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Sample records for malariae blood-stage dynamics

  1. Whole organism blood stage vaccines against malaria.

    PubMed

    Stanisic, Danielle I; Good, Michael F

    2015-12-22

    Despite a century of research focused on the development and implementation of effective control strategies, infection with the malaria parasite continues to result in significant morbidity and mortality worldwide. An effective malaria vaccine is considered by many to be the definitive solution. Yet, after decades of research, we are still without a vaccine that is capable of inducing robust, long lasting protection in naturally exposed individuals. Extensive sub-unit vaccine development focused on the blood stage of the malaria parasite has thus far yielded disappointing results. There is now a renewed focus on whole parasite vaccine strategies, particularly as they may overcome some of the inherent weaknesses deemed to be associated with the sub-unit approach. This review discusses the whole parasite vaccine strategy focusing on the blood stage of the malaria parasite, with an emphasis on recent advances and challenges in the development of killed and live attenuated vaccines. PMID:26428451

  2. Progress and prospects for blood-stage malaria vaccines

    PubMed Central

    Miura, Kazutoyo

    2016-01-01

    ABSTRACT There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part. PMID:26760062

  3. Progress and prospects for blood-stage malaria vaccines.

    PubMed

    Miura, Kazutoyo

    2016-06-01

    There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part. PMID:26760062

  4. Malaria invasion ligand RH5 and its prime candidacy in blood-stage malaria vaccine design

    PubMed Central

    Ord, Rosalynn L; Rodriguez, Marilis; Lobo, Cheryl A

    2015-01-01

    With drug resistance to available therapeutics continuing to develop against Plasmodium falciparum malaria, the development of an effective vaccine candidate remains a major research goal. Successful interruption of invasion of parasites into erythrocytes during the blood stage of infection will prevent the severe clinical symptoms and complications associated with malaria. Previously studied blood stage antigens have highlighted the hurdles that are inherent to this life-cycle stage, namely that highly immunogenic antigens are also globally diverse, resulting in protection only against the vaccine strain, or that naturally acquired immunity to blood stage antigens do not always correlate with actual protection. The blood stage antigen reticulocyte binding homolog RH5 is essential for parasite viability, has globally limited diversity, and is associated with protection from disease. Here we summarize available information on this invasion ligand and recent findings that highlight its candidacy for inclusion in a blood-stage malaria vaccine. PMID:25844685

  5. Deconvoluting heme biosynthesis to target blood-stage malaria parasites.

    PubMed

    Sigala, Paul A; Crowley, Jan R; Henderson, Jeffrey P; Goldberg, Daniel E

    2015-01-01

    Heme metabolism is central to blood-stage infection by the malaria parasite Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations. PMID:26173178

  6. Deconvoluting heme biosynthesis to target blood-stage malaria parasites

    PubMed Central

    Sigala, Paul A; Crowley, Jan R; Henderson, Jeffrey P; Goldberg, Daniel E

    2015-01-01

    Heme metabolism is central to blood-stage infection by the malaria parasite Plasmodium falciparum. Parasites retain a heme biosynthesis pathway but do not require its activity during infection of heme-rich erythrocytes, where they can scavenge host heme to meet metabolic needs. Nevertheless, heme biosynthesis in parasite-infected erythrocytes can be potently stimulated by exogenous 5-aminolevulinic acid (ALA), resulting in accumulation of the phototoxic intermediate protoporphyrin IX (PPIX). Here we use photodynamic imaging, mass spectrometry, parasite gene disruption, and chemical probes to reveal that vestigial host enzymes in the cytoplasm of Plasmodium-infected erythrocytes contribute to ALA-stimulated heme biosynthesis and that ALA uptake depends on parasite-established permeability pathways. We show that PPIX accumulation in infected erythrocytes can be harnessed for antimalarial chemotherapy using luminol-based chemiluminescence and combinatorial stimulation by low-dose artemisinin to photoactivate PPIX to produce cytotoxic reactive oxygen. This photodynamic strategy has the advantage of exploiting host enzymes refractory to resistance-conferring mutations. DOI: http://dx.doi.org/10.7554/eLife.09143.001 PMID:26173178

  7. Liver-inherent immune system: its role in blood-stage malaria

    PubMed Central

    Wunderlich, Frank; Al-Quraishy, Saleh; Dkhil, Mohamed A.

    2014-01-01

    The liver is well known as that organ which is obligately required for the intrahepatocyte development of the pre-erythrocytic stages of the malaria-causative agent Plasmodium. However, largely neglected is the fact that the liver is also a central player of the host defense against the morbidity- and mortality-causing blood stages of the malaria parasites. Indeed, the liver is equipped with a unique immune system that acts locally, however, with systemic impact. Its main “antipodal” functions are to recognize and to generate effective immunoreactivity against pathogens on the one hand, and to generate tolerance to avoid immunoreactivity with “self” and harmless substances as dietary compounds on the other hand. This review provides an introductory survey of the liver-inherent immune system: its pathogen recognition receptors including Toll-like receptors (TLRs) and its major cell constituents with their different facilities to fight and eliminate pathogens. Then, evidence is presented that the liver is also an essential organ to overcome blood-stage malaria. Finally, we discuss effector responses of the liver-inherent immune system directed against blood-stage malaria: activation of TLRs, acute phase response, phagocytic activity, cytokine-mediated pro- and anti-inflammatory responses, generation of “protective” autoimmunity by extrathymic T cells and B-1 cells, and T cell-mediated repair of liver injuries mainly produced by malaria-induced overreactions of the liver-inherent immune system. PMID:25408684

  8. Liver-inherent immune system: its role in blood-stage malaria.

    PubMed

    Wunderlich, Frank; Al-Quraishy, Saleh; Dkhil, Mohamed A

    2014-01-01

    The liver is well known as that organ which is obligately required for the intrahepatocyte development of the pre-erythrocytic stages of the malaria-causative agent Plasmodium. However, largely neglected is the fact that the liver is also a central player of the host defense against the morbidity- and mortality-causing blood stages of the malaria parasites. Indeed, the liver is equipped with a unique immune system that acts locally, however, with systemic impact. Its main "antipodal" functions are to recognize and to generate effective immunoreactivity against pathogens on the one hand, and to generate tolerance to avoid immunoreactivity with "self" and harmless substances as dietary compounds on the other hand. This review provides an introductory survey of the liver-inherent immune system: its pathogen recognition receptors including Toll-like receptors (TLRs) and its major cell constituents with their different facilities to fight and eliminate pathogens. Then, evidence is presented that the liver is also an essential organ to overcome blood-stage malaria. Finally, we discuss effector responses of the liver-inherent immune system directed against blood-stage malaria: activation of TLRs, acute phase response, phagocytic activity, cytokine-mediated pro- and anti-inflammatory responses, generation of "protective" autoimmunity by extrathymic T cells and B-1 cells, and T cell-mediated repair of liver injuries mainly produced by malaria-induced overreactions of the liver-inherent immune system. PMID:25408684

  9. An essential malaria protein defines the architecture of blood-stage and transmission-stage parasites.

    PubMed

    Absalon, Sabrina; Robbins, Jonathan A; Dvorin, Jeffrey D

    2016-01-01

    Blood-stage replication of the human malaria parasite Plasmodium falciparum occurs via schizogony, wherein daughter parasites are formed by a specialized cytokinesis known as segmentation. Here we identify a parasite protein, which we name P. falciparum Merozoite Organizing Protein (PfMOP), as essential for cytokinesis of blood-stage parasites. We show that, following PfMOP knockdown, parasites undergo incomplete segmentation resulting in a residual agglomerate of partially divided cells. While organelles develop normally, the structural scaffold of daughter parasites, the inner membrane complex (IMC), fails to form in this agglomerate causing flawed segmentation. In PfMOP-deficient gametocytes, the IMC formation defect causes maturation arrest with aberrant morphology and death. Our results provide insight into the mechanisms of replication and maturation of malaria parasites. PMID:27121004

  10. An essential malaria protein defines the architecture of blood-stage and transmission-stage parasites

    PubMed Central

    Absalon, Sabrina; Robbins, Jonathan A.; Dvorin, Jeffrey D.

