate that the ApiAP2 transcription factor PF3D7_1466400 is not essential in the asexual stage of P. falciparum, since its knockdown did not affect the normal development of the parasite.
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Khosh-Naucke, Melissa [Verfasser]. "Identification of novel parasitophorous vacuole proteins in P. falciparum parasites using BioID : Identifikation neuer Proteine der parasitophoren Vakuole des Malaria Parasiten P. falciparum mittels BioID / Melissa Khosh-Naucke." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2018. http://d-nb.info/1225041848/34.
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Naranjo, Prado Isabel Cristina 1987. "Avaliação ex-vivo dos efeitos antimaláricos da violaceína em isolados amazônicos de Plasmodium vivax e P. falciparum e análise da sua atividade em camundongos infectados com cepas de P. chabaudi resistentes a antimaláricos." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316728.
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Orientadores: Fabio Trindade Maranhão Costa, Stefanie Costa Pinto Lopes<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia<br>Made available in DSpace on 2018-08-24T13:56:29Z (GMT). No. of bitstreams: 1
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Previous issue date: 2014<br>Resumo: A malária é responsável por cerca de 300 milhões de casos de infecção e 1 milhão de mortes por ano. No Brasil, em 2012, foram registrados cerca de 1500 casos sendo a malária vivax responsável por 85% destes. Ainda, é frequentemente reportada falha terapêutica aos antimaláricos convencionais (como cloroquina e mefloquina) em infecções por P. falciparum, principalmente, mas também por P. vivax. Sendo assim, terapias combinadas com artemisinina e seus derivados (ACT) são atualmente recomendadas. No entanto, resistência aos derivados da artemisinina já é evidente e a busca por novos compostos com atividade antimalárica é urgente. A violaceína, pigmento violeta extraído de bactérias Gram negativas, demostrou apresentar elevada atividade antimalárica in vitro e in vivo em trabalho anterior de nosso grupo. Neste sentido, este projeto tem como objetivo aprofundar a investigação a respeito da atividade antimalárica da violaceína avaliando seu papel em isolados amazônicos de P. falciparum adaptados recentemente em cultura, e em P. vivax após imediata coleta de sangue de pacientes infectados. Além disso, investigamos o potencial da violaceína como terapia combinada junto ao artesunato no tratamento de parasitas murinos resistentes a este e a outros antimaláricos como a cloroquina. Inicialmente foram testadas dois diferentes tipos de violaceína in vitro contra P. falciparum 3D7: uma comercial extraída de Janthinobacterium lividum (vJl- IC50: 227 nM) e outra extraída de Chromobacterium violaceum (vCv- IC50: 390 nM). Apesar de não termos encontrado uma diferença na atividade antimalárica entre as duas violaceínas, a extraída de C. violaceum teve uma baixa toxicidade em eritrócitos (<400 nM) em células de hepatoma humano (<800 nM). Devido a esta baixa toxicidade, somente vCv foi avaliada quanto sua atividade antimalárica. Demonstramos que vCv apresentou IC50 similar ao encontrado para P. falciparum 3D7 (IC50 média= 419,8 nM) em 7 isolados de campo de P. falciparum. Ainda, em ensaios in vivo, utilizando cepas murinas de P. chabaudi, vCv conseguiu diminuir significativamente (P<0,05) a parasitemia no dia pico da infeção em cepas resistentes à cloroquina (30CQ) e a artesunato e mefloquina (ATNMF1). Adicionalmente, nos testes realizados em P. vivax a vCv parece evitar o amadurecimento parasitário nos quatro isolados testados. Coletivamente, podemos concluir que a vCv apresentou um efeito antimalárico em cepas de P. falciparum e pode ser especialmente útil quando usada em combinação com artesunato no tratamento de camundongos infectados com cepas resistentes. Finalmente, ensaios adicionais de amadurecimento com isolados de P. vivax necessitam ser conduzidos para a comprovação do efeito da vCv nesta espécie<br>Abstract: Malaria is responsible for about 300 million infections and one million deaths per year. In Brazil in 2012, about 1500 cases were reported and malaria vivax accounts for 85% of these. Still, it is frequently reported treatment failure with conventional antimalarials (as chloroquine and mefloquine) mainly in infections with P. falciparum but also by P. vivax parasite. Because of that combination therapies with artemisinin and its derivatives (ACT) are now currently recommended. In a previous work, our group demonstrated that violacein was able to inhibit the in vitro growth of laboratory strains of P. falciparum and also to strongly control the parasitemia of mice infected with P. chabaudi. This project aims to investigate further the antimalarial activity of violacein evaluating its activity in Amazonian isolates of P. falciparum recently adapted in culture, and in P. vivax isolates immediately after collecting blood from infected patients. Furthermore, we investigate the potential of violacein as combination therapy with artesunate in the treatment of murine strains which are resistant in different levels to artesunate, mefloquine and chloroquine. The antimalarial activity of violacein were initially investigated in vitro against P. falciparum 3D7 using two different types of violacein, one comercial, extracted from Janthinobacterium lividum (vJl-IC50: 227 nM), and another extracted from Chromobacterium violaceum (vCv-IC50: 390 nM) by our collaborators. In spite of no difference in the antimalarial activity between the two violaceins, the one extracted from C. violaceum had the lowest toxicity in erythrocytes (<400 nM) and in human hepatoma cells (<800 nM). Because of this, the antimalarial activity only of vCv was evaluated against 7 field isolates of P. falciparum showing a similar IC50 to that found for P. falciparum 3D7 (IC50= 419.8 nM). The antimalarial activity was also evaluated in murine strains of P. chabaudi showing a significant (P < 0.05) parasitemia decrease in the peak day in the two clones of P. chabaudi tested, one resistant to chloroquine (30CQ) and another resistant to artesunate and mefloquine (ATNMF1). Additionally, in P. vivax vCv was capable to reduce the parasite maturation in the four isolates tested. Therefore we can conclude that the vCv has an antimalarial effect on field isolates of P. falciparum and can be especially useful when used in combination with artesunate in the treatment of mice infected with resistant strains. Moreover, more assays should be conducted using blood infected with P. vivax to corroborate its effect in inhibiting the maturation of trophozoites<br>Mestrado<br>Imunologia<br>Mestra em Genética e Biologia Molecular
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Gershon, P. "Studies with P. falciparum in vitro : The antimalarial properties of antiribosomal antibiotics." Thesis, University of Liverpool, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356275.
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Hilal, Nabeel Hussain. "Defining the proteome of P. falciparum and the influence of antimalarial drug treatment." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421068.
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Nosten, François. "Chimio-resistance de p. Falciparum dans un foyer d'endemie du sud-est asiatique." Paris 6, 1994. http://www.theses.fr/1994PA066661.
