International malaria control initiatives such as the Roll Back Malaria Initiative (RBM) and the Medicines for Malaria Venture (MMV) mobilize resources and spur research aimed at vector control as well as the treatment and eventual eradication of the disease. These efforts have managed to reduce incidence of malaria by an estimated 37% worldwide since 2000. However, despite the promising success of control efforts such as these, the World Health Organization reports a staggering 438,000 deaths from malaria in 2015. The continuing high death toll of malaria as well as emerging insecticide and antimalarial drug resistance suggests that while encouraging, success in reducing malaria incidence may be tenuous. Current vector control strategies are often complicated by ecological and behavioral heterogeneity of vector mosquito populations. As an additional obstruction, mosquito genomes are highly plastic as evidenced by the wealth or chromosomal inversions that have occurred in this genus. Chromosomal inversions have been correlated with differences in adaptation to aridity, insecticide resistance, and differences in resting behavior. However, a good understanding of the molecular mechanisms for inversion generation is still lacking. One possible contributor to inversion formation in Anopheles mosquitoes includes repetitive DNA such as transposable elements (TEs), tandem repeats (TRs) and inverted repeats (IRs). This dissertation provides physical maps for two important malaria vectors, An. stephensi and An. albimanus (Ch.2 and Ch. 3) and then applies those maps to the identification of inversion breakpoints in malaria mosquitoes. Repeat content of each chromosomal arm and the molecular characterization of lineage specific breakpoints is also investigated (Ch. 2 and Ch.4). Our study reveals differences in patterns of chromosomal evolution of Anopheles mosquitoes vs. Drosophila. First, mosquito chromosomes tend to shuffle as intact elements via whole arm translocations and do not under fissions or fusions as seen in fruitflies. Second, the mosquito sex chromosome is changing at a much higher rate relative to the autosomes in malaria mosquitoes than in fruit flies. Third, our molecular characterization of inversion breakpoints indicates that TEs and TRs may participate in inversion genesis in an arm specific manner. / Ph. D. / Malaria is a complex and devastating disease vectored by the bite of a female Anopheles mosquito. This disease claimed an estimated 438,000 lives in 2015. The mobilization of funding and resources as part of global malaria eradication initiatives have reduced the global incidence of malaria by 37% in the last 15 years. Deaths from malaria are also 60% lower vs. the year 2000. These promising gains are threatened by the ability of Anopheles mosquitoes to adapt in the face of malaria control efforts. Anopheles mosquito chromosomes are known to be highly plastic, as evidenced by numerous chromosomal inversions. Recent years have seen increases in insecticide resistance, and behavioral change in mosquito populations that allow them to avoid insecticides and remain prolific vectors of disease. This ability of mosquito vectors to adapt threatens to unravel recent progress towards a malaria free world. The projects presented in this dissertation explore mechanisms of chromosomal evolution, specifically the potential role of repetitive DNA in the generation of chromosomal inversions. The exploration of chromosomal inversions was facilitated by the creation of physical maps for Anopheles species. Prominent malaria vectors An. stephensi andAn. albimanus were physically mapped in Chapter 2 and Chapter 3 respectively. In chapter 1 and chapter 3 physical maps are utilized for the identification of chromosomal inversion breakpoints using 2 species (Ch. 2) and many species (Ch. 4). Repeat content was quantified along each chromosomal arm (Ch 2,4) and in inversion breakpoint regions (Ch 3). This dissertation presents physical maps for two important malaria species that have been applied to the study of chromosomal evolution and will also serve as community tools for further study of malaria mosquitoes. Our work on chromosomal evolution has revealed the Anopheles chromosomes tend to undergo translocations as intact elements and do not under fissions and fusions as seen in fruitflies. We also find that the malaria mosquito sex chromosome changes much more rapidly relative to the autosomes than in fruitflies. Additionally, repetitive DNA including transposable elements (TEs) and tandem repeats (TRs) may be encouraging chromosomal inversions but with differing roles on different chromosomal arms.

