Plasmodium Research Papers - Academia.edu (original) (raw)

Entomological surveys were conducted to identify Anopheles malaria vector species, their feeding and resting behaviors, and characterization of larval habitats on Bongao Island, Tawi-tawi Province, in July and November, 2007. Survey... more

Entomological surveys were conducted to identify Anopheles malaria vector species, their feeding and resting behaviors, and characterization of larval habitats on Bongao Island, Tawi-tawi Province, in July and November, 2007. Survey parameters included all-evening human-landing collections (HLC), evening buffalo-baited trap (BBT) collections, daytime indoor and outdoor adult resting collections, adult female age-grading, identification of natural Plasmodium infections in mosquitoes, larval habitat identification and physical/biological characterization, and adult insecticide susceptibility assays. Both surveys revealed the predominant and putative malaria vector species on Bongao Island is Anopheles litoralis. Anophelesflavirostris was collected on only one occasion. The HLC during the July survey produced approximately 4 mosquitoes/human/night (mhn). The November survey yielded 1.27 mhn due, in part, to inclement weather conditions during time of sampling. Anopheles litoralis host ...

22 Protective antibodies in Plasmodium falciparum malaria are only acquired after years of 23 repeated infections. Chronic malaria exposure is associated with a large increase in 24 atypical memory B cells (MBCs) that resemble B cells... more

22 Protective antibodies in Plasmodium falciparum malaria are only acquired after years of 23 repeated infections. Chronic malaria exposure is associated with a large increase in 24 atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent 25 viral infections. Understanding the function of atypical MBCs and their relationship to 26 classical MBCs will be critical to developing effective vaccines for malaria and other 27 chronic infections. We show that VH gene repertoires and somatic hypermutation rates of 28 atypical and classical MBCs are indistinguishable indicating a common developmental 29 history. Atypical MBCs express an array of inhibitory receptors and B cell receptor 30 (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses 31 including proliferation, cytokine production and antibody secretion. Thus, in response to 32 chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs 33 becoming refractory to BCR-mediated activation and potentially interfering with the 34 acquisition of malaria immunity. 35 3 Introduction 36

The phospholipid organization in monkey erythrocytes upon Plasmodium knowlesi infection has been studied. Parasitized and nonparasitized erythrocytes from malaria-infected blood were separated and pure erythrocyte membranes from... more

The phospholipid organization in monkey erythrocytes upon Plasmodium knowlesi infection has been studied. Parasitized and nonparasitized erythrocytes from malaria-infected blood were separated and pure erythrocyte membranes from parasitized cells were isolated using Affi-Gei beads. In this way, the phospholipid content and composition of (i) the membrane of nonparasitized cells, (ii) the erythrocyte membrane of parasitized cells and (iii) the parasite could be determined. The phospholipid content and composition of the erythrocyte membranes of nonparasitized and parasitized cells and erythrocytes from chloroquine-treated monkeys cured from malaria, were the same as in normal erythrocytes. The phnspholipid content of the parasite increased during its development, but its composition remained unchanged. Three independent techniques, i.e., treatment of intact cells with phospholipase A 2 and sphingomyelinase C, fluorescamine labeling of aminophospholipids and a phosphatidylcholine-transfer protein-mediated exchange procedure have been applied to assess the disposition of phnspholipids in: (i) erythrocytes from healthy monkeys, (ii) nonparasitized and parasitized erythrocytes from monkeys infected with Plasmodium knowlesi, and (iii) erythrocytes from monkeys that had been cured from malaria by chloroquine treatment. The results obtained by these experiments do not show any abnormality in phospholipid asymmetry in the erythrocyte from malaria-infected (splenectomized) monkeys, neither in the nonparasitized cells, nor in the parasitized cells at any stage of parasite development. Nevertheless, a considerable degree of lipid bilayer destabilization in the membrane of the parasitized cells is apparent from the enhanced exchangeability of the PC from those cells, as well as from their increased permeability towards fluorescamine.

The STAT family of transcription factors activate expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT... more

The STAT family of transcription factors activate expression of immune system genes in vertebrates. The ancestral STAT gene (AgSTAT-A) appears to have duplicated in the mosquito Anopheles gambiae, giving rise to a second intronless STAT gene (AgSTAT-B), which we show regulates AgSTAT-A expression in adult females. AgSTAT-A participates in the transcriptional activation of nitric oxide synthase (NOS) in response to bacterial and plasmodial infection. Activation of this pathway, however, is not essential for mosquitoes to survive a bacterial challenge. AgSTAT-A silencing reduces the number of early Plasmodium oocysts in the midgut, but nevertheless enhances the overall infection by increasing oocyst survival. Silencing of SOCS, a STAT suppressor, has the opposite effect, reducing Plasmodium infection by increasing NOS expression. Chemical inhibition of mosquito NOS activity after oocyte formation increases oocyte survival. Thus, the AgSTAT-A pathway mediates a late phase anti-plasmodial response that reduces oocyst survival in An. gambiae.