    2016-01-01

    Blood-stage replication of the human malaria parasite Plasmodium falciparum occurs via schizogony, wherein daughter parasites are formed by a specialized cytokinesis known as segmentation. Here we identify a parasite protein, which we name P. falciparum Merozoite Organizing Protein (PfMOP), as essential for cytokinesis of blood-stage parasites. We show that, following PfMOP knockdown, parasites undergo incomplete segmentation resulting in a residual agglomerate of partially divided cells. While organelles develop normally, the structural scaffold of daughter parasites, the inner membrane complex (IMC), fails to form in this agglomerate causing flawed segmentation. In PfMOP-deficient gametocytes, the IMC formation defect causes maturation arrest with aberrant morphology and death. Our results provide insight into the mechanisms of replication and maturation of malaria parasites. PMID:27121004

  11. Evidence of Blood Stage Efficacy with a Virosomal Malaria Vaccine in a Phase IIa Clinical Trial

    PubMed Central

    Thompson, Fiona M.; Porter, David W.; Okitsu, Shinji L.; Westerfeld, Nicole; Vogel, Denise; Todryk, Stephen; Poulton, Ian; Correa, Simon; Hutchings, Claire; Berthoud, Tamara; Dunachie, Susanna; Andrews, Laura; Williams, Jack L.; Sinden, Robert; Gilbert, Sarah C.; Pluschke, Gerd; Zurbriggen, Rinaldo; Hill, Adrian V. S.

    2008-01-01

    Background Previous research indicates that a combination vaccine targeting different stages of the malaria life cycle is likely to provide the most effective malaria vaccine. This trial was the first to combine two existing vaccination strategies to produce a vaccine that induces immune responses to both the pre-erythrocytic and blood stages of the P. falciparum life cycle. Methods This was a Phase I/IIa study of a new combination malaria vaccine FFM ME-TRAP+PEV3A. PEV3A includes peptides from both the pre-erythrocytic circumsporozoite protein and the blood-stage antigen AMA-1. This study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. The participants were healthy, malaria naïve volunteers, from Oxford. The interventions were vaccination with PEV3A alone, or PEV3A+FFM ME-TRAP. The main outcome measure was protection from malaria in a sporozoite challenge model. Other outcomes included measures of parasite specific immune responses induced by either vaccine; and safety, assessed by collection of adverse event data. Results We observed evidence of blood stage immunity in PEV3A vaccinated volunteers, but no volunteers were completely protected from malaria. PEV3A induced high antibody titres, and antibodies bound parasites in immunofluorescence assays. Moreover, we observed boosting of the vaccine-induced immune response by sporozoite challenge. Immune responses induced by FFM ME-TRAP were unexpectedly low. The vaccines were safe, with comparable side effect profiles to previous trials. Although there was no sterile protection two major observations support an effect of the vaccine-induced response on blood stage parasites: (i) Lower rates of parasite growth were observed in volunteers vaccinated with PEV3A compared to unvaccinated controls (p = 0.012), and this was reflected in the PCR results from PEV3A vaccinated volunteers. These showed early control of parasitaemia by some volunteers in this

  12. Modulation of host responses to blood-stage malaria by interleukin-12: from therapy to adjuvant activity.

    PubMed

    Stevenson, M M; Su, Z; Sam, H; Mohan, K

    2001-01-01

    This review focuses on the role of interleukin (IL)-12, a proinflammatory cytokine with pleiotropic effects as a potent immunoregulatory molecule and hematopoietic growth factor, in infection with Plasmodium parasites, the causative agents of malaria. IL-12 has been demonstrated to have profound effects on the immune response to blood-stage malaria, to induce protection, and to alleviate malarial anemia. In combination with an anti-malarial drug, IL-12 is effective in an established malaria infection. This cytokine also has potent immune effects as a malaria vaccine adjuvant. However, IL-12 can also mediate pathology during blood-stage malaria. PMID:11226854

  13. The evolutionary consequences of blood-stage vaccination on the rodent malaria Plasmodium chabaudi.

    PubMed

    Barclay, Victoria C; Sim, Derek; Chan, Brian H K; Nell, Lucas A; Rabaa, Maia A; Bell, Andrew S; Anders, Robin F; Read, Andrew F

    2012-01-01

    Malaria vaccine developers are concerned that antigenic escape will erode vaccine efficacy. Evolutionary theorists have raised the possibility that some types of vaccine could also create conditions favoring the evolution of more virulent pathogens. Such evolution would put unvaccinated people at greater risk of severe disease. Here we test the impact of vaccination with a single highly purified antigen on the malaria parasite Plasmodium chabaudi evolving in laboratory mice. The antigen we used, AMA-1, is a component of several candidate malaria vaccines currently in various stages of trials in humans. We first found that a more virulent clone was less readily controlled by AMA-1-induced immunity than its less virulent progenitor. Replicated parasites were then serially passaged through control or AMA-1 vaccinated mice and evaluated after 10 and 21 rounds of selection. We found no evidence of evolution at the ama-1 locus. Instead, virulence evolved; AMA-1-selected parasites induced greater anemia in naïve mice than both control and ancestral parasites. Our data suggest that recombinant blood stage malaria vaccines can drive the evolution of more virulent malaria parasites. PMID:22870063

  14. Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

    PubMed Central

    Khoury, David S.; Cromer, Deborah; Best, Shannon E.; James, Kylie R.; Kim, Peter S.; Engwerda, Christian R.; Haque, Ashraful

    2014-01-01

    Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection. PMID:24144725

  15. Effect of mature blood-stage Plasmodium parasite sequestration on pathogen biomass in mathematical and in vivo models of malaria.