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

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

No

Malaria ist noch immer die häufigste parasitäre Erkrankung in den Tropen. Vor allem afrikanische Kinder < 5 Jahren sind betroffen. Die steigende Chloroquinresistenz ist für einen deutlichen Anstieg der Kindersterblichkeit verantwortlich. Mehrere Studien belegen, dass die Kombination von Chloroquin (CQ) mit Sulfadoxin-Pyrimethamin (SP) in Afrika bei niedriggradiger CQ-Resistenz die therapeutische Wirksamkeit erhöht und damit auch die Resistenzentwicklung gegenüber beiden Medikamenten verzögern kann. Bei 315 Kindern im Alter von 6-59 Monaten wurde von Nov. 2000 bis Nov. 2001 eine Studie zur Epidemiologie der Malaria und zum Therapieausgang von CQ und SP in Tamale/Nord-Ghana durchgeführt. Bei Vorliegen einer Malaria wurde mit CQ und SP behandelt und der Therapieausgang gemäß eines modifizierten WHO-Protokolls von 1996 ermittelt. Die Gesamtzahl der Malaria-Episoden im Zeitraum betrug 836. In der Regenzeit erkrankte mit 23,7% ein signifikant höherer Anteil der Kinder an Malaria als in der Trockenzeit mit 9,4%. Ein frühes Therapieversagen (ETF) wurde in 5% der Fälle beobachtet, ein spätes Therapieversagen (LTF) in 19,5% der Fälle. 211 Fälle (68,7%) hatten einen klinischen Therapieerfolg (ACR). Alter < 3 Jahren war ein unabhängiger Einflussfaktor für ETF und Gesamttherapieversagen. Eine hohe Parasitendichte war ein unabhängiger Einflussfaktor für LTF und Gesamttherapieversagen. Das Risiko, ein Gesamttherapieversagen (ETF + LTF) zu entwickeln, war in der Regenzeit um das 6-fache gegenüber der Trockenzeit erhöht. Bei allen erstmalig mit CQ und SP behandelten Fällen (n = 206) war der ACR (72,3%) statistisch grenzwertig höher als bei zweiter oder mehrfacher Behandlung (61,4%; n = 101). Bei den mehrfach therapierten Fällen bestand mit 27% gegenüber 16% bei den erstmalig therapierten Fällen ein signifikant höheres Risiko, ein LTF zu entwickeln. Die Erholung des Hb-Gehalts bei den erfolgreich therapierten Fällen betrug 0,6 g/dl und unterschied sich signifikant vom Hb-Anstieg (0,4 g/dl) bei Fällen mit LTF. Ein Vergleich des ACR der beschriebenen Studie mit einer zuvor durchgeführten CQ-Studie ergab keinen signifikanten Unterschied. Die Ergebnisse dieser Studie legen die Schlussfolgerung nahe, dass sich die Therapie aus CQ und SP wegen der hohen CQ-Resistenz und der sich rasch entwickelnden SP-Resistenz zumindest in Nordghana nicht eignet. / Malaria remains the most frequent parasite disease in the tropics. Especially African children under 5 years are at risk. The rising chloroquine resistance is the cause for a significant increase in childhood mortality. Several studies indicate that the combination of chloroquin (CQ) and sulfadoxine-pyrimethamine (SP) in Africa with low-grade CQ resistance increases the therapeutic efficacy and can thus slow down the development of resistance to both drugs. The epidemiology of malaria and the therapeutic outcome of CQ and SP was assessed in a cohort study of 315 children aged 6-59 months from November 2000-November 2001 in Tamale/Northern Ghana. In the case of malaria a combination therapy of CQ and SP was given and the therapeutic outcome was assessed in a modified WHO protocol. The total number of all malaria episodes in the observation period was 836. In the rainy season, the amount of the children with malaria was significantly higher than in the dry season (23,7% vs. 9,4%). Early treatment failure (ETF) was observed in 5% of the cases and late treatment failure (LTF) in 19,5%. 211 cases (68,7%) fulfilled the criteria for adequate clinical response (ACR). Age under 3 years was an independent predictor for ETF and overall therapeutic failure. High initial parasite density was an independent predictor for LTF and overall therapeutic failure. The risk of developing an overall therapeutic failure (ETF + LTF) was 6 times greater in the rainy season than in the dry sason. In all cases with the first treatment of CQ and SP (n = 206), the percentage of ACR (72,3%) was significantly greater than in cases treated twice or more (61,4%, n = 101). Cases with 2 or more treatments were at a significantly higher risk of developing a LTF than cases with one treatment (27% vs. 16%). The recovery of the hb levels in cases with successful treatment was 0,6 g/dl and was significantly different from the haemoglobin increase in cases with LTF. A comparison between the therapeutic success of CQ and SP with CQ alone did not show a significant difference. The results of this study indicate that the combination therapy of CQ and SP is no longer useful for treatment of uncomplicated malaria in Northern Ghana because of the high CQ resistance and the increasing resistance of SP.