Objective: Vivax malaria is common in Pakistan. We carried out this study to determine the effects of this infection on blood counts and the impact of splenomegaly on these results. Methods: This was a retrospective observational study... more

Objective: Vivax malaria is common in Pakistan. We carried out this study to determine the effects of this infection on blood counts and the impact of splenomegaly on these results.
Methods: This was a retrospective observational study carried out at 1 Mountain Medical Battalion, Bagh, Azad Kashmir. Old medical records of all patients admitted with vivax malaria from Jan 2010 to Oct 2012 were scrutinized. The presence or absence of a palpable spleen and the results of complete blood counts and platelet counts measured at the time of admission were noted down. Anaemia was defined as Hb<13g/dl in men, leukopenia as total leukocyte count (TLC)<4000/µl and thrombocytopenia as platelets count <150000/µl. Data was analysed with STATA version 12.1. The results of haematology parameters were compared amongst patients with splenomegaly and the rest.
Results: Anaemia was seen in 22.15%, neutropenia in 23.49% and thrombocytopenia in 90.60% of the 149 male patients having a mean age of 27.54±5.11 years. The differences in mean blood counts and the number of patients with haematological abnormalities in the two groups were statistically insignificant.
Conclusion: Since the blood counts are not affected by presence or absence of splenomegaly, mechanisms other than hypersplenism are important.

Background: Malaria microscopy, while the gold standard for malaria diagnosis, has limitations. Efficacy estimates in drug and vaccine malaria trials are very sensitive to small errors in microscopy endpoints. This fact led to the... more

Background: Malaria microscopy, while the gold standard for malaria diagnosis, has limitations. Efficacy estimates in drug and vaccine malaria trials are very sensitive to small errors in microscopy endpoints. This fact led to the establishment of a Malaria Diagnostics Centre of Excellence in Kisumu, Kenya. The primary objective was to ensure valid clinical trial and diagnostic test evaluations. Key secondary objectives were technology transfer to host countries, establishment of partnerships, and training of clinical microscopists.

Over a century ago, the malaria expedition of the brilliant microbiologist Robert Koch to the Dutch East Indies (Indonesia) and German New Guinea (now Papua New Guinea, or PNG), resulted in profound observations that are still central to... more

Over a century ago, the malaria expedition of the brilliant microbiologist Robert Koch to the Dutch East Indies (Indonesia) and German New Guinea (now Papua New Guinea, or PNG), resulted in profound observations that are still central to our current understanding of the epidemiology and acquisition of immunity to the malaria parasite Plasmodium. The tradition of malaria research in PNG pioneered by Koch continues to this day, with a number of recent studies still continuing to elucidate his original concepts and hypotheses. These include age and exposure-related acquisition of immunity, species-specific and cross-species immunity, correlates of protective immunity and determining the prospects for anti-malaria vaccines.

Malaria in La Guajira, the most northern state of Colombia, shows two different epidemiological patterns. Malaria is endemic in the municipality of Dibulla whereas in Riohacha it is characterised by sporadic outbreaks. This study aimed to... more

Malaria in La Guajira, the most northern state of Colombia, shows two different epidemiological patterns. Malaria is endemic in the municipality of Dibulla whereas in Riohacha it is characterised by sporadic outbreaks. This study aimed to establish whether differences in transmission patterns could be attributed to different vector species. The most abundant adult female species were Anopheles aquasalis, exclusive to Riohacha, and Anopheles darlingi, restricted to Dibulla. Anopheles mosquitoes were identified using morphology and the molecular markers internal transcribed spacer 2 and cytochrome c oxidase I. All specimens (n = 1,393) were tested by ELISA to determine natural infection rates with Plasmodium falciparum and Plasmodium vivax. An. darlingi was positive for P. vivax 210, with an infection rate of 0.355% and an entomological inoculation rate of 15.87 infective bites/person/year. Anopheles albimanus larvae were the most common species in Riohacha, found in temporary swamps;...

Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification... more

Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from wester...

Malaria is endemic to Bangladesh. In this longitudinal study, we used hydrologic, topographic, and socioeconomic risk factors to explain single and multiple malaria infections at individual and household levels. Malaria incidence was... more

Malaria is endemic to Bangladesh. In this longitudinal study, we used hydrologic, topographic, and socioeconomic risk factors to explain single and multiple malaria infections at individual and household levels. Malaria incidence was determined for 1,634 households in 54 villages in 2009 and 2010. During the entire study period 21.8% of households accounted for all (n = 497) malaria cases detected; 15.4% of households had 1 case and 6.4% had 2 cases. The greatest risk factors for malaria infection were low bed net ratio per household, house construction materials (wall), and high density of houses. Hydrologic and topographic factors were not significantly associated with malaria risk. This study identifies stable malaria hotspots and risk factors that should be considered for cost-effective targeting of malaria interventions that may contribute to potential elimination of malaria in Bangladesh.

Background: Sets of Giemsa-stained, blood smear slides with systematically verified composite diagnoses would contribute substantially to development of externally validated quality assurance systems for the microscopic diagnosis of... more

Background: Sets of Giemsa-stained, blood smear slides with systematically verified composite diagnoses would contribute substantially to development of externally validated quality assurance systems for the microscopic diagnosis of malaria.

Background: Parasite concentration methods facilitate molecular, biochemical and immunological research on the erythrocytic stages of Plasmodium. In this paper, an adaptation of magnetic MACS ® columns for the purification of human... more

Background: Parasite concentration methods facilitate molecular, biochemical and immunological research on the erythrocytic stages of Plasmodium. In this paper, an adaptation of magnetic MACS ® columns for the purification of human Plasmodium species is presented. This method was useful for the concentration/purification of either schizonts or gametocytes.