    PubMed

    Khoury, David S; Cromer, Deborah; Best, Shannon E; James, Kylie R; Kim, Peter S; Engwerda, Christian R; Haque, Ashraful; Davenport, Miles P

    2014-01-01

    Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection. PMID:24144725

  16. Insights into the preclinical treatment of blood-stage malaria by the antibiotic borrelidin

    PubMed Central

    Azcárate, IG; Marín-García, P; Camacho, N; Pérez-Benavente, S; Puyet, A; Diez, A; Ribas de Pouplana, L; Bautista, JM

    2013-01-01

    Background and Purpose Blood-stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl-tRNA synthetases have been validated as antimalarial drug targets. We explored long-term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria. Experimental Approach Long-term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed. Key Results Borrelidin protected against lethal malaria at 0.25 mg·kg−1·day−1. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re-infection on further challenges, 75 and 340 days after the initial infection. This long-term immunity in borrelidin-treated mice resulted in negligible parasitaemia after re-infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long-term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts. Conclusions and Implications Low borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria. PMID:23488671

  17. Reversible host cell remodeling underpins deformability changes in malaria parasite sexual blood stages

    PubMed Central

    Dearnley, Megan; Chu, Trang; Zhang, Yao; Looker, Oliver; Huang, Changjin; Klonis, Nectarios; Yeoman, Jeff; Kenny, Shannon; Arora, Mohit; Osborne, James M.; Chandramohanadas, Rajesh; Zhang, Sulin; Dixon, Matthew W. A.; Tilley, Leann

    2016-01-01

    The sexual blood stage of the human malaria parasite Plasmodium falciparum undergoes remarkable biophysical changes as it prepares for transmission to mosquitoes. During maturation, midstage gametocytes show low deformability and sequester in the bone marrow and spleen cords, thus avoiding clearance during passage through splenic sinuses. Mature gametocytes exhibit increased deformability and reappear in the peripheral circulation, allowing uptake by mosquitoes. Here we define the reversible changes in erythrocyte membrane organization that underpin this biomechanical transformation. Atomic force microscopy reveals that the length of the spectrin cross-members and the size of the skeletal meshwork increase in developing gametocytes, then decrease in mature-stage gametocytes. These changes are accompanied by relocation of actin from the erythrocyte membrane to the Maurer’s clefts. Fluorescence recovery after photobleaching reveals reversible changes in the level of coupling between the membrane skeleton and the plasma membrane. Treatment of midstage gametocytes with cytochalasin D decreases the vertical coupling and increases their filterability. A computationally efficient coarse-grained model of the erythrocyte membrane reveals that restructuring and constraining the spectrin meshwork can fully account for the observed changes in deformability. PMID:27071094

  18. Reversible host cell remodeling underpins deformability changes in malaria parasite sexual blood stages.

    PubMed

    Dearnley, Megan; Chu, Trang; Zhang, Yao; Looker, Oliver; Huang, Changjin; Klonis, Nectarios; Yeoman, Jeff; Kenny, Shannon; Arora, Mohit; Osborne, James M; Chandramohanadas, Rajesh; Zhang, Sulin; Dixon, Matthew W A; Tilley, Leann

    2016-04-26

    The sexual blood stage of the human malaria parasite Plasmodium falciparum undergoes remarkable biophysical changes as it prepares for transmission to mosquitoes. During maturation, midstage gametocytes show low deformability and sequester in the bone marrow and spleen cords, thus avoiding clearance during passage through splenic sinuses. Mature gametocytes exhibit increased deformability and reappear in the peripheral circulation, allowing uptake by mosquitoes. Here we define the reversible changes in erythrocyte membrane organization that underpin this biomechanical transformation. Atomic force microscopy reveals that the length of the spectrin cross-members and the size of the skeletal meshwork increase in developing gametocytes, then decrease in mature-stage gametocytes. These changes are accompanied by relocation of actin from the erythrocyte membrane to the Maurer's clefts. Fluorescence recovery after photobleaching reveals reversible changes in the level of coupling between the membrane skeleton and the plasma membrane. Treatment of midstage gametocytes with cytochalasin D decreases the vertical coupling and increases their filterability. A computationally efficient coarse-grained model of the erythrocyte membrane reveals that restructuring and constraining the spectrin meshwork can fully account for the observed changes in deformability. PMID:27071094

  19. Protection against malaria in mice is induced by blood stage-arresting histamine-releasing factor (HRF)-deficient parasites.

    PubMed

    Demarta-Gatsi, Claudia; Smith, Leanna; Thiberge, Sabine; Peronet, Roger; Commere, Pierre-Henri; Matondo, Mariette; Apetoh, Lionel; Bruhns, Pierre; Ménard, Robert; Mécheri, Salaheddine

    2016-07-25

    Although most vaccines against blood stage malaria in development today use subunit preparations, live attenuated parasites confer significantly broader and more lasting protection. In recent years, Plasmodium genetically attenuated parasites (GAPs) have been generated in rodent models that cause self-resolving blood stage infections and induce strong protection. All such GAPs generated so far bear mutations in housekeeping genes important for parasite development in red blood cells. In this study, using a Plasmodium berghei model compatible with tracking anti-blood stage immune responses over time, we report a novel blood stage GAP that lacks a secreted factor related to histamine-releasing factor (HRF). Lack of HRF causes an IL-6 increase, which boosts T and B cell responses to resolve infection and leave a cross-stage, cross-species, and lasting immunity. Mutant-induced protection involves a combination of antiparasite IgG2c antibodies and FcγR(+) CD11b(+) cell phagocytes, especially neutrophils, which are sufficient to confer protection. This immune-boosting GAP highlights an important role of opsonized parasite-mediated phagocytosis, which may be central to protection induced by all self-resolving blood stage GAP infections. PMID:27432939

  20. Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria

    PubMed Central

    Leoratti, Fabiana MS; Durlacher, Rui R; Lacerda, Marcus VG; Alecrim, Maria G; Ferreira, Antonio W; Sanchez, Maria CA; Moraes, Sandra L

    2008-01-01

    Background The development of protective immunity against malaria is slow and to be maintained, it requires exposure to multiple antigenic variants of malaria parasites and age-associated maturation of the immune system. Evidence that the protective immunity is associated with different classes and subclasses of antibodies reveals the importance of considering the quality of the response. In this study, we have evaluated the humoral immune response against Plasmodium falciparum blood stages of individuals naturally exposed to malaria who live in endemic areas of Brazil in order to assess the prevalence of different specific isotypes and their association with different malaria clinical expressions. Methods Different isotypes against P. falciparum blood stages, IgG, IgG1, IgG2, IgG3, IgG4, IgM, IgE and IgA, were determined by ELISA. The results were based on the analysis of different clinical expressions of malaria (complicated, uncomplicated and asymptomatic) and factors related to prior malaria exposure such as age and the number of previous clinical malaria attacks. The occurrence of the H131 polymorphism of the FcγIIA receptor was also investigated in part of the studied population. Results The highest levels of IgG, IgG1, IgG2 and IgG3 antibodies were observed in individuals with asymptomatic and uncomplicated malaria, while highest levels of IgG4, IgE and IgM antibodies were predominant among individuals with complicated malaria. Individuals reporting more than five previous clinical malaria attacks presented a predominance of IgG1, IgG2 and IgG3 antibodies, while IgM, IgA and IgE antibodies predominated among individuals reporting five or less previous clinical malaria attacks. Among individuals with uncomplicated and asymptomatic malaria, there was a predominance of high-avidity IgG, IgG1, IgG2 antibodies and low-avidity IgG3 antibodies. The H131 polymorphism was found in 44.4% of the individuals, and the highest IgG2 levels were observed among asymptomatic

  1. Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase

    PubMed Central

    Sturm, Angelika; Mollard, Vanessa; Cozijnsen, Anton; Goodman, Christopher D.; McFadden, Geoffrey I.