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Le paludisme a plasmodium falciparum, la plus importante parasitose humaine, a connu un regain d'intensite depuis dix ans. Le controle de cette maladie se heurte au developpement rapide de la resistance du parasite a tous les antipaludiques disponibles. La situation est preoccupante dans les communautes de refugies vivant le long de la frontiere thailando-birmane. Une structure de recherche a ete installee au cur de ce foyer endemique en 1986. Cette these presente une partie des travaux menes depuis huit ans, dans le but de definir les meilleurs moyens de prevenir et de traiter les infections a p. Falciparum multi-resistant qui representent le principal probleme de sante de ces populations. De par la stabilite et la cooperation de la population et le grand nombre d'observations realisees, ces etudes ont permis d'acquerir de nombreuses informations nouvelles. La plupart concerne la mefloquine, l'un des antipaludiques les plus recents. Ses proprietes pharmacologiques ont pu etre etablies chez l'enfant et la femme enceinte. Son utilite et sa tolerabilite en prophylaxie du paludisme pendant la grossesse ont ete mesurees. L'evolution de la resistance a ce medicament a ete continuellement suivie pour adapter les protocoles de traitement en consequence. Des marqueurs de l'efficacite de la mefloquine ainsi que les facteurs de risque associes a des echecs therapeutiques ont ete identifies. Son association a l'artesunate, un derive du qinghaosu, a permis de prolonger le role de la mefloquine dans le traitement de premiere intention des acces non compliques a p. Falciparum. Par contre l'halofantrine, autre antipaludique recent ne represente pas une alternative viable dans cette region du monde du fait des resistances croisees avec la mefloquine et de sa toxicite cardiaque. La lutte contre le paludisme a p. Falciparum passe par la connaissance de sa micro-epidemiologie, de l'entomologie, ainsi que par l'evaluation prospective des interventions de prevention et de traitement
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Jurzynski, Christophe. "Cytoadhérence de P. Falciparum : nouveaux facteurs de virulence et modifications des cellules endothéliales." Aix-Marseille 2, 2008. http://www.theses.fr/2008AIX20657.
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Les mécanismes de la pathogenèse des formes graves du paludisme restent à ce jour largement incompris. Il est cependant généralement admis que la séquestration des érythrocytes infectés par Plasmodium falciparum (EI) dans la microvascularisation de certains organes, est l'élément déclencheur de pathologies telles que le neuropaludisme, l'oedème pulmonaire, ou le paludisme de la femme enceinte. L'étude de cette séquestration s'est essentiellement focalisée sur l'identification des ligands parasitaires et des récepteurs endothéliaux, qui permettent la cytoadhérence des EI aux cellules endothéliales microvasculaires, avec l'idée que chaque forme grave du paludisme serait due à la présence d'un phénotype de cytoadhérence particulier. Malgré les nombreux récepteurs endothéliaux identifiés, cette hypothèse ne s'est vue confirmée que dans le cas du paludisme de la femme enceinte, lié à la présence d'EI cytoadhérant via la chondroitine-4-sulfate présente à la surface des syncytiotrophoblastes. L'une des hypothèses qui permet d'expliquer ce peu de succès est que les phénotypes parasitaires de cytoadhérence impliqués dans les autres formes graves du paludisme n'ont pas encore été identifiés. Il est également possible que d'autres mécanismes résultant de la cytoadhérence soient en jeu, tels que l'induction d'apoptose, la perméabilisation de la barrière hématoencéphalique ou la modification des cellules endothéliales. Mon travail de thèse s'est focalisé sur ces deux axes, en utilisant comme bases des observations précédemment réalisées au laboratoire, qui montraient d'une part l'existence d'une cytoadhérence des EI sur les cellules CHO745, qui n'expriment aucun récepteur connu de la cytoadhérence, et d'autre part un phénomène de régulation de la cytoadhérence de certains EI. J'ai participé à la mise en évidence d'un nouveau phénotype de cytoadhérence, utilisant la molécule NCAM (neural cell adhesion molecule), sous sa forme faiblement polysialilée, comme récepteur de cytoadhérence. J'ai également démontré l'existence d'un deuxième nouveau phénotype, dont le récepteur de cytoadhérence pourrait être le NCAM sous sa forme hautement polysialilée, déduction qui reste à démontrer. Les parasites de ces deux nouveaux phénotypes sont capables d'interagir avec plusieurs récepteurs, caractéristique ayant précédemment été associée à la gravité de l'infection palustre. La caractérisation de la cytoadérence de ces deux phénotypes en conditions de flux m'a permis de mettre en évidence l'existence d'une nouvelle forme de cytoadhérence, optimale pour l'obstruction des microvaisseaux, que nous avons appelée macroagrégats cytoadhérents. J’ai pu montrer que des parasites d’un phénotype de cytoadhérence minoritaire (CSA) pouvait induire la mise en place de signaux via le CD44, les Src-kinases et les MAP kinases, qui aboutissaient à l’inhibition de la cytoadhérence de parasites d’un phénotype de cytoadhérence majoritaire (CD36). Cette inhibition, qui pourrait passer par un remaniement de la répartition du CD36 à la surface des cellules, pourrait être considérée comme un facteur de virulence puisqu’elle favorise la cytoadhérence d'EI d’un phénotype minoritaire plus apte à induire l'obstruction des microvaisseaux et à créer des conditions favorables à la séquestration d'EI de phénotypes moins performants. Ces travaux ouvrent un certain nombre de pistes pour mieux comprendre la pathogenèse des formes graves, ainsi que pour développer des moyens de contrôle de la cytoadhérence et donc de la parasitémie.
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Zakiuddin, Ilmasse. "Réponses immunitaires humorales et cellulaires dans l'acquisition de la protection contre P. Falciparum." Grenoble 1, 1991. http://www.theses.fr/1991GRE10113.
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Une étude pluridisciplinaire intégrée a été réalisée pour définir un moyen efficace capable d'estimer le niveau de prémunition contre p. Falciparum, acquis par des personnes vivant au Burkina-Faso. Elle a consisté à suivre ces sujets pendant toute une période de transmission palustre, au niveau clinique, parasitologique et immunologique, l'intensité de la transmission a été aussi appréciée en parallèle. Dans une étude préliminaire, nous avons évalué la réactivité des lymphocytes de sujets ayant différents statuts immunitaires anti-palustres, en présence d'antigènes de schizontes soniques (ag som) et d'antigènes solubles semi-purifiés relargues dans le milieu de culture (ag spe). La prolifération in vitro, des lymphocytes de personnes plus ou moins prémunies, vivant en zone d'endémie, est peu fréquenté et peu élevée, comparée aux européens pourtant primo-infestes. Cependant, leurs taux d'anticorps spécifiques sont significativement plus élevés que celui des sujets récemment sensibilisés. La déplétion de cellules t cd8#+ ne permet pas de restaurer ces faibles réponses. D'autre part, nous avons noté une importante variation de réponses inter-lots antigéniques et inter-souches. Devant la complexité de ces résultats, nous avons choisi d'effectuer le suivi longitudinal cellulaire en utilisant des antigènes mieux définis (ag recombinants et peptides synthétiques) provenant des stades érythrocytaires (ag resa, ag glurp) et sporozoitaire (ag csp). Trois groupes ont pu être constitués grâce au suivi clinique : enfants non prémunis (ap#+), enfants en voie de prémunition (ap#) et adultes prémunis. En général, les lymphocytes des enfants ap#+ prolifèrent plus fréquemment et plus intensément. Ces réponses peuvent varier en fonction de l'origine ethnique des sujets. Parallèlement, les taux de divers anticorps spécifiques, de l'il-2r soluble, de la b2m et du tnf ont été mesurés dans le plasma. Une corrélation des divers paramètres étudiés a été réalisée afin de mieux comprendre l'intrication des réponses immunitaires dans l'acquisition lente de la protection dans le paludisme
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Gaudart, Jean. "Analyse spatio-temporelle et modélisation des épidémies : application au paludisme à P. falciparum." Aix-Marseille 2, 2007. http://www.theses.fr/2007AIX20692.