Background Assessments of the epidemiology of malaria over time are needed to understand changes in transmission and guide control and elimination strategies. Methods A longitudinal population study was established in 1985 in Nyamisati... more

Background Assessments of the epidemiology of malaria over time are needed to understand changes in transmission and guide control and elimination strategies. Methods A longitudinal population study was established in 1985 in Nyamisati village in the Rufiji River Delta, Tanzania. A physician and research team lived in the village 1984-2000. Parasite prevalence by microscopy and two PCR methods, spleen rates and haemoglobin levels were measured in repeated cross-sectional surveys between 1985 and 2010. Passive surveillance of malaria cases was maintained until end 1999. Bed nets were distributed after the surveys 1993, 1999 and 2010. Results In 1985, overall parasite prevalence by microscopy was 70% (90% in children ages two to nine years). The prevalence decreased gradually by microscopy (38.9% 1994, 26.7% 1999) and msp2

Background Substantial reductions in malaria have been reported in several African countries after distribution of insecticide-treated bednets and the use of artemisinin-based combination therapies (ACTs). Our aim was to assess the eff... more

Background Substantial reductions in malaria have been reported in several African countries after distribution of insecticide-treated bednets and the use of artemisinin-based combination therapies (ACTs). Our aim was to assess the eff ect of these policies on malaria morbidity, mosquito populations, and asymptomatic infections in a west African rural population.

We studied the phylogeny of avian haemosporidian parasites, Haemoproteus and Plasmodium , in a number of African resident and European migratory songbird species sampled during spring and autumn in northern Nigeria. The phylogeny of the... more

We studied the phylogeny of avian haemosporidian parasites, Haemoproteus and Plasmodium , in a number of African resident and European migratory songbird species sampled during spring and autumn in northern Nigeria. The phylogeny of the parasites was constructed through sequencing part of their mitochondrial cytochrome b gene. We found eight parasite lineages, five Haemoproteus and three Plasmodium , infecting multiple host species. Thus, 44% of the 18 haemospiridian lineages found in this study were detected in more than one host species, indicating that host sharing is a more common feature than previously thought. Furthermore, one of the Plasmodium lineages infected species from different host families, Sylviidae and Ploceidae, expressing exceptionally large host range. We mapped transmission events, e.g. the occurrence of the parasite lineages in resident bird species in Europe or Africa, onto a phylogenetic tree. This yielded three clades, two Plasmodium and one Haemoproteus , in which transmission seems to occur solely in Africa. One Plasmodium clade showed European transmission, whereas the remaining two Haemoproteus clades contained mixes of lineages of African, European or unknown transmission. The mix of areas of transmission in several branches of the phylogenetic tree suggests that transmission of haemosporidian parasites to songbirds has arisen repeatedly in Africa and Europe. Blood parasites could be viewed as a cost of migration, as migratory species in several cases were infected with parasite lineages from African resident species. This cost of migration could have considerable impact on the evolution of migration and patterns of winter distribution in migrating birds.

Pregnant women are at increased risk for malaria infection. Although important advances have been made in the last years, the mechanisms that explain the increased susceptibility are not yet fully understood. Malaria infection in... more

Pregnant women are at increased risk for malaria infection. Although important advances have been made in the last years, the mechanisms that explain the increased susceptibility are not yet fully understood. Malaria infection in pregnancy is associated with maternal and fetal morbidity and mortality. The severity of the disease depends on the level of pre-pregnancy acquired immunity against malaria, and the consequences of infection are more severe in non-immune women. In highly endemic areas, the frequency and severity of the infection is higher in primigravida and decreases with increasing parity. In non-immune women, the risk is similar across the parity and malaria may be an important direct cause of maternal mortality. Malaria infection during pregnancy has important negative effects on infant's health, causing intrauterine growth retardation and prematurity or directly through congenital infection. In this paper, we review the pathology, diagnosis, and current recommendations for treatment and prevention of malaria in the pregnant woman and her infant.

Microbial infectious diseases continue to be one of the leading causes of morbidity and mortality. It has been estimated that microbial species comprise about 60% of the Earth's biomass. This, together with the fact that their... more

Microbial infectious diseases continue to be one of the leading causes of morbidity and mortality. It has been estimated that microbial species comprise about 60% of the Earth's biomass. This, together with the fact that their genetic, metabolic and physiological diversity is extraordinary, makes them a major threat to the health and development of populations across the world. Widespread antibiotic resistance, the emergence of new pathogens in addition to the resurgence of old ones, and the lack of effective new therapeutics exacerbate the problems. Thus, the need to discover and develop new antimicrobial agents is critical to improving mankind's future health. Plant secondary metabolites (PSMs) offer particular promise in this sense. Plant Kingdom could be considered a rich source of the most diverse structures (e.g. there are more than 12,000 known alkaloids, more than 8,000 phenolic compounds and over 25,000 different terpenoids), many of which were proven to possess str...

The ability to invade tissues is a unique characteristic of the malaria stages that develop/differentiate within the mosquitoes (ookinetes and sporozoites). On the other hand, tissue invasion by many pathogens has often been associated... more

The ability to invade tissues is a unique characteristic of the malaria stages that develop/differentiate within the mosquitoes (ookinetes and sporozoites). On the other hand, tissue invasion by many pathogens has often been associated with increased matrix metalloprotease (MMP) activity in the invaded tissues. By employing cell biology and reverse genetics, we studied the expression and explored putative functions of one of the three MMPs encoded in the genome of the malaria vector Anopheles gambiae, namely, the Anopheles gambiae MMP1 (AgMMP1) gene, during the processes of blood digestion, midgut epithelium invasion by Plasmodium ookinetes, and oocyst development. We show that AgMMP1 exists in two alternative isoforms resulting from alternative splicing; one secreted (S-MMP1) and associated with hemocytes, and one membrane type (MT-MMP1) enriched in the cell attachment sites of the midgut epithelium. MT-MMP1 showed a remarkable response to ookinete midgut invasion manifested by inc...