    2015-01-01

    Mitochondrial ATP synthase is driven by chemiosmotic oxidation of pyruvate derived from glycolysis. Blood-stage malaria parasites eschew chemiosmosis, instead relying almost solely on glycolysis for their ATP generation, which begs the question of whether mitochondrial ATP synthase is necessary during the blood stage of the parasite life cycle. We knocked out the mitochondrial ATP synthase β subunit gene in the rodent malaria parasite, Plasmodium berghei, ablating the protein that converts ADP to ATP. Disruption of the β subunit gene of the ATP synthase only marginally reduced asexual blood-stage parasite growth but completely blocked mouse-to-mouse transmission via Anopheles stephensi mosquitoes. Parasites lacking the β subunit gene of the ATP synthase generated viable gametes that fuse and form ookinetes but cannot progress beyond this stage. Ookinetes lacking the β subunit gene of the ATP synthase had normal motility but were not viable in the mosquito midgut and never made oocysts or sporozoites, thereby abrogating transmission to naive mice via mosquito bite. We crossed the self-infertile ATP synthase β subunit knockout parasites with a male-deficient, self-infertile strain of P. berghei, which restored fertility and production of oocysts and sporozoites, which demonstrates that mitochondrial ATP synthase is essential for ongoing viability through the female, mitochondrion-carrying line of sexual reproduction in P. berghei malaria. Perturbation of ATP synthase completely blocks transmission to the mosquito vector and could potentially be targeted for disease control. PMID:25831536

  2. Subcompartmentalisation of Proteins in the Rhoptries Correlates with Ordered Events of Erythrocyte Invasion by the Blood Stage Malaria Parasite

    PubMed Central

    Zuccala, Elizabeth S.; Gout, Alexander M.; Dekiwadia, Chaitali; Marapana, Danushka S.; Angrisano, Fiona; Turnbull, Lynne; Riglar, David T.; Rogers, Kelly L.; Whitchurch, Cynthia B.; Ralph, Stuart A.; Speed, Terence P.; Baum, Jake

    2012-01-01

    Host cell infection by apicomplexan parasites plays an essential role in lifecycle progression for these obligate intracellular pathogens. For most species, including the etiological agents of malaria and toxoplasmosis, infection requires active host-cell invasion dependent on formation of a tight junction – the organising interface between parasite and host cell during entry. Formation of this structure is not, however, shared across all Apicomplexa or indeed all parasite lifecycle stages. Here, using an in silico integrative genomic search and endogenous gene-tagging strategy, we sought to characterise proteins that function specifically during junction-dependent invasion, a class of proteins we term invasins to distinguish them from adhesins that function in species specific host-cell recognition. High-definition imaging of tagged Plasmodium falciparum invasins localised proteins to multiple cellular compartments of the blood stage merozoite. This includes several that localise to distinct subcompartments within the rhoptries. While originating from the same organelle, however, each has very different dynamics during invasion. Apical Sushi Protein and Rhoptry Neck protein 2 release early, following the junction, whilst a novel rhoptry protein PFF0645c releases only after invasion is complete. This supports the idea that organisation of proteins within a secretory organelle determines the order and destination of protein secretion and provides a localisation-based classification strategy for predicting invasin function during apicomplexan parasite invasion. PMID:23049965

  3. IFNγ Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection

    PubMed Central

    Jagannathan, Prasanna; Nankya, Felistas; Stoyanov, Cristina; Eccles-James, Ijeoma; Sikyomu, Esther; Naluwu, Kate; Wamala, Samuel; Nalubega, Mayimuna; Briggs, Jessica; Bowen, Katherine; Bigira, Victor; Kapisi, James; Kamya, Moses R.; Dorsey, Grant; Feeney, Margaret E.

    2015-01-01

    Background. The malaria-specific T-cell response is believed to be important for protective immunity. Antimalarial chemoprevention may affect this response by altering exposure to malaria antigens. Methods. We performed interferon γ (IFNγ) ELISpot assays to assess the cellular immune response to blood-stage and pre-erythrocytic antigens longitudinally from 1 to 3 years of age in 196 children enrolled in a randomized trial of antimalarial chemoprevention in Tororo, Uganda, an area of high transmission intensity. Results. IFNγ responses to blood-stage antigens, particularly MSP1, were frequently detected, strongly associated with recent malaria exposure, and lower in those adherent to chemoprevention compared to nonadherent children and those randomized to no chemoprevention. IFNγ responses to pre-erythrocytic antigens were infrequent and similar between children randomized to chemoprevention or no chemoprevention. Responses to blood-stage antigens were not associated with subsequent protection from malaria (aHR 0.96, P = .83), but responses to pre-erythrocytic antigens were associated with protection after adjusting for prior malaria exposure (aHR 0.52, P = .009). Conclusions. In this high transmission setting, IFNγ responses to blood-stage antigens were common and associated with recent exposure to malaria but not protection from subsequent malaria. Responses to pre-erythrocytic antigens were uncommon, not associated with exposure but were associated with protection from subsequent malaria. PMID:25520427

  4. ChAd63-MVA–vectored Blood-stage Malaria Vaccines Targeting MSP1 and AMA1: Assessment of Efficacy Against Mosquito Bite Challenge in Humans

    PubMed Central

    Sheehy, Susanne H; Duncan, Christopher JA; Elias, Sean C; Choudhary, Prateek; Biswas, Sumi; Halstead, Fenella D; Collins, Katharine A; Edwards, Nick J; Douglas, Alexander D; Anagnostou, Nicholas A; Ewer, Katie J; Havelock, Tom; Mahungu, Tabitha; Bliss, Carly M; Miura, Kazutoyo; Poulton, Ian D; Lillie, Patrick J; Antrobus, Richard D; Berrie, Eleanor; Moyle, Sarah; Gantlett, Katherine; Colloca, Stefano; Cortese, Riccardo; Long, Carole A; Sinden, Robert E; Gilbert, Sarah C; Lawrie, Alison M; Doherty, Tom; Faust, Saul N; Nicosia, Alfredo; Hill, Adrian VS; Draper, Simon J

    2012-01-01

    The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1—results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets. PMID:23089736

  5. Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites.

    PubMed

    Paul, Aditya S; Moreira, Cristina K; Elsworth, Brendan; Allred, David R; Duraisingh, Manoj T

    2016-08-01

    The apicomplexan parasites that cause malaria and babesiosis invade and proliferate within erythrocytes. To assess the potential for common antiparasitic treatments, we measured the sensitivities of multiple species of Plasmodium and Babesia parasites to the chemically diverse collection of antimalarial compounds in the Malaria Box library. We observed that these parasites share sensitivities to a large fraction of the same inhibitors and we identified compounds with strong babesiacidal activity. PMID:27246780

  6. Assessment of Humoral Immune Responses to Blood-Stage Malaria Antigens following ChAd63-MVA Immunization, Controlled Human Malaria Infection and Natural Exposure

    PubMed Central

    Elias, Sean C.; Miura, Kazutoyo; Milne, Kathryn H.; de Cassan, Simone C.; Collins, Katharine A.; Halstead, Fenella D.; Bliss, Carly M.; Ewer, Katie J.; Osier, Faith H.; Hodgson, Susanne H.; Duncan, Christopher J. A.; O’Hara, Geraldine A.; Long, Carole A.; Hill, Adrian V. S.; Draper, Simon J.

    2014-01-01

    The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite – MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors – ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other

  7. Report of a consultation on the optimization of clinical challenge trials for evaluation of candidate blood stage malaria vaccines, 18-19 March 2009, Bethesda, MD, USA.