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

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

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

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

Le paludisme est responsable de la mort de près d'un million de personnes chaque année. Cette maladie est causée par le Plasmodium, parasite protozoaire appartenant à la famille des Apicomplexes. Dans cette thèse, nous avons développé des approches de biologie de systèmes pour l'étude du métabolisme des phospholipides (PL) métabolisme et de sa régulation chez Plasmodium. Ces voies métaboliques sont d'une importance primordiale pour la survie du parasite. À l'étape intra-érythrocytaire du développement, les espèces de Plasmodium exploitent un nombre important de voies de synthèse phospholipidique, qui sont rarement trouvées ensemble dans un seul organisme : (i) la voie dépendante ancestrale CDP-diacylglycerol des procaryotes ( ii) les voies eucaryotes de novo CDP- choline et CDP-éthanolamine (Kennedy) ( iii ) de plus P.falciparum et P. knowlesi emploient des réactions supplémentaires qui relient une à l'autre certaines de ces routes. Une voie de synthèse caractéristique aux plantes, qui utilise la sérine en tant que source supplémentaire de phosphatidyl-choline (PC) et de phosphatidyl-éthanolamine (PE), est nommée la voie méthyltransférase décarboxylase - phosphoéthanolamine sérine (SDPM). Pour comprendre la dynamique d'acquisition et le métabolisme des phospholipides chez Plasmodium, nous avons construit un modèle cinétique quantitatif basé sur des données fluxomiques. La dynamique in vitro d'incorporation de phospholipides révèle plusieurs voies de synthèse. Nous avons construit un réseau métabolique détaillé et nous avons identifié les valeurs de ses paramètres cinétiques (taux maximaux et constantes Michaelis). Afin d'obtenir une recherche globale dans l'espace de paramètres, nous avons conçu une méthode d'optimisation hybride, discrète et continue. Des paramètres discrets ont été utilisés pour échantillonner le cône des flux admissibles, alors que les constantes des Michaelis et les taux maximaux ont été obtenus par la minimisation locale d'une fonction objective. Cette méthode nous a également permis de prédire la répartition des flux au sein du réseau pour différents précurseurs métaboliques. Cette analyse quantitative a également été utilisée pour comprendre les liens éventuels entre les différentes voies. La principale source de PC est la voie Kennedy CDP-choline. Des expériences de knock-out in silico ont montré l'importance comparable des voies phosphoéthanolamine-N-méthyltransférase (PMT) et de la phosphatidyléthanolamine-N-méthyltransférase (PEMT) pour la synthèse de PC. Les valeurs des flux indiquent que plus grande partie de la PE dérivée de la sérine est formée par décarboxylation, alors que la synthèse de PS est majoritairement effectuée par des réactions d'échange de base. L'analyse de sensitivité de la voie CDP- choline montre que l'entrée de choline dans le parasite et la réaction cytidylyltransferase de la phosphocholine ont les plus grands co-efficients de contrôle sur cette voie, mais ne permet pas de distinguer une réaction comme l'unique étape limitante. Ayant comme objectif la compréhension de la régulation de l'expression génique chez Plasmodium falciparum et son influence sur le fonctionnement métabolique, nous avons effectué une étude bioinformatique intégrative des données du transcriptome et du métabolome pour les principales enzymes impliquées dans le métabolisme PL. L'étude de la dépendance temporelle des variables métaboliques et transcriptomiques au cours du cycle intra-érythrocytaire, a mis en évidence deux modes d'activation des voies PL. Les voies Kennedy sont activées pendant la phase schizogonique et au début de la phase anneau, alors que les voies SDPM et d'échange de bases sont activées lors de la fin de la phase anneau cycle et lors de la phase tropozoïte. / Malaria is responsible of the death of up to one million people each year. This disease is caused by Plasmodium, a protozoan parasite. In this thesis we have developed systems biology approaches to the study of phospholipid (PL) metabolism and its regulation in Plasmodium. These pathways are of primary importance for the survival of the parasite. At the blood stage, Plasmodium species display a bewildering number of PL synthetic pathways that are rarely found together in a single organism (i) the ancestral prokaryotic CDPdiacylglycerol dependent pathway (ii) the eukaryotic type de novo CDP-choline and CDPethanolamine (Kennedy) pathways (iii) P. falciparum and P. knowlesi exhibits additional reactions that bridge some of these routes. A plant-like pathway that relies on serine to provide additional PC and PE, is named the serine decarboxylase-phosphoethanolamine methyltransferase (SDPM) pathway. To understand the dynamics of PL acquisition and metabolism in Plasmodium we have used fluxomic data to build a quantitative kinetic model. In vitro incorporation dynamics of phospholipids unravels multiple synthetic pathways. A detailed metabolic network with values of the kinetic parameters (maximum rates and Michaelis constants) has been built. In order to obtain a global search in the parameter space, we have designed a hybrid, discrete and continuous, optimisation method. Discrete parameters were used to sample the cone of admissible fluxes, whereas the continuous Michaelis and maximum rates constants were obtained by local minimization of an objective function.The model was used to predict the distribution of fluxes within the network of various metabolic precursors. The quantitative analysis was used to understand eventual links between different pathways. The major source of phosphatidylcholine (PC) is the CDP-choline Kennedy pathway. In silico knock-out experiments showed comparable importance of phosphoethanolamine-N-methyltransferase (PMT) and phosphatidylethanolamine-N-methyltransferase (PEMT) for PC synthesis. The flux values indicate that, major part of serine derived phosphatidylethanolamine (PE) is formed via serine decarboxylation, whereas the phosphatidylserine (PS) is mainly predominated by base-exchange reactions. Metabolic control analysis of CDP-choline pathway shows that the carrier-mediated choline entry into the parasite and the phosphocholine cytidylyltransferase reaction have the largest control coefficients in this pathway, but does not distinguish a reaction as an unique rate-limiting step.With a vision to understand regulation of gene expression in Plasmodium falciparum and its influence on the metabolite expression, we have performed an integrative bioinformatic studies. The study integrates transcriptome and metabolome data for the main enzymes involved in PL metabolism. The study of the correlated time dependence of metabolic and transcriptomic variables during the intraerythrocytic cycle showed that there are two modes of activation of PL pathways. Kennedy pathways are activated during schizogony and early ring stages, whereas SDPM and base exchange pathways are activated during late ring and tropozoite stages.