The International Forum of Vox Sanguinis is meant to obtain information concerning important and ⁄ or controversial subjects of transfusion medicine. Transfusiontransmitted malaria is severe and often fatal. The measures taken to prevent... more

The International Forum of Vox Sanguinis is meant to obtain information concerning important and ⁄ or controversial subjects of transfusion medicine. Transfusiontransmitted malaria is severe and often fatal. The measures taken to prevent it in non-endemic areas have been successful, although cases still occur occasionally. However, the number of immigrants from and travellers to endemic areas has increased considerably and is still increasing. Furthermore, new tests have been developed to detect plasmodium antibodies and are used for selected group of donors in various blood centres. Also, tests to detect plasmodium antigens and nucleic acid amplification testing (NAT) for parasite DNA have been developed. It seemed therefore of interest to evaluate the preventive measures taken at present in non-endemic areas. To obtain the relevant information, the following questions were sent to transfusion services.

The call for malaria control, over the last century, marked a new epoch in the history of this disease. Many control strategies targeting either the Plasmodium parasite or the Anopheles vector were shown to be effective. Yet, the... more

The call for malaria control, over the last century, marked a new epoch in the history of this disease. Many control strategies targeting either the Plasmodium parasite or the Anopheles vector were shown to be effective. Yet, the emergence of drug resistant parasites and insecticide resistant mosquito strains, along with numerous health, environmental, and ecological side effects of many chemical agents, highlighted the need to develop alternative tools that either complement or substitute conventional malaria control approaches. The use of biological means is considered a fundamental part of the recently launched malaria eradication program and has so far shown promising results, although this approach is still in its infancy. This review presents an overview of the most promising biological control tools for malaria eradication, namely fungi, bacteria, larvivorous fish, parasites, viruses and nematodes.

Résumé Contexte. -Le paludisme est un véritable problème de santé publique en Afrique subsaharienne ; plus de 300 millions de nouveaux cas et environ deux millions de décès surviennent chaque année. La transfusion sanguine est une voie... more

Résumé Contexte. -Le paludisme est un véritable problème de santé publique en Afrique subsaharienne ; plus de 300 millions de nouveaux cas et environ deux millions de décès surviennent chaque année. La transfusion sanguine est une voie potentielle de transmission du Plasmodium, mais il n'existe encore aucun consensus sur les mesures à prendre pour prévenir le paludisme post-transfusionnel en zone d'endémie. Ce travail avait pour but de comparer quelques outils disponibles et de discuter des différentes stratégies à mettre en oeuvre. Matériel et méthodes. -L'étude a porté sur 3001 donneurs de sang recrutés dans sept centres de transfusion sanguine au Sénégal au cours de deux périodes : la saison sèche (juin-juillet 2003) et la saison des pluies (octobre-novembre 2003). Nous avons évalué l'efficacité du questionnaire de sélection des donneurs de sang à exclure ceux qui sont potentiellement porteurs asymptomatiques du Plasmodium. Sur chaque don, étaient effectués un dépistage de l'Ag pLDH et des anticorps anti-Plasmodium par technique Elisa (DiaMed, Cressier sur Morat, Suisse), la goutte épaisse et le frottis sanguin, ainsi que le dépistage du VIH, de l'Ag HBs, du VHC et de la syphilis. Résultats. -L'âge médian des donneurs de sang était de 27,7 ans. La séroprévalence des anticorps antiplasmodiaux était de 65,3 % et celle de l'antigène pLDH, de 0,53 %, positivité confirmée par microscopie. La prévalence des autres marqueurs infectieux était de 11,7 % pour l'Ag HBs, 0,83 % pour la syphilis, 0,49 % pour l'hépatite C et 0,46 % pour le VIH. Les facteurs de risque associés à un portage asymptomatique du Plasmodium étaient la saison des pluies, le caractère irrégulier des dons, le nombre élevé d'antécédents d'accès palustre et l'absence de traitement lors du dernier épisode. Conclusion. -Le Plasmodium représente le troisième risque de transmission d'agents infectieux par la transfusion sanguine après l'hépatite B, la syphilis, et avant le VHC et le VIH au Sénégal. Le questionnaire médical a montré ses limites dans sa capacité à éliminer les porteurs asymptomatiques, ce qui justifie la proposition d'introduction du dépistage. La recherche de l'Ag pLDH du Plasmodium par technique Elisa nous semble être le meilleur outil de dépistage en zone d'endémie. La stratégie de dépistage systématique est la plus appropriée en termes de sécurité transfusionnelle. # 2009 Elsevier Masson SAS. Tous droits réservés.