    PubMed

    Moorthy, V S; Diggs, C; Ferro, S; Good, M F; Herrera, S; Hill, A V; Imoukhuede, E B; Kumar, S; Loucq, C; Marsh, K; Ockenhouse, C F; Richie, T L; Sauerwein, R W

    2009-09-25

    Development and optimization of first generation malaria vaccine candidates has been facilitated by the existence of a well-established Plasmodium falciparum clinical challenge model in which infectious sporozoites are administered to human subjects via mosquito bite. While ideal for testing pre-erythrocytic stage vaccines, some researchers believe that the sporozoite challenge model is less appropriate for testing blood stage vaccines. Here we report a consultation, co-sponsored by PATH MVI, USAID, EMVI and WHO, where scientists from all institutions globally that have conducted such clinical challenges in recent years and representatives from regulatory agencies and funding agencies met to discuss clinical malaria challenge models. Participants discussed strengthening and harmonizing the sporozoite challenge model and considered the pros and cons of further developing a blood stage challenge possibly better suited for evaluating the efficacy of blood stage vaccines. This report summarizes major findings and recommendations, including an update on the Plasmodium vivax clinical challenge model, the prospects for performing experimental challenge trials in malaria endemic countries and an update on clinical safety data. While the focus of the meeting was on the optimization of clinical challenge models for evaluation of blood stage candidate malaria vaccines, many of the considerations are relevant for the application of challenge trials to other purposes. PMID:19654061

  8. The Malaria Secretome: From Algorithms to Essential Function in Blood Stage Infection

    PubMed Central

    van Ooij, Christiaan; Tamez, Pamela; Bhattacharjee, Souvik; Hiller, N. Luisa; Harrison, Travis; Liolios, Konstantinos; Kooij, Taco; Ramesar, Jai; Balu, Bharath; Adams, John; Waters, Andy; Janse, Chris; Haldar, Kasturi

    2008-01-01

    The malaria agent Plasmodium falciparum is predicted to export a “secretome” of several hundred proteins to remodel the host erythrocyte. Prediction of protein export is based on the presence of an ER-type signal sequence and a downstream Host-Targeting (HT) motif (which is similar to, but distinct from, the closely related Plasmodium Export Element [PEXEL]). Previous attempts to determine the entire secretome, using either the HT-motif or the PEXEL, have yielded large sets of proteins, which have not been comprehensively tested. We present here an expanded secretome that is optimized for both P. falciparum signal sequences and the HT-motif. From the most conservative of these three secretome predictions, we identify 11 proteins that are preserved across human- and rodent-infecting Plasmodium species. The conservation of these proteins likely indicates that they perform important functions in the interaction with and remodeling of the host erythrocyte important for all Plasmodium parasites. Using the piggyBac transposition system, we validate their export and find a positive prediction rate of ∼70%. Even for proteins identified by all secretomes, the positive prediction rate is not likely to exceed ∼75%. Attempted deletions of the genes encoding the conserved exported proteins were not successful, but additional functional analyses revealed the first conserved secretome function. This gave new insight into mechanisms for the assembly of the parasite-induced tubovesicular network needed for import of nutrients into the infected erythrocyte. Thus, genomic screens combined with functional assays provide unexpected and fundamental insights into host remodeling by this major human pathogen. PMID:18551176

  9. Assessment of Immune Interference, Antagonism and Diversion following Human Immunization with Bi-Allelic Blood-Stage Malaria Viral Vectored Vaccines and Controlled Malaria Infection

    PubMed Central

    Elias, Sean C.; Collins, Katharine A.; Halstead, Fenella D.; Choudhary, Prateek; Bliss, Carly M.; Ewer, Katie J.; Sheehy, Susanne H.; Duncan, Christopher J. A.; Biswas, Sumi; Hill, Adrian V. S.; Draper, Simon J.

    2012-01-01

    Overcoming antigenic variation is one of the major challenges in the development of an effective vaccine against Plasmodium falciparum, a causative agent of human malaria. Inclusion of multiple antigen variants in subunit vaccine candidates is one strategy that has aimed to overcome this problem for the leading blood-stage malaria vaccine targets, merozoite surface protein 1 (MSP1) and apical membrane antigen 1 (AMA1). However previous studies, utilizing malaria antigens, have concluded that inclusion of multiple allelic variants, encoding altered peptide ligands (APL), in such a vaccine may be detrimental to both the priming and in vivo re-stimulation of antigen-experienced T cells. Here we analyze the T cell responses to two alleles of MSP1 and AMA1 induced by vaccination of malaria-naïve adult volunteers with bi-valent viral vectored vaccine candidates. We show a significant bias to the 3D7/MAD20 allele compared to the Wellcome allele for the 33kDa region of MSP1, but not for the 19kDa fragment or the AMA1 antigen. Whilst this bias could be caused by ‘immune interference’ at priming, the data don’t support a significant role for ‘immune antagonism’ during memory T cell re-stimulation, despite observation of the latter at a minimal epitope level in vitro. A lack of class I HLA epitopes in the Wellcome allele that are recognized by vaccinated volunteers may in fact contribute to the observed bias. We also show that controlled infection with 3D7 strain P. falciparum parasites neither boosts existing 3D7-specific T cell responses nor appears to ‘immune divert’ cellular responses towards the Wellcome allele. PMID:23293353

  10. Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers

    PubMed Central

    McCarthy, James S.; Baker, Mark; O'Rourke, Peter; Marquart, Louise; Griffin, Paul; Hooft van Huijsduijnen, Rob; Möhrle, Jörg J.

    2016-01-01

    Objectives OZ439, or artefenomel, is an investigational synthetic ozonide antimalarial with similar potency, but a significantly improved pharmacokinetic profile, compared with artemisinins. We wished to measure key pharmacokinetic and pharmacodynamic parameters and the pharmacokinetic/pharmacodynamic relationship of artefenomel in humans to guide the drug's further development as combination therapy in patients. Patients and methods We tested artefenomel in the human induced blood-stage malaria (IBSM) model. Plasmodium infection was monitored by quantitative PCR (qPCR) and upon reaching 1000 parasites/mL single doses of 100, 200 and 500 mg of artefenomel were administered orally with evaluation of drug exposure and parasitaemia until rescue treatment after 16 days or earlier, if required. Results A single 100 mg dose had only a transient effect, while the 200 mg dose resulted in a significant reduction in parasitaemia before early recrudescence. At the highest (500 mg) dose, initial clearance of parasites below the limit of detection of qPCR was observed, with a 48 h parasite reduction ratio (PRR48) >10 000 and a parasite clearance half-life of 3.6 h (95% CI 3.4–3.8 h). However, at this dose, recrudescence was seen in four of eight subjects 6–10 days after treatment. Pharmacokinetic/pharmacodynamic modelling predicted an MIC of 4.1 ng/mL. Conclusions These results confirm the antimalarial potential of artefenomel for use in a single-exposure combination therapy. The observations from this study support and will assist further clinical development of artefenomel. PMID:27272721

  11. In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

    PubMed Central

    Borges da Silva, Henrique; Fonseca, Raíssa; Cassado, Alexandra dos Anjos; Machado de Salles, Érika; de Menezes, Maria Nogueira; Langhorne, Jean; Perez, Katia Regina; Cuccovia, Iolanda Midea; Ryffel, Bernhard; Barreto, Vasco M.; Marinho, Cláudio Romero Farias; Boscardin, Silvia Beatriz; Álvarez, José Maria; D’Império-Lima, Maria Regina; Tadokoro, Carlos Eduardo

    2015-01-01

    Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection. PMID:25658925

  12. Blood-stage malaria of Plasmodium chabaudi induces differential Tlr expression in the liver of susceptible and vaccination-protected Balb/c mice.