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Introduction : l'étude de la distribution spatiotemporelle du paludisme permet l'élaboration de carte de risque. A l'instar de Ross, nous proposons une approche statistique et une modélisation déterministe. Analyse spatiale et spatiotemporelle : parmi les méthodes décrivant l'hétérogénéité spatiale, nous développons une méthode par arbre de régression oblique (SpODT) découpant la région en zones de risques différents. Cinq méthodes générales de détection de clusters sont comparées et appliquées à la description du risque à Bancoumana, Mali. La recherche de clusters spatiotemporels met en évidence les variations saisonnières et spatiales du risque palustre. Modélisation déterministe : nous proposons un modèle adapté à Bancoumana tenant compte de la pluviométrie simulée par 4 méthodes (distribution empirique, chaîne de Markov cachées, nonlinéaire, nonparamétrique). Un modèle de réaction-diffusion modélise la progression des anophèles à partir de leurs gîtes et l'évolution spatiotemporelle du risque.
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Van, Brummelen Anna Catharina. "Functional genomics analysis of the effects of co-inhibition of the malarial S-adenosylmethionine decarboxylase/ornithine decarboxylase." Thesis, University of Pretoria, 2008. http://hdl.handle.net/2263/25135.
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Polyamines are ubiquitous components of all living cells and their depletion usually causes growth arrest or cytostasis, a strategy employed for treatment of West-African trypanosomiasis. In the malaria parasite, Plasmodium falciparum, polyamine biosynthesis is regulated by the uniquely bifunctional protein, Sadenosylmethionine decarboxylase/ornithine decarboxylase (PfAdoMetDC/ODC). The unique nature of this protein could provide a selective mechanism for antimalarial treatment. To validate polyamine depletion and specifically PfAdoMetDC/ODC, as drug target for antimalarial therapeutic intervention, polyamine biosynthesis was completely restrained via the inhibition of both catalytic sites of PfAdoMetDC/ODC with DFMO and MDL73811. The physiological effects during the resulting cytostasis were studied with a comprehensive functional genomics approach. The study was preceded by various assays to determine the treatment dosage that would result in complete cytostasis, without non-specific chemical cytotoxicity. The results obtained revealed that the cytostatic mechanism with growth arrest of the treated parasites and normal progression of the untreated controls require special consideration for basic comparisons of response in terms of the assay methodology used and data analysis. This is particularly important when studying a multistage organism such as P. falciparum, which constantly develops and change during the intraerythrocytic developmental cycle, such that growth arrest compared to normal progression would result in significant differences merely due to stage. This critical principle was kept in mind throughout the investigation and was applied to the relative quantification of RNA, proteins and metabolites via a relative time zero approach as opposed to the standard parallel time point comparison. Three independent functional genomics investigations, namely transcriptomics, proteomics and metabolomics were conducted, in which highly synchronised 3D7 parasite cultures were treated during the schizont stage and parasites were sampled during a time course at three time points (just before and during cytostasis). Transcriptome analysis revealed the occurrence of a generalised transcriptional arrest just prior to the growth arrest. To our knowledge this is the first time that transcriptional arrest as the preceding mechanism of cytostasis due to polyamine depletion, was demonstrated. However, despite the transcriptional arrest, the abundance of 538 transcripts was differentially affected and included three perturbation-specific compensatory transcriptional responses: the increased abundance of the transcripts for lysine decarboxylase and ornithine aminotransferase (OAT) and the decreased abundance of that for S-adenosylmethionine synthetase (AdoMet synthetase). Pearson correlations indicated more subtle effects of the perturbation on the proteome and even more so on the metabolome where homeostasis was generally maintained, except downstream to the enzymatic blockade at PfAdoMetDC/ODC. The perturbation-specific compensatory roles of OAT in the regulation of ornithine and AdoMet synthetase in the regulation of AdoMet were confirmed on both the protein and metabolite levels, confirming their biological relevance. The results provide evidence that P. falciparum respond to alleviate the detrimental effects of polyamine depletion via the regulation of its transcriptome and subsequently the proteome and metabolome, which supports a role for transcriptional control in the regulation of polyamine and methionine metabolism within the parasite. The study concludes that polyamines are essential molecules for parasite survival and that PfAdoMetDC/ODC is a valid target for antimalarial drug development.<br>Thesis (PhD)--University of Pretoria, 2008.<br>Biochemistry<br>unrestricted
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Villa, Manon. "Impact de l’utilisation des médicaments antipaludiques sur la transmission de Plasmodium sp." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTG042.
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Le paludisme a encore aujourd’hui une incidence importante dans les populations humaines, notamment en Afrique sub-saharienne, malgré le développement de médicaments antipaludiques. Ces derniers diminuent la mortalité et la morbidité liée à la maladie et peuvent impacter la transmission des parasites dans l’humain ou dans le vecteur. Les études sur les effets des médicaments antipaludiques sur la transmission du paludisme se sont pour le moment concentrées sur l’homme. Dans cette thèse, nous nous intéressons aux effets de deux antipaludiques majeurs, l’artésunate (AS) et la sulfadoxine-pyriméthamine (SP), sur la transmission du paludisme non seulement dans l’hôte vertébré mais aussi dans le vecteur. Grâce à un modèle de laboratoire, la malaria aviaire (Plasmodium relictum), nous avons montré que la SP diminue fortement la charge et la prévalence en sporozoïtes de moustiques infectés nourris sur des oiseaux traités et nous sommes en train d’étudier le lien avec le microbiome et le transcriptome dans le tube digestif du moustique. Ce médicament influence la transmission du paludisme en agissant directement sur les parasites dans le vecteur et de ce fait peut exercer une pression de sélection non seulement dans les humains traités (comme c'est largement accepté) mais aussi dans les vecteurs prenant un repas sanguin traité. Nous n’avons pas observé d’effet d’AS dans le vecteur. Par contre, lors d’une expérience au laboratoire utilisant des lignées de P. relictum sélectionnées pour être résistants à l'AS, nous avons observé que les coûts biologiques associés à la résistance à l’AS s’expriment dans le vecteur (diminution de l’intensité d’infection) mais pas dans le vertébré non traité. De plus, nous avons comparé la prévalence d’allèles de résistance sur les gènes pfcrt, dhfr et pfmdr de Plasmodium falciparum entre les hommes et les vecteurs dans 4 sites d’Afrique de l’Ouest. Nous avons mis en évidence une différence de prévalence d’allèles de résistance entre les hommes et les vecteurs, et même entre espèces vectrices. Ces différences peuvent représenter des coûts associés à la résistance ou mettre en lumière le rôle de sentinelle de la résistance des vecteurs pour des allèles de résistance en faible prévalence dans l’homme. Le vecteur est donc un maillon important dans l’étude de l’émergence et la propagation des allèles de résistance aux médicaments et de l’impact des antipaludiques sur la transmission du paludisme<br>Malaria incidence still is high especially in sub-Saharan Africa. Antimalarial drugs reduce the disease mortality and morbidity but could also impact the parasite's transmission. Current knowledge about the impact of drugs on malaria transmission come mainly from studies quantifying the transmissible blood stages of the parasite (gametocytes) in the vertebrate host. Our knowledge of how these drugs may impact the vector stages of the parasite is still very limited. In this thesis, I investigated the effects of two main antimalarial drugs, artesunate (AS) and sulfadoxine-pyrimethamine (SP), on parasite transmission through a series of laboratory experiments and field studies.Our laboratory experiments (with the avian malaria parasite, Plasmodium relictum) showed that SP decreases drastically sporozoite prevalence and burden and in infected vectors fed on SP-treated birds. We are currently studying the mechanistic underpinnings of these results by exploring the effect of the drug on the mosquito gut microbiome and transcriptome. Our results suggest that SP could exert a selection pressure not only in treated humans (as has been widely reported) but also in the vector feeding on treated humans. Our experiments didn’t show such an effect in mosquitoes fed on an AS-treated bloodmeal. In a separate experiment, where we selected for AS resistance in P. relictum, we were able to establish the existence of fitness costs linked to AS-resistance in the vector (lower intensity of infection) but not in the untreated vertebrate host.We have also compared the prevalence of 3 key drug resistance alleles (in the pfcrt, dhfr and pfmdr loci) between humans and vectors infected with the human malaria parasite Plasmodium falciparum across 4 different sites in West Africa. We show allele-dependent differences in prevalence both between humans and vectors, and between vector species. These differences may not only be indicative of the of costs of drug resistance being different for vectors and humans but also highlight the potential role of the vectors as sentinels for the detection of drug resistant mutations that are rare in humans. In sum, our results show the importance of investigating the effect of drugs on the vector stages of Plasmodium parasites for understanding the emergence and spread of drug resistance mutations on malaria transmission
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Kyriacou, Helen M. "Var gene transcription and clinical disease manifestation in African P. falciparum malaria field isolates." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/2583.