Understanding the epidemiological features and metrics of malaria in endemic populations is a key component to monitoring and quantifying the impact of current and past control efforts to inform future ones. The International Centers of... more

Understanding the epidemiological features and metrics of malaria in endemic populations is a key component to monitoring and quantifying the impact of current and past control efforts to inform future ones. The International Centers of Excellence for Malaria Research (ICEMR) has the opportunity to evaluate the impact of malaria control interventions across endemic regions that differ in the dominant Plasmodium species, mosquito vector species, resistance to antimalarial drugs and human genetic variants thought to confer protection from infection and clinical manifestations of plasmodia infection. ICEMR programs are conducting field studies at multiple sites with the aim of generating standardized surveillance data to improve the understanding of malaria transmission and to monitor and evaluate the impact of interventions to inform malaria control and elimination programs. In addition, these epidemiological studies provide a vast source of biological samples linked to clinical and e...

| Almost all the drugs that are widely used today against Plasmodium spp., the causative agent of malaria, target the asexual blood stages of the parasite. Widespread drug resistance severely restricts our ability to control malaria and... more

| Almost all the drugs that are widely used today against Plasmodium spp., the causative agent of malaria, target the asexual blood stages of the parasite. Widespread drug resistance severely restricts our ability to control malaria and makes it necessary to seek novel antimalarial compounds. Here, we advocate the development of true causal chemoprophylactic drugs that will fully inhibit the obligate short-lived hepatic forms that precede blood infections. Such drugs will prevent pathology and interrupt transmission, and could therefore have an important role in the control of malaria and its eventual eradication.

In the last decade, there has been an upsurge of interest in developing malaria rapid diagnostic test (RDT) kits for the detection of Plasmodium species. Three antigens -Plasmodium falciparum histidine-rich protein 2 (PfHRP2), plasmodial... more

In the last decade, there has been an upsurge of interest in developing malaria rapid diagnostic test (RDT) kits for the detection of Plasmodium species. Three antigens -Plasmodium falciparum histidine-rich protein 2 (PfHRP2), plasmodial aldolase and plasmodial lactate dehydrogenase (pLDH) -are currently used for RDTs. Tests targeting HRP2 contribute to more than 90 % of the malaria RDTs in current use. However, the specificities, sensitivities, numbers of false positives, numbers of false negatives and temperature tolerances of these tests vary considerably, illustrating the difficulties and challenges facing current RDTs. This paper describes recent developments in malaria RDTs, reviewing RDTs detecting PfHRP2, pLDH and plasmodial aldolase. The difficulties associated with RDTs, such as genetic variability in the Pfhrp2 gene and the persistence of antigens in the bloodstream following the elimination of parasites, are discussed. The prospect of overcoming the problems associated with current RDTs with a new generation of alternative malaria antigen targets is also described.

Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use... more

Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development. ß

Recent evidence from a large, randomized, controlled trial has suggested that the universal administration of iron to children in malaria-endemic areas is associated with an increase in adverse health outcomes. The purpose of this paper... more

Recent evidence from a large, randomized, controlled trial has suggested that the universal administration of iron to children in malaria-endemic areas is associated with an increase in adverse health outcomes. The purpose of this paper is to summarize the available ecologic and intervention trials related to iron and malaria in children, and to set these against current knowledge of the biology of host-pathogen interactions involving iron metabolism. We conclude that, although not fully consistent, the balance of evidence confirms that administration of iron (usually in combination with folic acid) increases the incidence of malaria when given without prophylaxis and in the absence of universal access to treatment. The mechanisms by which additional iron can benefit the parasite are far from clear. There is evidence to suggest that the apparent detrimental effect of iron supplementation may vary according to levels of antecedent iron status, the presence of hemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency, and other host genetic variants, such as variants in haptoglobin. The effects of malaria on host iron metabolism are also reviewed and reveal that the key cause of malaria-induced anemia is a maldistribution of iron and suppression of erythropoiesis rather than an exacerbation of gross iron deficiency. We tentatively conclude that, if it is to be recommended, universal iron supplementation in malarious areas should only be considered in conjunction with some form of prophylaxis (e.g., intermittent preventive therapy [IPT]) or in the context of good health services with ready access to facilities for malaria diagnosis and treatment. An alternative approach would be to screen for anemia and target supplementation only to anemic children. With regard to treatment, there is good evidence that iron supplementation should be withheld until the treatment schedule is complete, both because iron may inhibit treatment and because the absorption of oral iron is blocked by the inflammatory response.

Among the various parasitic diseases, malaria is the deadliest one. Due to the emergence of high drug resistance to the existing drug candidates there is a global need for development of new drug candidates which will be effective against... more

Among the various parasitic diseases, malaria is the deadliest one. Due to the emergence of high drug resistance to the existing drug candidates there is a global need for development of new drug candidates which will be effective against resistant strains of malaria parasite. In silico molecular modeling approaches have been playing an important role in the discovery of novel lead molecules having antimalarial activity. Present review is an effort to cover all the developments related to the application of computational techniques for the design and discovery of novel antimalarial compounds since the year 2011 onwards.

This paper is an overview of vaccine antigens against malaria produced in plants. Plant-based expression systems represent an interesting production platform due to their reduced manufacturing costs and high scalability. At present,... more

This paper is an overview of vaccine antigens against malaria produced in plants. Plant-based expression systems represent an interesting production platform due to their reduced manufacturing costs and high scalability. At present, different Plasmodium antigens and expression strategies have been optimized in plants. Furthermore, malaria antigens are one of the few examples of eukaryotic proteins with vaccine value expressed in plants, making plant-derived malaria antigens an interesting model to analyze. Up to now, malaria antigen expression in plants has allowed the complete synthesis of these vaccine antigens, which have been able to induce an active immune response in mice. Therefore, plant production platforms offer wonderful prospects for improving the access to malaria vaccines.