    PubMed

    Al-Quraishy, Saleh; Dkhil, Mohamed A; Alomar, Suliman; Abdel-Baki, Abdel Azeem S; Delic, Denis; Wunderlich, Frank; Araúzo-Bravo, Marcos J

    2016-05-01

    Protective vaccination induces self-healing of otherwise lethal blood-stage infections of Plasmodium chabaudi malaria. Here, we investigate mRNA expression patterns of all 12 members of the Toll-like receptor (Tlr) gene family in the liver, a major effector organ against blood-stage malaria, during lethal and vaccination-induced self-healing infections of P. chabaudi in female Balb/c mice. Gene expression microarrays reveal that all 12 Tlr genes are constitutively expressed, though at varying levels, and specifically respond to infection. Protective vaccination does not affect constitutive expression of any of the 12 Tlr genes but leads to differential expression (p < 0.05) of seven Tlrs (1, 2, 4, 7, 8, 12, and 13) in response to malaria. Quantitative PCR substantiates differential expression at p < 0.01. There is an increased expression of Tlr2 by approximately five-fold on day 1 post-infection (p.i.) and Tlr1 by approximately threefold on day 4 p.i.. At peak parasitemia on day 8 p.i., none of the 12 Tlrs display any differential expression. After peak parasitemia, towards the end of the crisis phase on day 11 p.i., expression of Tlrs 1, 4, and 12 is increased by approximately four-, two-, and three-fold, respectively, and that of Tlr7 is decreased by approximately two-fold. Collectively, our data suggest that though all 12 members of the Tlr gene family are specifically responsive to malaria in the liver, not only Tlr2 at the early stage of infection but also the Tlrs 1, 4, 7, and 12 towards the end of crisis phase are critical for vaccination-induced resolution and survival of otherwise lethal blood-stage malaria. PMID:26809341

  13. Protective Vaccination against Blood-Stage Malaria of Plasmodium chabaudi: Differential Gene Expression in the Liver of Balb/c Mice toward the End of Crisis Phase

    PubMed Central

    Al-Quraishy, Saleh A.; Dkhil, Mohamed A.; Abdel-Baki, Abdel-Azeem A.; Delic, Denis; Wunderlich, Frank

    2016-01-01

    Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination-protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0.01) differences in hepatic gene and lincRNA expression in vaccination-protected vs. non-vaccinated mice toward the end of crisis phase. In vaccination-protected mice, infections induce up-regulations of 276 genes and 40 lincRNAs and down-regulations of 200 genes and 43 lincRNAs, respectively, by >3-fold as compared to the corresponding constitutive expressions. Massive up-regulations, partly by >100-fold, are found for genes as RhD, Add2, Ank1, Ermap, and Slc4a, which encode proteins of erythrocytic surface membranes, and as Gata1 and Gfi1b, which encode transcription factors involved in erythrocytic development. Also, Cldn13 previously predicted to be expressed on erythroblast surfaces is up-regulated by >200-fold, though claudins are known as main constituents of tight junctions acting as paracellular barriers between epithelial cells. Other genes are up-regulated by <100- and >10-fold, which can be subgrouped in genes encoding proteins known to be involved in mitosis, in cell cycle regulation, and in DNA repair. Our data suggest that protective vaccination enables the liver to respond to P. chabaudi infections with accelerated regeneration and extramedullary erythropoiesis during crisis, which contributes to survival of otherwise lethal blood-stage malaria. PMID:27471498

  14. Protective Vaccination against Blood-Stage Malaria of Plasmodium chabaudi: Differential Gene Expression in the Liver of Balb/c Mice toward the End of Crisis Phase.

    PubMed

    Al-Quraishy, Saleh A; Dkhil, Mohamed A; Abdel-Baki, Abdel-Azeem A; Delic, Denis; Wunderlich, Frank

    2016-01-01

    Protective vaccination induces self-healing of otherwise fatal blood-stage malaria of Plasmodium chabaudi in female Balb/c mice. To trace processes critically involved in self-healing, the liver, an effector against blood-stage malaria, is analyzed for possible changes of its transcriptome in vaccination-protected in comparison to non-protected mice toward the end of the crisis phase. Gene expression microarray analyses reveal that vaccination does not affect constitutive expression of mRNA and lincRNA. However, malaria induces significant (p < 0.01) differences in hepatic gene and lincRNA expression in vaccination-protected vs. non-vaccinated mice toward the end of crisis phase. In vaccination-protected mice, infections induce up-regulations of 276 genes and 40 lincRNAs and down-regulations of 200 genes and 43 lincRNAs, respectively, by >3-fold as compared to the corresponding constitutive expressions. Massive up-regulations, partly by >100-fold, are found for genes as RhD, Add2, Ank1, Ermap, and Slc4a, which encode proteins of erythrocytic surface membranes, and as Gata1 and Gfi1b, which encode transcription factors involved in erythrocytic development. Also, Cldn13 previously predicted to be expressed on erythroblast surfaces is up-regulated by >200-fold, though claudins are known as main constituents of tight junctions acting as paracellular barriers between epithelial cells. Other genes are up-regulated by <100- and >10-fold, which can be subgrouped in genes encoding proteins known to be involved in mitosis, in cell cycle regulation, and in DNA repair. Our data suggest that protective vaccination enables the liver to respond to P. chabaudi infections with accelerated regeneration and extramedullary erythropoiesis during crisis, which contributes to survival of otherwise lethal blood-stage malaria. PMID:27471498

  15. Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method.

    PubMed

    Orbán, Ágnes; Rebelo, Maria; Molnár, Petra; Albuquerque, Inês S; Butykai, Adam; Kézsmárki, István

    2016-01-01

    Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using β-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66-76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method - besides being label and reagent-free, automated and rapid - has a high in vivo sensitivity and is ready for in-field evaluation. PMID:26983695

  16. Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method

    PubMed Central

    Orbán, Ágnes; Rebelo, Maria; Molnár, Petra; Albuquerque, Inês S.; Butykai, Adam; Kézsmárki, István

    2016-01-01

    Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using β-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66–76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method – besides being label and reagent-free, automated and rapid – has a high in vivo sensitivity and is ready for in-field evaluation. PMID:26983695

  17. Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method

    NASA Astrophysics Data System (ADS)

    Orbán, Ágnes; Rebelo, Maria; Molnár, Petra; Albuquerque, Inês S.; Butykai, Adam; Kézsmárki, István

    2016-03-01

    Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using β-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66–76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method – besides being label and reagent-free, automated and rapid – has a high in vivo sensitivity and is ready for in-field evaluation.