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The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variant surface antigens, encoded by the var gene family, play a crucial role in malaria pathogenesis through mediating immunomodulation and host cell adhesion. Var genes can be sub-grouped according to genetic or functional features. This thesis examined var gene transcription of conserved groups of var genes in the context of clinical malaria disease manifestation in African field isolates. Analysis of var gene transcription in 26 P. falciparum field isolates from Malian children revealed that field isolates from children with cerebral malaria show significantly higher transcription of group A var genes than the field isolates from children with equally high parasite burdens but no symptoms or signs of severe malaria (hyperparasitaemia). These results suggest that group A var genes are important determinants of parasite virulence and strengthen the growing body of evidence associating group A var expression with severe disease in children. Analysis of var gene transcription in six P. falciparum placental malaria field isolates showed that var2csa was transcribed in all placental malaria field isolates, but not in 10 childhood isolates examined. This finding, also reported in other recent and subsequent studies, suggests that var2csa expression is a critical factor in the onset of clinical malaria disease in pregnant women. Examination of type 3 var gene transcription in laboratory and field isolates established that these var genes were commonly transcribed in blood-stage parasites, and sequence analysis of the transcribed domains confirmed a very high level of conservation across this var gene sub-family. Finally, rosetting is a property of some group A PfEMP1 and is associated with disease severity in African childhood malaria. Certain glycoconjugate compounds can disrupt rosetting, possibly due to the functional similarities of interactions between rosetting PfEMP1 and host rosetting ligands. A non-toxic compound (curdlan sulfate) was found to be effective at disrupting rosettes in all 18 rosetting field isolates examined, showing potential for use in treatment of severe malaria due to rosetting P. falciparum isolates. The findings presented in this thesis expand current knowledge of the role and significance of var genes/PfEMP1 in P. falciparum malaria disease pathogenesis. The work demonstrates the importance of continued research on var genes/PfEMP1 in further understanding this complex parasite, and ultimately in combating this severe disease.
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DeConti, Derrick K. "Systematic Analysis of Duplications and Deletions in the Malaria Parasite P. falciparum: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/869.
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Duplications and deletions are a major source of genomic variation. Duplications, specifically, have a significant impact on gene genesis and dosage, and the malaria parasite P. falciparum has developed resistance to a growing number of anti-malarial drugs via gene duplication. It also contains highly duplicated families of antigenically variable allelic genes. While specific genes and families have been studied, a comprehensive analysis of duplications and deletions within the reference genome and population has not been performed. We analyzed the extent of segmental duplications (SD) in the reference genome for P. falciparum, primarily by a whole genome self alignment. We discovered that while 5% of the genome identified as SD, the distribution within the genome was partition clustered, with the vast majority localized to the subtelomeres. Within the SDs, we found an overrepresentation of genes encoding antigenically diverse proteins exposed to the extracellular membrane, specifically the var, rifin, and stevor gene families. To examine variation of duplications and deletions within the parasite populations, we designed a novel computational methodology to identify copy number variants (CNVs) from high throughput sequencing, using a read depth based approach refined with discordant read pairs. After validating the program against in vitro lab cultures, we analyzed isolates from Senegal for initial tests into clinical isolates. We then expanded our search to a global sample of 610 strains from Africa and South East Asia, identifying 68 CNV regions. Geographically, genic CNV were found on average in less than 10% of the population, indicating that CNV are rare. However, CNVs at high frequency were almost exclusively duplications associated with known drug resistant CNVs. We also identified the novel biallelic duplication of the crt gene – containing both the chloroquine resistant and sensitive allele. The synthesis of our SD and CNV analysis indicates a CNV conservative P. falciparum genome except where drug and human immune pressure select for gene duplication.
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DeConti, Derrick K. "Systematic Analysis of Duplications and Deletions in the Malaria Parasite P. falciparum: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/869.
Full textAbstract:
Duplications and deletions are a major source of genomic variation. Duplications, specifically, have a significant impact on gene genesis and dosage, and the malaria parasite P. falciparum has developed resistance to a growing number of anti-malarial drugs via gene duplication. It also contains highly duplicated families of antigenically variable allelic genes. While specific genes and families have been studied, a comprehensive analysis of duplications and deletions within the reference genome and population has not been performed. We analyzed the extent of segmental duplications (SD) in the reference genome for P. falciparum, primarily by a whole genome self alignment. We discovered that while 5% of the genome identified as SD, the distribution within the genome was partition clustered, with the vast majority localized to the subtelomeres. Within the SDs, we found an overrepresentation of genes encoding antigenically diverse proteins exposed to the extracellular membrane, specifically the var, rifin, and stevor gene families. To examine variation of duplications and deletions within the parasite populations, we designed a novel computational methodology to identify copy number variants (CNVs) from high throughput sequencing, using a read depth based approach refined with discordant read pairs. After validating the program against in vitro lab cultures, we analyzed isolates from Senegal for initial tests into clinical isolates. We then expanded our search to a global sample of 610 strains from Africa and South East Asia, identifying 68 CNV regions. Geographically, genic CNV were found on average in less than 10% of the population, indicating that CNV are rare. However, CNVs at high frequency were almost exclusively duplications associated with known drug resistant CNVs. We also identified the novel biallelic duplication of the crt gene – containing both the chloroquine resistant and sensitive allele. The synthesis of our SD and CNV analysis indicates a CNV conservative P. falciparum genome except where drug and human immune pressure select for gene duplication.
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Farouk, Salah Eldin. "T cell and antibody responses in Plasmodium falciparum malaria and their relation to disease susceptibility." Doctoral thesis, Stockholm : Wenner-Grens institut för experimentell biologi, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-320.
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Hari, Har Joshi Srisin Khusmith. "Monoclonal antibody based ELISA for the detection of P. falciparum and P. vivax antigens in Malaria endemic populations in southern Nepal /." Abstract, 2003. http://mulinet3.li.mahidol.ac.th/thesis/2546/46E-Hari-J.pdf.