We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba... more

We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica, Plasmodium berghei, Leishmania mexicana and Trypanosoma cruzi). Compound 1 (benzologue of NIT) showed broad antiprotozoal effect against all parasites tested, showing IC 50 's <5lM. This compound was five-times more active than NIT, and 18-times more potent than metronidazole against G. intestinalis. It was 10-times more active than pentamidine against L. mexicana, and it was sevenfold more potent than benznidazole versus T. cruzi. This compound could be considered as a new broad spectrum antiprotozoal agent.

The Malaria Research and Reference Reagent Resource-recommended PLF/UNR/VIR polymerase chain reaction (PCR) was used to detect Plasmodium vivax in Anopheles spp. mosquitoes collected in South Korea. Samples that were amplified were... more

The Malaria Research and Reference Reagent Resource-recommended PLF/UNR/VIR polymerase chain reaction (PCR) was used to detect Plasmodium vivax in Anopheles spp. mosquitoes collected in South Korea. Samples that were amplified were sequenced and compared with known Plasmodium spp. by using the PlasmoDB.org Basic Local Alignment Search Tool/n and the National Center for Biotechnology Information Basic Local Alignment Search Tool/n tools. Results show that the primers PLF/UNR/VIR used in this PCR can produce uninterpretable results and non-specific sequences in field-collected mosquitoes. Three additional PCRs (PLU/VIV, specific for 18S small subunit ribosomal DNA; Pvr47, specific for a nuclear repeat; and GDCW/PLAS, specific for the mitochondrial marker, cytB) were then used to find a more accurate and interpretable assay. Samples that were amplified were again sequenced. The PLU/VIV and Pvr47 assays showed cross-reactivity with non-Plasmodium spp. and an arthropod fungus (Zoophthora lanceolata). The GDCW/PLAS assay amplified only Plasmodium spp. but also amplified the non-human specific parasite P. berghei from an Anopheles belenrae mosquito. Detection of P. berghei in South Korea is a new finding.

Background & objectives: Field trials of lambda-cyhalothrin 10 CS (ICON 10 CS) in indoor residual spraying (IRS) with 25 mg a.i./m 2 against Anopheles culicifacies was undertaken vs malathion IRS (25% WP-2 g a.i./ m 2) in Tumkur district,... more

Background & objectives: Field trials of lambda-cyhalothrin 10 CS (ICON 10 CS) in indoor residual spraying (IRS) with 25 mg a.i./m 2 against Anopheles culicifacies was undertaken vs malathion IRS (25% WP-2 g a.i./ m 2) in Tumkur district, Karnataka; vs deltamethrin IRS (2.5% WP-20 mg a.i./m 2) in Dharmapuri district; and vs lambda-cyhalothrin (10 WP-25 mg a.i./m 2) in Ramanathapuram district, Tamil Nadu, India. Methods: Spray operations in the experimental villages were done by the National Institute of Malaria Research (NIMR) and in the control villages by the respective State Health Department staff. Persistence of efficacy of insecticide sprayed in villages was assessed by contact bioassays against vector mosquitoes. Entomological indicators such as per structure density, parity rates of vector mosquitoes and sporozoite rates were measured in all the three study areas using standard procedures. Mass blood surveys and active fever case detections were carried out in experimental and control villages to study the impact of IRS on malaria transmission. Results: Persistence of effectiveness of ICON 10 CS was observed up to 2-3 months in all the three study areas. ICON 10 CS was found effective at par with or better than the insecticides used in the national programme in reducing the mosquito densities and in interrupting malaria transmission in the study villages. Vector density, parity rates and malaria cases considerably reduced in the ICON 10 CS-sprayed villages. Conclusion: Field trials at three sites have established that ICON 10 CS formulation was relatively more effective than malathion 25% WP, deltamethrin 2.5% WP and lambda-cyhalothrin 10% WP in some evaluation parameters like indoor resting mosquitoes, parity rates in vector mosquitoes and persistence of effectiveness. It can be used for IRS for malaria vector control with two rounds of spray at an interval of 3 months for curtailing the malaria transmission and an additional round is recommended in perennial malaria transmission areas.

Remnants oflipoproteins, intestinal chylomicrons, and very low density lipoproteins (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of... more

Remnants oflipoproteins, intestinal chylomicrons, and very low density lipoproteins (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs), and that their subsequent internalization into hepatocytes is mediated by members of the LDLreceptor gene family. Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein (CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs. Lactoferrin, a protein with antibacterial properties found in breast milk and neutrophil granules, is also rapidly cleared from the circulation by hepatocytes, and can inhibit the hepatic uptake of lipoprotein remnants. Here we provide evidence that sporozoites, lactoferrin, and remnant lipoproteins are cleared from the blood by similar mechanisms. CS, lactoferrin, and remnant lipoproteins compete in vitro and in vivo for binding sites on liver cells. The relevance of this binding event for sporozoite infectivity is highlighted by our demonstration that apoliprotein E-enriched [3-VLDL and lactoferrin inhibit sporozoite invasion of HepG2 cells. In addition, malaria sporozoites are less infective in LDL-receptor knockout (LDLR-/-) mice maintained on a high fat diet, as compared with littermates maintained on a normal diet. We conclude that the clearance oflipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane.

The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called “non-immune” comprising all humans who... more

The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called “non-immune” comprising all humans who have never acquired immunity against malaria and the second type is called “semi-immune”. Non-immune are divided into susceptible, exposed and infectious and semi-immune are divided into susceptible, exposed, infectious and immune. We obtain an explicit formula for the reproductive number, R 0 which is a function of the weight of the transmission semi-immune-mosquito-semi-immune, R 0a , and the weight of the transmission non-immune-mosquito-non-immune, R 0e . Then, we study the existence of endemic equilibria by using bifurcation analysis. We give a simple criterion when R 0 crosses one for forward and backward bifurcation. We explore the possibility of a control for malaria through a specific sub-group such as non-immune or semi-immune or mosquitoes.

Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most... more

Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most vulnerable populations, claiming the lives of nearly one million children and pregnant women each year. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite's complex life cycle with a view toward developing the tools that will contribute to the prevention of disease and death and, ultimately, to the goal of malaria eradication. In so doing, we hope to inspire immunologists to participate in defeating this devastating disease. 157 Erratum Annu. Rev. Immunol. 2014.32:157-187. Downloaded from www.annualreviews.org by University of Virginia on 08/18/14. For personal use only.

Pathogens of the genus Plasmodium are unicellular parasites that infect a variety of animals, including reptiles, birds and mammals. All Plasmodium species target host erythrocytes and replicate asexually within this niche. In humans,... more

Pathogens of the genus Plasmodium are unicellular parasites that infect a variety of animals, including reptiles, birds and mammals. All Plasmodium species target host erythrocytes and replicate asexually within this niche. In humans, proliferation within erythrocytes causes disease symptoms ranging from asymtomatic infection to severe disease, including mild to severe febrile and respiratory symptoms, profound anaemia and obstruction of blood flow. The most serious form of human malaria is caused by Plasmodium falciparum, a pathogen that is responsible for several million deaths annually throughout the developing world. Malaria parasites succeed in evading the host immune response to establish long-term, persistent infections, thus increasing the efficiency by which they are transmitted to the mosquito vector. The ability to evade the host immune system, in particular the avoidance of antibody-mediated immunity against parasite-encoded surface proteins, is the result of amplificati...

In order to sustain the gains achieved by current malaria control strategies, robust surveillance systems that monitor dynamics of vectors and their roles in malaria transmission over time are essential. This longitudinal study... more

In order to sustain the gains achieved by current malaria control strategies, robust surveillance systems that monitor dynamics of vectors and their roles in malaria transmission over time are essential. This longitudinal study demonstrates the trends in malaria vector dynamics and their relative contribution to malaria transmission in hyperendemic transmission settings in Tanzania. The study was conducted in two villages within the Kilombero Valley, in rural Tanzania for five consecutive years (2008-2012). Seventy-two houses were selected per village and each house was sampled for mosquitoes monthly using a CDC light trap. Collected mosquitoes were assessed for species identity and sporozoite infection status using PCR and ELISA, respectively. Anopheles funestus and Anopheles arabiensis susceptibility to insecticides was assessed using WHO guidelines. A total of 100,810 malaria vectors were collected, of which 76% were Anopheles gambiae s. l. and 24% were An. funestus. Of all An. f...

Objective: To determine the accuracy of thrombocytopenia as a diagnostic marker for malaria. Study Design: Cross-sectional study. Place and Duration of Study: Department of Medicine, 1 Mountain Medical Battalion (Bagh, Azad Kashmir) from... more

Objective: To determine the accuracy of thrombocytopenia as a diagnostic marker for malaria. Study Design: Cross-sectional study. Place and Duration of Study: Department of Medicine, 1 Mountain Medical Battalion (Bagh, Azad Kashmir) from July to September 2013. Methodology: Adult patients presenting with a short history of fever without any localizing symptoms or signs were included. Exclusion criteria included patients with fever of > 7 days duration, those in whom an underlying diagnosis could be easily confirmed on the basis of history and physical examination, those on antibiotics/ antimalarials or antiplatelet agents and patients with Dengue fever. Platelet counts in venous whole blood samples were analysed with Sysmex KX-21 Haematology analyzer. Thick and thin peripheral blood smears were then prepared and examined for malarial parasites. Diagnosis of malaria was established on the basis of smear findings. Results: There were 245 patients in total. Out of the 109 patients with thrombocytopenia, 61 had vivax malaria. Platelets count was normal in 136 patients, including 4 with vivax malaria. Falciparum malaria was not seen in any patient. All cases with malaria were uncomplicated. Various measures of accuracy thus calculated were sensitivity 93.85%, specificity 73.33%, positive predictive value 55.96%, negative predictive value 97.06%, positive likelihood ratio of 3.52, negative likelihood ratio of 0.08, diagnostic odds ratio 41.94 and diagnostic accuracy of 78.78%. Conclusion: Thrombocytopenia has an excellent sensitivity and a very good specificity for vivax malaria. Normal platelet counts provide very strong evidence against malaria as the etiology of fever without a focus.

a b s t r a c t Based on the historical success of natural products as antimalarial drugs and the urgent need for new antimalarials, a number of South African medicinal plants have been evaluated for their antimalarial properties. This... more

a b s t r a c t Based on the historical success of natural products as antimalarial drugs and the urgent need for new antimalarials, a number of South African medicinal plants have been evaluated for their antimalarial properties. This paper reviews the major studies conducted and their findings. Overall three ethnobotanical screening programmes have been conducted on South African plants while there have been a few studies adopting a more direct approach, where plants within a particular genus were screened for antiplasmodial activity. The paper also summarizes the bioactive molecules identified from selected plants having antiplasmodial activity. Overall the results of all studies conducted to date confirm the potential of South African medicinal plants in antimalarial drug discovery and identified a number of promising taxa and compounds for further investigation as plant-based antimalarial agents.