  18. Real-time in vivo imaging of transgenic bioluminescent blood stages of rodent malaria parasites in mice.

    PubMed

    Franke-Fayard, Blandine; Waters, Andrew P; Janse, Chris J

    2006-01-01

    This protocol describes a methodology for imaging the sequestration of infected erythrocytes of the rodent malaria parasite Plasmodium berghei in the bodies of live mice or in dissected organs, using a transgenic parasite that expresses luciferase. Real-time imaging of infected erythrocytes is performed by measuring bioluminescence produced by the enzymatic reaction between luciferase and its substrate luciferin, which is injected into the mice several minutes prior to imaging. The bioluminescence signal is detected by an intensified charge-coupled device (I-CCD) photon-counting video camera. Sequestration of infected erythrocytes is imaged during short-term infections with synchronous parasite development or during ongoing infections. With this technology, sequestration patterns of the schizont stage can be quantitatively analyzed within 1-2 d after infection. Real-time in vivo imaging of infected erythrocytes will provide increased insights into the dynamics of sequestration and its role in pathology, and can be used to evaluate strategies that prevent sequestration. PMID:17406270

  19. The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody.

    PubMed

    Douglas, Alexander D; Williams, Andrew R; Illingworth, Joseph J; Kamuyu, Gathoni; Biswas, Sumi; Goodman, Anna L; Wyllie, David H; Crosnier, Cécile; Miura, Kazutoyo; Wright, Gavin J; Long, Carole A; Osier, Faith H; Marsh, Kevin; Turner, Alison V; Hill, Adrian V S; Draper, Simon J

    2011-01-01

    Current vaccine strategies against the asexual blood stage of Plasmodium falciparum are mostly focused on well-studied merozoite antigens that induce immune responses after natural exposure, but have yet to induce robust protection in any clinical trial. Here we compare human-compatible viral-vectored vaccines targeting ten different blood-stage antigens. We show that the full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) is highly susceptible to cross-strain neutralizing vaccine-induced antibodies, out-performing all other antigens delivered by the same vaccine platform. We find that, despite being susceptible to antibody, PfRH5 is unlikely to be under substantial immune selection pressure; there is minimal acquisition of anti-PfRH5 IgG antibodies in malaria-exposed Kenyans. These data challenge the widespread beliefs that any merozoite antigen that is highly susceptible to immune attack would be subject to significant levels of antigenic polymorphism, and that erythrocyte invasion by P. falciparum is a degenerate process involving a series of parallel redundant pathways. PMID:22186897

  20. Humoral Responses to Plasmodium falciparum Blood-Stage Antigens and Association with Incidence of Clinical Malaria in Children Living in an Area of Seasonal Malaria Transmission in Burkina Faso, West Africa▿

    PubMed Central

    Nebie, Issa; Diarra, Amidou; Ouedraogo, Alphonse; Soulama, Issiaka; Bougouma, Edith C.; Tiono, Alfred B.; Konate, Amadou T.; Chilengi, Roma; Theisen, Michael; Dodoo, Daniel; Remarque, Ed; Bosomprah, Samuel; Milligan, Paul; Sirima, Sodiomon B.

    2008-01-01

    There is longstanding evidence that immunoglobulin G (IgG) has a role in protection against clinical malaria, and human antibodies of the cytophilic subclasses are thought to be particularly critical in this respect. In this cohort study, 286 Burkinabè children 6 months to 15 years old were kept under malaria surveillance in order to assess the protective role of antibody responses against four antigens which are currently being evaluated as vaccine candidates: apical membrane antigen 1 (AMA1), merozoite surface protein 1-19 (MSP1-19), MSP3, and glutamate-rich protein (GLURP). Total IgG, IgM, and IgG subclass responses were measured just before the malaria transmission season. The incidence of malaria was 2.4 episodes per child year of risk. After adjusting for the confounding effects of age, the level of total IgG to GLURP was strongly associated with reduced malaria incidence (incidence rate ratio associated with a doubling of total IgG, 0.79; 95% confidence interval, 0.66 to 0.94; P = 0.009.); there was a borderline statistically significant association between the level of total IgG to MSP3 and malaria incidence and no evidence of an association for total IgG to AMA1 and to MSP1-19. Of the IgG subclass responses studied, only IgG3 and IgG4 against GLURP and IgG1 against AMA1 were associated with reduced risk of clinical malaria. There was no evidence of an interaction between responses to AMA1 and baseline parasitemia in their effects on malaria incidence. Currently included in malaria vaccine formulations for clinical trials in humans, these blood-stage antigens, AMA1 and GLURP, offer good prospects for malaria vaccine development. PMID:18070896

  1. Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease.

    PubMed

    Ioannidis, Lisa J; Nie, Catherine Q; Ly, Ann; Ryg-Cornejo, Victoria; Chiu, Chris Y; Hansen, Diana S

    2016-02-01

    CXCL10, or IFN-γ-inducible protein 10, is a biomarker associated with increased risk for Plasmodium falciparum-mediated cerebral malaria (CM). Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM. In addition to organ-specific effects, the absence of CXCL10 during infection was also found to reduce parasite biomass. To identify the cellular sources of CXCL10 responsible for these processes, we irradiated and reconstituted wild-type (WT) and CXCL10(-/-) mice with bone marrow from either WT or CXCL10(-/-) mice. Similar to CXCL10(-/-) mice, chimeras unable to express CXCL10 in hematopoietic-derived cells controlled infection more efficiently than WT controls. In contrast, expression of CXCL10 in knockout mice reconstituted with WT bone marrow resulted in high parasite biomass levels, higher brain parasite and leukocyte sequestration rates, and increased susceptibility to CM. Neutrophils and inflammatory monocytes were identified as the main cellular sources of CXCL10 responsible for the induction of these processes. The improved control of parasitemia observed in the absence of CXCL10-mediated trafficking was associated with a preferential accumulation of CXCR3(+)CD4(+) T follicular helper cells in the spleen and enhanced Ab responses to infection. These results are consistent with the notion that some inflammatory responses elicited in response to malaria infection contribute to the development of high parasite densities involved in the induction of severe disease in target organs. PMID:26718341

  2. Combining Viral Vectored and Protein-in-adjuvant Vaccines Against the Blood-stage Malaria Antigen AMA1: Report on a Phase 1a Clinical Trial

    PubMed Central

    Hodgson, Susanne H; Choudhary, Prateek; Elias, Sean C; Milne, Kathryn H; Rampling, Thomas W; Biswas, Sumi; Poulton, Ian D; Miura, Kazutoyo; Douglas, Alexander D; Alanine, Daniel GW; Illingworth, Joseph J; de Cassan, Simone C; Zhu, Daming; Nicosia, Alfredo; Long, Carole A; Moyle, Sarah; Berrie, Eleanor; Lawrie, Alison M; Wu, Yimin; Ellis, Ruth D; Hill, Adrian V S; Draper, Simon J

    2014-01-01

    The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines—chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising “mixed-modality” regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible. PMID:25156127

  3. Combining viral vectored and protein-in-adjuvant vaccines against the blood-stage malaria antigen AMA1: report on a phase 1a clinical trial.

    PubMed

    Hodgson, Susanne H; Choudhary, Prateek; Elias, Sean C; Milne, Kathryn H; Rampling, Thomas W; Biswas, Sumi; Poulton, Ian D; Miura, Kazutoyo; Douglas, Alexander D; Alanine, Daniel Gw; Illingworth, Joseph J; de Cassan, Simone C; Zhu, Daming; Nicosia, Alfredo; Long, Carole A; Moyle, Sarah; Berrie, Eleanor; Lawrie, Alison M; Wu, Yimin; Ellis, Ruth D; Hill, Adrian V S; Draper, Simon J

    2014-12-01

    The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines--chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible. PMID:25156127

  4. Phase 1b Randomized Trial and Follow-Up Study in Uganda of the Blood-Stage Malaria Vaccine Candidate BK-SE36

    PubMed Central

    Yeka, Adoke; Balikagala, Betty; Suzuki, Nahoko; Shirai, Hiroki; Yagi, Masanori; Ito, Kazuya; Fukushima, Wakaba; Hirota, Yoshio; Nsereko, Christopher; Okada, Takuya; Kanoi, Bernard N.; Tetsutani, Kohhei; Arisue, Nobuko; Itagaki, Sawako; Tougan, Takahiro; Ishii, Ken J.; Ueda, Shigeharu; Egwang, Thomas G.; Horii, Toshihiro