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Travaillé-Aubert, Christelle. "Paludisme en zone d'hyperendémie : apport de la réponse cytokinique et transcriptomique." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5022/document.
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Parmi les manifestations cliniques du paludisme où P. falciparum est le principal responsable des formes graves, les manifestations pulmonaires sont souvent sous-estimées. Malgré de nombreuses études tentant de mieux comprendre les mécanismes inflammatoires mis en jeu dans l'aggravation de la maladie, des zones d'ombres persistent. Pour étudier les interactions hôte-parasite et identifier des biomarqueurs de classification et d'évolutivité de l'accès palustre, nous avons effectué une étude de cohorte longitudinale prospective à l'Hôpital Monkole de Kinshasa, par une approche combinée immunologique et transcriptomique sur 30 jours. L'étude devant porter initialement sur les atteintes pulmonaires a été recentrée sur l'étude de la sévérité de l'accès palustre devant le peu de patients présentant des atteintes pulmonaires.A travers l'approche immunologique, une réponse pro-inflammatoire de type Th1 modérée est activée à l'admission des patients impaludés. L'approche transcriptomique a permis de le relier à une activation modérée des monocytes/macrophages médiée par la voie de signalisation de l'IL-12, toutefois plus importante chez les accès graves. L'infection palustre, et plus particulièrement l'accès grave paraissent être fortement sous dépendance de la réponse Th17 et plus particulièrement à l'activité des neutrophiles. La mise en place d'une réponse Th2 est également observée chez les patients impaludés. A J7, la réponse Th2 est majoritaire, associée à une importante activité hématopoïétique. A J30, les patients sont guéris et présentent globalement un profil similaire aux témoins.Ces résultats sont à confirmer et à approfondir par une augmentation de notre cohorte<br>Among complications of the malaria access, mostly due to P. falciparum, the pulmonary injuries are often underestimated. Despite numerous studies trying to better understand the inflammatory mechanisms involved in disease worsening, they are still poorly understood. In view to study the host-parasite interactions and identify biomarkers according to severity of malaria, a prospective longitudinal cohort study was carried out in Monkole Hospital (Kinshasa) through a combined immunological and transcriptomic approach, with a follow up on 30 days. Initially, the study concerned the pulmonary injuries, but was focused on the the severity of malaria because of a weak patients number with lung damages.The immunological approach highlighted a moderate Th1 pro-inflammatory response at admission. The transcriptomic approach allowed to connect it with a moderate activation of monocytes/macrophages, mediated by IL-12 signaling pathway, higher in severe malaria. Malaria infection, particularly severe malaria, appears to be strongly dependent on Th17 response, especially to neutrophil activity. The establishment of a Th2 response is also observed in malaria patients. On day 7, Th2 response is predominant, associated with significant hematopoietic activity. On day 30, patients are cured and present a similar profile to healthy controls.These results have to be confirmed with an increased cohort
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Pedro, Liliana Antunes. "Natural Product and Fragment-Based Drug Discovery Against Malaria Protein Targets by Native Mass Spectrometry." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/367370.
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Malaria control interventions have been effective in reducing malaria incidence and mortality rates globally over the last decade. However, increasing resistance of Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax), the two most prevalent parasite species, to the most used antimalarial drugs, threatens to halt the progress. Given the current limited arsenal of antimalarial drugs has been inspired by natural product scaffolds, these have the potential to be the source of new and structurally different antimalarial drugs, acting through novel mechanisms of action, that are urgently needed. Translating the structural and biologically relevant diversity of natural products into an efficient and effective drug development process is, nonetheless, not trivial. Fragment-based drug discovery (FBDD) is a relatively recent and promising approach for drug discovery. It involves the identification of small molecular weight compounds, called fragments, that weakly bind to a biological target and their elaboration through chemical synthesis to produce high affinity and selective drugs. For a rational and effective elaboration process, structural and thermodynamic information are essential.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Natural Sciences<br>Science, Environment, Engineering and Technology<br>Full Text
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Pereira, Lucas Borges. "Caracterização da apirase do parasita P. falciparum e análise do papel do Ca2+ no egresso de T. gondii." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-17082016-151526/.
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Plasmodium falciparum e Toxoplasma gondii são protozoários parasitas pertencentes ao filo Apicomplexa. Apirases são enzimas metabolizadoras de nucleotídeos extracelulares. Nesta tese mostramos pela primeira vez a presença de um membro desta família de enzimas em P. falciparum, o qual foi capaz de degradar ATP extracelular. Análises por RT-qPCR revelaram a expressão da apirase durante todo o ciclo intraeritrocítico. A adição de inibidores desta classe de enzimas foi capaz de prejudicar o desenvolvimento dos parasitas e a invasão de novas hemácias pelos merozoitos, sugerindo assim um papel da apirase nestes processos. A via de sinalização por Ca2+ é universal e vital para todas as células. Para melhor entender a fisiologia celular de P. falciparum construímos uma nova linhagem de parasitas transgênicos, PfGCaMP3, que nos tornam capazes de monitorar a dinâmica de Ca2+ sem o uso de protocolos invasivos de marcação. De modo semelhante utilizamos uma nova linhagem de T. gondii expressando de forma estável o indicador de Ca2+ GCaMP3 para estudar o papel deste íon na saída da célula. T. gondii possui o Ca2+ necessário para promover este processo, entretanto Ca2+ extracelular age como um fator intensificador neste passo essencial do ciclo lítico.<br>Plasmodium falciparum and Toxoplasma gondii are protozoan parasites that belong to phylum Apicomplexa. Apirases are metabolizing enzymes of extracellular nucleotides. In this work we show for the first time the presence of an apyrase in P. falciparum, which was able to degrade extracellular ATP. RTqPCR analysis revealed the expression of apyrase throughout the intraerythrocytic cycle. Addition of apyrase inhibitors was able to impair the development of the parasites and the invasion of new erythrocytes by merozoites, thus suggesting a role of apyrase in these processes. Calcium signaling is universal and vital to all cells. To better understand the cellular physiology of P. falciparum we construct a new strain of transgenic parasites, PfGCaMP3, which enable us to monitor the Ca2+ dynamics without using invasive protocols. Similarly we use a new strain of T. gondii that stably express the Ca2+ indicator GCaMP3 to study the role Ca2+ in parasite egress. T. gondii has the Ca2+ required to promote this process, however extracellular Ca2+ acts as an enhancer factor in this crucial step of the lytic cycle.
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Wohlk, Bruna Lovizutto Protti. "Expressão heteróloga, purificação e caracterização da proteína hipoxantina guanina fosforribosiltransferase de Plasmodium falciparum." Universidade Federal do Amazonas, 2012. http://tede.ufam.edu.br/handle/tede/2247.
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Previous issue date: 2012-03-27<br>Coordenação de Aperfeiçoamento de Pessoal de Nível Superior<br>A malária continua a ser a maior causa de morbidade e mortalidade mundial com até três milhões de mortes anuais. O tratamento da malária, causada por Plasmodium. falciparum, dependeu por décadas do uso da aminoquinolina cloroquina. Contudo a resistência à cloroquina em uma escala global expôs a capacidade com que o parasita pode desenvolver resistência a drogas. É, portanto, necessário o desenvolvimento de estudos que assegurem que drogas mais eficazes sejam descobertas de forma sustentável e que novos alvos moleculares para agentes antimalária sejam revelados. Através de análises de biologia celular e molecular foi possível sequenciar o genoma de P. falciparum e identificou-se novos alvos alvos terapêuticos antimalária. A proteína alvo estudada neste projeto foi a Hipoxantina guanina fosforribosiltransferase do P. falciparum, que está relacionada com a via de recuperação das purinas .O gene da enzima foi identificado no genoma do P. falciparum, e produzido por síntese química com códons preferenciais de Escherichia coli, clonado em um forte promotor de expressão para esta bactéria, expresso e a proteína recombinante purificada mostrou-se ativa. A enzima será utilizada futuramente em estudos de binding e inibição com novos compostos químicos e/ou componentes de extratos de microrganismos e plantas amazônicas
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Przyborski, Jude Marek. "Analysis of protein trafficking signals of a member of the P. falciparum stevor multi-gene family." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404839.