A deterministic differential equation model for the population dynamics of the human malaria vector is derived and studied. Conditions for the existence and stability of a non-zero steady-state vector population density are derived. These... more

A deterministic differential equation model for the population dynamics of the human malaria vector is derived and studied. Conditions for the existence and stability of a non-zero steady-state vector population density are derived. These reveal that a threshold parameter, the vectorial basic reproduction number exist and the vector can established itself in the community if and only if this parameter exceeds unity. When a non-zero steady-state population density exists, it can be stable but it can also be driven to instability via a Hopf bifurcation to periodic solutions, as a parameter is varied in parameter space. By considering a special case, an asymptotic perturbation analysis is used to derive the amplitude of the oscillating solutions for the full nonlinear system. The present modelling exercise and results show that it is possible to study the population dynamics of disease vectors, and hence oscillatory behaviour as it is often observed in most indirectly transmitted infectious diseases of humans, without recourse to external seasonal forcing.

Background: Sampling malaria vectors and measuring their biting density is of paramount importance for entomological surveys of malaria transmission. Human landing catch (HLC) has been traditionally regarded as a gold standard method for... more

Background: Sampling malaria vectors and measuring their biting density is of paramount importance for entomological surveys of malaria transmission. Human landing catch (HLC) has been traditionally regarded as a gold standard method for surveying human exposure to mosquito bites. However, due to the risk of human participant exposure to mosquito-borne parasites and viruses, a variety of alternative, exposure-free trapping methods were compared in lowland, south-east Zambia. Methods: Centres for Disease Control and Prevention miniature light trap (CDC-LT), Ifakara Tent Trap model C (ITT-C), resting boxes (RB) and window exit traps (WET) were all compared with HLC using a 3 × 3 Latin Squares design replicated in 4 blocks of 3 houses with long lasting insecticidal nets, half of which were also sprayed with a residual deltamethrin formulation, which was repeated for 10 rounds of 3 nights of rotation each during both the dry and wet seasons.

Background. Getting DNA became capital since the emergence of molecular assays. Plasmodium DNA is used for malaria diagnosis by PCR, monitoring of molecular resistance or for clinical vaccine trial. DNA is commonly extracted from liquid... more

Eukaryotic cells can degrade their own components, cytosolic proteins and organelles, using dedicated hydrolases contained within the acidic interior of their lysosomes. This degradative process, called autophagy, is used under starvation... more

Eukaryotic cells can degrade their own components, cytosolic proteins and organelles, using dedicated hydrolases contained within the acidic interior of their lysosomes. This degradative process, called autophagy, is used under starvation conditions to recycle redundant or less important macromolecules, facilitates metabolic re-modeling in response to environmental cues, and is also often important during cell differentiation. In this review, we discuss the role played by autophagy during the life cycles of the major parasitic protists. To provide context, we also provide an overview of the different forms of autophagy and the successive steps in the autophagic processes, including the proteins involved, as revealed in recent decades by studies using the model organism Saccharomyces cerevisiae, methylotrophic yeasts and mammalian cells. We describe for trypanosomatid parasites how autophagy plays a role in the differentiation from one life cycle stage to the next one and, in the case of the intracellular parasites, for virulence. For malarial parasites, although only a limited repertoire of canonical autophagy-related proteins can be detected, autophagy seems to play a role in the removal of redundant organelles important for cell invasion, when sporozoites develop into intracellular trophozoites inside the hepatocytes. The complete absence of a canonical autophagy pathway from the microaerophile Giardia lamblia is also discussed. Finally, the essential role of autophagy for differentiation and pathogenicity of some pathogenic protists suggests that the proteins involved in this process may represent new targets for drug development. Opportunities and strategies for drug design targeting autophagy proteins are discussed. (3)P, phosphatidylinositol 3-phosphate; RNAi, RNA interference; TOR, target-of-rapamycin. ଝ Note: Different nomenclature rules exist for acronyms of proteins and genes in mammals, yeasts and protists. To avoid confusion, the nomenclature system for trypanosomatids (upper case for proteins, italicized upper case for genes) has been used throughout in this paper, also for proteins and genes from other organisms . .be (A. Brennand), melisa.gualdron@uclouvain.be (M. Gualdrón-López), icoppens@jhsph.edu (I. Coppens), drigden@liverpool.ac.uk (D.J. Rigden), m.ginger@lancaster.ac.uk (M.L. Ginger), paul.michels@uclouvain.be (P.A.M. Michels).

The epidemiology of malaria in "low-transmission" areas has been underestimated. Molecular detection methods have revealed higher prevalences of malaria than conventional microscopy or rapid diagnostic tests, but these typically... more

The epidemiology of malaria in "low-transmission" areas has been underestimated. Molecular detection methods have revealed higher prevalences of malaria than conventional microscopy or rapid diagnostic tests, but these typically evaluate finger-prick capillary blood samples (∼5 μl) and therefore cannot detect parasite densities of <200/ml. Their use underestimates true parasite carriage rates. To characterize the epidemiology of malaria in low-transmission settings and plan elimination strategies, more sensitive quantitative PCR (qPCR) is needed to identify and quantify low-density malaria parasitemias. A highly sensitive "high-volume" quantitative PCR (qPCR) method based on Plasmodium sp. 18S RNA was adapted for blood sample volumes of ≥250 μl and scaled for high throughput. The methods were validated by assessment of the analytical sensitivity and specificity, diagnostic sensitivity, and specificity, efficiency, precision, analytical and diagnostic accuracie...