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DUARTE, Patrícia Alexandra Oliveira. "Estudo da presença de polimorfismos associados à resistência de P. falciparum aos ACTs em Timor Leste." Master's thesis, Instituto de Higiene e Medicina Tropical, 2019. http://hdl.handle.net/10362/75617.
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Em 2016 a malária foi considerada endémica em 91 países e apesar do decréscimo, estima-se que em 2017 terão ocorrido cerca de 219 milhões de novos casos de malária a nível mundial. Face à propagação da resistência do Plasmodium falciparum à maioria dos antimaláricos disponíveis, a Organização Mundial de Saúde (OMS) recomenda a utilização de terapêuticas combinadas à base de artemisinina (ACT) como tratamento da malária não complicada. Em Timor-Leste os ACTs foram implementados em 2007, sendo o artemeter-lumefantrina (AL) usado como tratamento de primeira linha da malária desde então. A resistência à artemisinina e seus derivados foi confirmada no Sudeste Asiático, por isso o risco de aparecimento e propagação de resistência à artemisinina e seus derivados tem levado a esforços no sentido de serem realizados estudos de resistência em todas as regiões endémicas para a malária. Assim sendo estudos contínuos através do uso de marcadores moleculares que permitam a determinação de resistência aos antimaláricos são muito importantes de forma a detetar precocemente o aparecimento e evitar o alastramento de parasitas P. falciparum resistentes/tolerantes aos ACTs.
Neste estudo pretendeu-se optimizar a técnica de Polymerase Chain Reaction (PCR) e desenhar novos primers para detecção de polimorfismos pontuais nos genes pfmdr2 e pfarps10 bem como determinar a frequência de polimorfismos, nos genes pfk13, pfmdr1, pfmdr2 e pfarps10, associados à resposta aos ACTs em isolados de P. falciparum provenientes de Timor-Leste. As amostras utilizadas foram recolhidas entre 2012 e 2013, correspondendo a um período depois da introdução dos ACTs em Timor-Leste. Os polimorfismos nos codões 86, 184 e 1246 do gene pfmdr1, no gene pfmdr2 os codões 423, 484, 492 e por último no gene pfarps10 o codão 127 foram analisados através de amplificação de DNA pela técnica de PCR e sequenciação.
Em relação ao gene pfmdr1 verificou-se uma prevalência do alelo selvagem (wild-type) N86 (85%), assim como nos alelos F184 (54,2%) e D1246 (100%). Em relação ao gene pfmdr2 para os codões 484 e 492 mantém-se esta tendência (T484 81,8%; I492 90,9%), já no codão 423 o alelo mais prevalente é 423Y, mutante (81,8%). Por último, no gene pfarps10 apenas se verificou a presença do alelo selvagem (V127 100%).
Assim sendo é extremamente importante manter uma vigilância molecular sobre o país uma vez que este se encontra numa fase de pré-eliminação da doença.<br>In 2016 malaria was considered endemic in 91 countries and despite this decrease, uptdated estimates indicate that 219 million malaria new cases occurred globally in 2017. In view of the spread of Plasmodium falciparum resistance to most available antimalarials, the World Health Organization (WHO) recommends the use of combination artemisinin-based therapy (ACT) as a treatment for uncomplicated malaria. In East-Timor, ACTs were implemented in 2007, with artemether-lumefantrine (AL) being used as first-line malaria treatment ever since. Resistance to artemisinin and its derivatives has been confirmed in Southeast Asia, so the risk of emerge and spread of resistance to artemisinin and its derivatives has led to efforts to carry out resistance studies in all endemic regions to malaria. Thus, continuous studies through the use of molecular markers that allow the determination of resistance to antimalarials are very important in to monitor the emergence and avoid the spread of parasites P. falciparum resistant/tolerant to ACTs. The aim of this study was to optimize the Polymerase Chain Reaction (PCR) technique and to design new primers to detect point polymorphisms in the pfmdr2 and pfarps10 genes as well as to determine the frequency of polymorphisms in the pfk13, pfmdr1, pfmdr2 and pfarps10 genes associated with the response to ACTs in P. falciparum isolates from Timor-Leste. The samples used were collected between 2012 and 2013, corresponding to a period after the introduction of ACTs in East-Timor. Polymorphisms at codons 86, 184 and 1246 of the pfmdr1 gene, in the pfmdr2 gene codons 423, 484, 492 and lastly in the pfarps10 codon 127 gene were analyzed by amplification of DNA using a PCR method and sequencing. In relation to the pfmdr1 gene, a prevalence of the wild-type N86 (85%) was observed, as well as in the F184 (54.2%) and D1246 (100%) alleles. In relation to the pfmdr2 gene at codons 484 and 492, this trend remains (T484 81.8%, I492 90.9%), at codon 423 the most prevalent allele is 423Y, mutant (81.8%). Finally, was only found the presence of the wild allele (V127 100%) in the pfarps10 gene. Therefore, it is extremely important to maintain a molecular surveillance of the country once it is in a phase of pre-elimination of the disease.
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Lekana-Douki, Jean-Bernard. "Paludisme grave : protéines de surface de l'hématie parasitée par P. Falciparum impliquées dans la séquestration parasitaire." Paris 12, 2002. http://www.theses.fr/2002PA120035.
Full textAbstract:
Les formes graves du paludisme sont associées à la séquestration parasitaire. Les protéines de surface des hématies parasitées (HP) sont à la fois les ligands de cette séquestration et les cibles de la réponse immunitaire. Elles représentent donc des candidats potentiels pour le développement d'une stratégie antipaludique. La cytoadhérence placentaire des HP matures est régie par l'interaction du DBLy3 de PfEMP1 avec la CSA alors que RSP2 est le ligand des formes jeunes. La production d'anticorps conformationnels contre les antigènes mineurs représente un obstacle majeur. Pour outrepasser cela, nous avons développé la technique d'immunisation des souris précédemment rendues tolérantes. Ainsi, nous avons produit des anticorps monoclonaux qui reconnaissent des conformations natives du DBLy3 (CSA) et RSP2. Après l'expression de DBLy3 (CSA) fonctionnelle dans le système d'expression des cellules d'insectes, nous avons produit des anticorps anti_DBLy3 (CSA) inhibant la cytoadhérence chez le singe et la souris. Ces anticorps nous ont permis de montrer que le DBL contient des épitopes conservés malgré sa diversité des séquences primaires. Les anticorps anti-RSP2 inhibent la cytoadhérence des formes jeunes des HP (CSA) et l'invasion des mérozoi͏̈tes. Ces anticorps nous ont permis de montrer que l'expression de RSP2 commence au stade trophozoi͏̈te, et qu'elle est accumulée dans les rhoptries avant d'être transportée à la surface du mérozoi͏̈te. RSP2 est transférée à la surface de l'hématie lorsque le mérozoi͏̈te s'y attache, sans que l'invasion ne soit nécessaire. Réunis, ces résultats promeuvent l'élaboration d'une stratégie thérapeutique anti- séquestration contre le paludisme gestationnel, et plus généralement contre la cytoadhérence des HP (CSA)<br>Sequestration of Plasinodium falciparum-infected erythrocytes is associated with severe malaria. Plasmodium falc parasites express variant adhesion molecules on the surface of infected erythrocytes (lE) which act as targets for natural protection. It was shown that sequestration in placenta is mediated by binding to CSA via DBLy3 domain of PfEMP1 for the mature IE and by RSP2 for rIE. Conventional immunization procedures rarely result in the successful production of monoclonal antibodies (mAbs) against such conformational vaccine candidates. Here we have produced the anti-DBLy3 (CSA) by rendering mice tolerant to normal red blood cells and CHO745. This procedure has permitted us to develop the anti-RSP2 too. Moreover we have produced the simian and murine anti-DBLy3 from recombinant DBLy3 (CSA) We have shown that a anti-DBLy3 (CSA) cross-reactive specifically with the mature IE (CSA) surface, suggesting that the DBLy3 (CSA) induce a pan-reactive immune response. Then the anti-recombinant DBLY3 (CSA) antibodies inhibit the CSA specific binding of parasites. The anti-RSP2 mAbs inhibit the rIE (CSA) cytoadhesion and merozoi͏̈te invasion. We shown that RSP2 is express during all parasite cycle but is localization on the erythrocyte surface is exclusive to the 20 first hour of cycle. During schizont stage, RSP2 is translated on the merozoi͏̈te surface via the rhoptries. It is transferred on the erythrocyte surface during merozoi͏̈te attachment without necessary entry parasite. Together, these results are the important step toward the development of a anti cytoadhesion vaccine that could protect against lE (CSA) sequestration and in particulary pregnant women
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Nderu, David [Verfasser], and Thirumalaisamy P. [Akademischer Betreuer] Velavan. "Plasmodium falciparum genetic diversity and malaria diagnosis in Kenyan population / David Nderu ; Betreuer: Thirumalaisamy P. Velavan." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1200916999/34.
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Nderu, David Verfasser], and Thirumalaisamy P. [Akademischer Betreuer] [Velavan. "Plasmodium falciparum genetic diversity and malaria diagnosis in Kenyan population / David Nderu ; Betreuer: Thirumalaisamy P. Velavan." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1200916999/34.
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Guenot, Marianne. "Understanding the interaction between Human Vγ9Vδ2 T cells and P. falciparum Blood stages : from activation to Effector functions". Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR21974/document.
Full textAbstract:
Le développement d'un vaccin anti-paludique est limité par notre connaissance incomplète des effecteurs agissant contre P.falciparum. Nous avons mis en évidence que les cellules T Vγ9Vδ2 sont activées par la forme intra-érythrocytaire (schizonte) et par les phosphoantigènes de P.falciparum, et peuvent inhiber la croissance du parasite in vitro par un mécanisme dépendant de la granulysine ciblant la forme invasive du parasite (mérozoïte). Ces résultats suggérent que les lymphocytes T Vγ9Vδ2 jouent un rôle dans le contrôle précoce de la charge parasitaire. Cependant, le mécanisme médiant l’interaction entre les schizontes, les mérozoïtes les cellules T Vγ9Vδ2 et reste élusif. L'objectif de cette thèse est d’étudier les interactions entre les stades sanguins de P. falciparum et les cellules T Vγ9Vδ2, afin de mieux comprendre leurs activités anti-parasitaires, dans le but à long terme d’une utilisation clinique. Dans ce travail, nous étudions l'importance du contact direct avec les parasites dans l’activation et les activités anti-parasitaires des cellules T Vγ9Vδ2, par des approches de microscopie confocale et de cytométrie en flux. Nous suggérons que les cellules T Vγ9Vδ2 forment peu ou pas de contacts avec les mérozoïtes, et très peu de contacts avec le schizonte. De plus, nous montrons que, contrairement à une lignée cellulaire tumorale cible (Daudi), le contact avec les schizontes n'affecte pas l'activation des cellules T Vγ9Vδ2, suggérant que les phosphoantigenes du parasite sont libérés dans le milieu. Nous démontrons que les phosphoantigènes produits par la voie DOXP sont probablement libérés par un processus actif, dépendant des new permeation pathways (NPP). Ensembles, ces résultats suggèrent que l'activation et l'activité antiparasitaire des cellules T Vγ9Vδ2 n’est pas dépendante du contact, mais est médié par des facteurs solubles<br>The limited knowledge of immune effector against Plasmodium falciparum precludes the development of a malaria efficient vaccine. We have recently evidenced that Vγ9Vδ2 T cells act as a new immune effector early in malaria infection. These cells are activated by the mature intraerythrocytic form (schizont) and by parasite-derived antigens (phosphoantigens). After activation, they inhibit in vitro parasite growth by targeting the extraerythrocytic invasive form (merozoite), by a granulysin-dependent mechanism. However, the mechanism by which Vγ9Vδ2 T cells are activated by schizonts and target merozoites remains elusive. The aim of this PhD project is to describe the interactions between P.falciparum blood stages and γδ T cells, in order to better understand their anti-parasitic activities and in the long term goal to manipulate these cells to prevent malaria. In the work, we investigate the importance of cell to parasite contact in Vγ9Vδ2 T cell activation and anti-parasitic activity by time-lapse and fixed confocal imaging, and cytometry. We suggest that Vγ9Vδ2 T cells form little or no contacts with merozoites, and very few contacts with the mature intraerythrocytic (schizont) form of the parasite. Moreover, we show that cytotoxic activities are elicited by schizonts, but that contrary to a known tumor cell line (Daudi cells), contact has no effect on the level of activation, suggesting that parasite-derived phosphoantigens are secreted in the microenvironment. We pursue the characterization of the parasite-derived phosphoantigens and demonstrate that they are produced by the DOXP pathway. Lastly, we show that phosphoantigens are most likely released by an active process, dependent on the new permeation pathways. Altogether, these results shed light on an unconventional mode of activation by P.falciparum blood stages and antiparasitic activity of Vγ9Vδ2 T cells, which is not contact-dependent, but rather is mediated by soluble factors
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Moorthy, Vasee S. "Analysis of DNA and recombinant viral vaccines against P. falciparum in malaria-naïve and malaria-exposed humans". Thesis, Open University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409866.
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Collins, Joey Marisha. "Proteasome Inhibition in P. falciparum: MG132 as a tool compound and the generation of MG132-tolerant parasites." Thesis, Boston College, 2015. http://hdl.handle.net/2345/bc-ir:104638.
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Thesis advisor: Marc Muskavitch<br>The ubiquitin-proteasome system (UPS), composed of classes of proteins central to the process of cellular protein turnover in eukaryotes, is essential to the life cycle of the malaria parasite, Plasmodium falciparum. Although the UPS has been well characterized in other organisms, the extent of its involvement in different stages of P. falciparum growth and development has not been investigated in depth. MG132, a small-molecule proteasome inhibitor known to target the 20S proteasome core (part of the catalytic center for selective protein degradation), has been used successfully in many research studies that require proteasome inhibition. We present data supportive of the conclusion that MG132 is highly effective as a tool for P. falciparum research. In this thesis, I describe the effects of partial and complete proteasome inhibition on parasite growth and development by the use of variable concentrations of MG132. I also assess the effects of MG132 on 20S P. falciparum proteasome enzymatic activities. I have generated parasite lines that exhibit tolerance, or low-level resistance, to MG132, through intermittent compound exposure. Sequencing of the catalytic β-5 subunit of the MG132-tolerant parasites reveals non-synonymous point mutations in three tolerant parasite lines. The use of MG132 as a tool compound for study of the UPS in P. falciparum facilitates research into detailed roles of the proteasome using reversible partial and complete inhibition. MG132-tolerant lines are also valuable tools for studying the genesis of different levels of drug resistance and cross-resistance in parasite evolution<br>Thesis (PhD) — Boston College, 2015<br>Submitted to: Boston College. Graduate School of Arts and Sciences<br>Discipline: Biology
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Villena, Patiño Fredy Ernesto. "Estudio genómico de la variante 1 de P. falciparum linaje B (Bv1) en áreas endémicas de malaria." Master's thesis, Universidad Nacional Mayor de San Marcos, 2022. https://hdl.handle.net/20.500.12672/17751.
Full textAbstract:
Plasmodium falciparum plantea un desafío importante para la eliminación de
la malaria debido al riesgo de la resistencia a antimaláricos y su perfil clínico severo.
En este estudio, nuestro objetivo fue explorar el perfil genómico de las muestras de
P. falciparum recolectadas en Loreto y Tumbes entre el 2006 y el 2017. El ADN de
P. falciparum extraído de sangre total fue enriquecido y secuenciado en la
plataforma MiSeq Illumina. Los SNPs fueron llamados y usados para explorar
marcadores de resistencia, estimar la diversidad poblacional y evaluar la estructura
poblacional. Veinticuatro aislados de Loreto (n=18) y Tumbes (n=6) fueron
secuenciados, resultando en un promedio de 2,492,353 reads por muestra. La
estructura poblacional mostró la presencia de tres subpoblaciones que coincidían
con linajes previamente tipificados en Perú: Bv1 (n=17), clona D (n=4) y tipo AcreLoreto (n=3). La genotipificación de los marcadores de resistencia a antimaláricos
mostró una alta prevalencia de mutaciones asociados con resistencia a cloroquina;
62.5% en Pfmdr1 y 87.5% en Pfcrt. Además, se hallaron mutaciones en los genes
Pfdhfr y Pfdhps asociadas con resistencia a sulfadoxina-pirimetamina en el 88.8%
de las muestras Bv1. Nuestros resultados muestran evidencia de un potencial
reemplazo clonal mediado por el linaje Bv1 en Loreto desde el 2011. Este
reemplazo podría ser el resultado de la ventaja selectiva de Bv1 a la presión de
selección indirecta impulsada por el uso de CQ para el tratamiento de P. vivax.
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Yu, Xiao Min. "Synthesis and biological evaluation of 9-aminoacridine derivatives as antimalarial agents against P. Falciparum : structure-activity relationship." Paris 11, 2010. http://www.theses.fr/2010PA112330.
Full textAbstract:
Dans ce travail, 40 nouveaux dérivés de la 9-aminoacridine ont été synthétisés et caractérisés avec des rendements optimisables. Des stratégies de synthèse relativement faciles et non coûteuses ont été adoptées. Ces composés sont basés sur les noyaux 6-chloro-2-methoxy-9-aminoacridine ou 9-aminoacridine. Ils comprennent des chaînes latérales différentes (longueur et groupement terminal) sur la position 9' du noyau d'acridine. L'activité anti-malaria de ces composés est testée in vitro sur des souches P. Falciparum sensibles à la CQ et des souches résistantes à la CQ. Afin de comprendre leur propriété anti-malaria, deux mécanismes proposés sont étudiés in vitro : l'inhibition de la formation de la β-hématine et l'inhibition de l'activité de topoisomerases par l'intercalation dans l'ADN. De plus, l'effet cytotoxique de ces composés est évalué in vitro sur les cellules KB (human epidermoid carcinoma)<br>Ln this work, 40 novel 9-aminoacridines were synthesized and characterized, through relatively convenient and low cost synthetic strategies with optimizable yields. These compounds are based on either 6-chloro-2-methoxy-9-aminoacridine or 9-aminoacridine moiety and contain different nature (length and terminal group) of the side chain at 9-position. The in vitro antimalarial potency of these compounds was evaluated against both CQ-sensitive and CQ-resistant P. Falciparum strains. Ln order to elucidate their antimalarial property, two mechanisms of action proposed for antimalarial acridine derivatives were studied in vitro: inhibition of β-hematin formation and inhibition of topoisomerase activity by intercalation into DNA. Additionally, in order to determine their safety profile, all compounds were screened for their in vitro cytotoxicity upon mammalian KB cells (human epidermoid carcinoma)
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Mbengue, Alassane. "Aspects moléculaires et cellulaires des modifications induites par Plasmodium falciparum dans le globule rouge humain parasité." Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20176/document.
Full textAbstract:
Ma thèse s'inscrit dans l'étude des modifications du globule rouge humain induites par P. falciparum. Ces modifications qui représentent une remarquable adaptation du parasite à un environnement plus complexe qu'il n'y paraît au premier abord et expliquent sa persistance chez l'Homme sont détaillées dans une revue et un chapitre de livre dont je suis co-auteur. Mes travaux de recherche ont porté sur la caractérisation fonctionnelle des structures de Maurer, un compartiment membranaire exporté par le parasite dans le globule rouge parasitaire et directement lié à la physiopathologie du paludisme grave. J'ai contribué à la caractérisation fonctionnelle de nouvelles protéines de ces structures, codées par trois familles multigéniques sub-télomériques en cluster avec la famille Pfmc-2tm, et présentant de façon étonnante un fort degré de conservation (article 1). La diminution d'expression de ces gènes, obtenue par titration d'un facteur transcriptionnel, entraine un défaut de libération des mérozoïtes. Mon deuxième projet porte sur l'identification des modalités d'export de la protéine transmembranaire résidente des structures de Maurer PfSBP1. Mes travaux montrent que PfSBP1 est exportée sous forme soluble dans le cytoplasme érythrocytaire, en interaction avec le complexe chaperon parasitaire PfTCP1 (article 2)<br>Plasmodium falciparum causes the most severe forms of human malaria, a pathology associated with the erythrocytic asexual stages of the parasite. My work focused on the remodeling of the infected erythrocytes induced by P. falciparum and detailed in a review and a book chapter that I co-authored. These modifications illustrate a remarkable adaptation of P. falciparum resulting in its persistence in humans. My PhD thesis was dedicated to the functional characterization of Maurer's clefts, a membrane compartment transposed by the parasite in the cytoplasm of its host cell, and central to the export of virulence factors to the host cell surface. I have conducted two projects and contributed first to the functional characterization of novel exported protein encoded by three highly conserved multigene sub-telomeric families in cluster with the Pfmc-2tm family. Down regulation of these gene families by promoter titration impacted the release of infectious merozoites from the host cell (annex 1). My second project was dedicated to the identification of the modality of export of the resident and Maurer's clefts transmembrane protein PfSBP1. I have shown that PfSBP1 is exported as a soluble protein in the host cell cytoplasm in interaction with the parasite Thermosome complex protein 1 (PfTCP1) chaperone complex (annex 2)