    2013-01-01

    Background Up to now a malaria vaccine remains elusive. The Plasmodium falciparum serine repeat antigen-5 formulated with aluminum hydroxyl gel (BK-SE36) is a blood-stage malaria vaccine candidate that has undergone phase 1a trial in malaria-naive Japanese adults. We have now assessed the safety and immunogenicity of BK-SE36 in a malaria endemic area in Northern Uganda. Methods We performed a two-stage, randomized, single-blinded, placebo-controlled phase 1b trial (Current Controlled trials ISRCTN71619711). A computer-generated sequence randomized healthy subjects for 2 subcutaneous injections at 21-day intervals in Stage1 (21–40 year-olds) to 1-mL BK-SE36 (BKSE1.0) (n = 36) or saline (n = 20) and in Stage2 (6–20 year-olds) to BKSE1.0 (n = 33), 0.5-mL BK-SE36 (BKSE0.5) (n = 33), or saline (n = 18). Subjects and laboratory personnel were blinded. Safety and antibody responses 21-days post-second vaccination (Day42) were assessed. Post-trial, to compare the risk of malaria episodes 130–365 days post-second vaccination, Stage2 subjects were age-matched to 50 control individuals. Results Nearly all subjects who received BK-SE36 had induration (Stage1, n = 33, 92%; Stage2, n = 63, 96%) as a local adverse event. No serious adverse event related to BK-SE36 was reported. Pre-existing anti-SE36 antibody titers negatively correlated with vaccination-induced antibody response. At Day42, change in antibody titers was significant for seronegative adults (1.95-fold higher than baseline [95% CI, 1.56–2.43], p = 0.004) and 6–10 year-olds (5.71-fold [95% CI, 2.38–13.72], p = 0.002) vaccinated with BKSE1.0. Immunogenicity response to BKSE0.5 was low and not significant (1.55-fold [95% CI, 1.24–1.94], p = 0.75). In the ancillary analysis, cumulative incidence of first malaria episodes with ≥5000 parasites/µL was 7 cases/33 subjects in BKSE1.0 and 10 cases/33 subjects in BKSE0.5 vs. 29 cases/66 subjects in the control group

  5. CD8+ T Cells from a Novel T Cell Receptor Transgenic Mouse Induce Liver-Stage Immunity That Can Be Boosted by Blood-Stage Infection in Rodent Malaria

    PubMed Central

    Mollard, Vanessa; Sturm, Angelika; Neller, Michelle A.; Cozijnsen, Anton; Gregory, Julia L.; Davey, Gayle M.; Jones, Claerwen M.; Lin, Yi-Hsuan; Haque, Ashraful; Engwerda, Christian R.; Nie, Catherine Q.; Hansen, Diana S.; Murphy, Kenneth M.; Papenfuss, Anthony T.; Miles, John J.; Burrows, Scott R.; de Koning-Ward, Tania; McFadden, Geoffrey I.; Carbone, Francis R.; Crabb, Brendan S.; Heath, William R.

    2014-01-01

    To follow the fate of CD8+ T cells responsive to Plasmodium berghei ANKA (PbA) infection, we generated an MHC I-restricted TCR transgenic mouse line against this pathogen. T cells from this line, termed PbT-I T cells, were able to respond to blood-stage infection by PbA and two other rodent malaria species, P. yoelii XNL and P. chabaudi AS. These PbT-I T cells were also able to respond to sporozoites and to protect mice from liver-stage infection. Examination of the requirements for priming after intravenous administration of irradiated sporozoites, an effective vaccination approach, showed that the spleen rather than the liver was the main site of priming and that responses depended on CD8α+ dendritic cells. Importantly, sequential exposure to irradiated sporozoites followed two days later by blood-stage infection led to augmented PbT-I T cell expansion. These findings indicate that PbT-I T cells are a highly versatile tool for studying multiple stages and species of rodent malaria and suggest that cross-stage reactive CD8+ T cells may be utilized in liver-stage vaccine design to enable boosting by blood-stage infections. PMID:24854165

  6. Stearylamine Liposomal Delivery of Monensin in Combination with Free Artemisinin Eliminates Blood Stages of Plasmodium falciparum in Culture and P. berghei Infection in Murine Malaria

    PubMed Central

    Rohra, Shilpa; Raza, Mohsin; Hasan, Gulam Mustafa; Dutt, Suparna

    2015-01-01

    The global emergence of drug resistance in malaria is impeding the therapeutic efficacy of existing antimalarial drugs. Therefore, there is a critical need to develop an efficient drug delivery system to circumvent drug resistance. The anticoccidial drug monensin, a carboxylic ionophore, has been shown to have antimalarial properties. Here, we developed a liposome-based drug delivery of monensin and evaluated its antimalarial activity in lipid formulations of soya phosphatidylcholine (SPC) cholesterol (Chol) containing either stearylamine (SA) or phosphatidic acid (PA) and different densities of distearoyl phosphatidylethanolamine-methoxy-polyethylene glycol 2000 (DSPE-mPEG-2000). These formulations were found to be more effective than a comparable dose of free monensin in Plasmodium falciparum (3D7) cultures and established mice models of Plasmodium berghei strains NK65 and ANKA. Parasite killing was determined by a radiolabeled [3H]hypoxanthine incorporation assay (in vitro) and microscopic counting of Giemsa-stained infected erythrocytes (in vivo). The enhancement of antimalarial activity was dependent on the liposomal lipid composition and preferential uptake by infected red blood cells (RBCs). The antiplasmodial activity of monensin in SA liposome (50% inhibitory concentration [IC50], 0.74 nM) and SPC:Chol-liposome with 5 mol% DSPE-mPEG 2000 (IC50, 0.39 nM) was superior to that of free monensin (IC50, 3.17 nM), without causing hemolysis of erythrocytes. Liposomes exhibited a spherical shape, with sizes ranging from 90 to 120 nm, as measured by dynamic light scattering and high-resolution electron microscopy. Monensin in long-circulating liposomes of stearylamine with 5 mol% DSPE-mPEG 2000 in combination with free artemisinin resulted in enhanced killing of parasites, prevented parasite recrudescence, and improved survival. This is the first report to demonstrate that monensin in PEGylated stearylamine (SA) liposome has therapeutic potential against malaria

  7. Stearylamine Liposomal Delivery of Monensin in Combination with Free Artemisinin Eliminates Blood Stages of Plasmodium falciparum in Culture and P. berghei Infection in Murine Malaria.

    PubMed

    Rajendran, Vinoth; Rohra, Shilpa; Raza, Mohsin; Hasan, Gulam Mustafa; Dutt, Suparna; Ghosh, Prahlad C

    2016-03-01

    The global emergence of drug resistance in malaria is impeding the therapeutic efficacy of existing antimalarial drugs. Therefore, there is a critical need to develop an efficient drug delivery system to circumvent drug resistance. The anticoccidial drug monensin, a carboxylic ionophore, has been shown to have antimalarial properties. Here, we developed a liposome-based drug delivery of monensin and evaluated its antimalarial activity in lipid formulations of soya phosphatidylcholine (SPC) cholesterol (Chol) containing either stearylamine (SA) or phosphatidic acid (PA) and different densities of distearoyl phosphatidylethanolamine-methoxy-polyethylene glycol 2000 (DSPE-mPEG-2000). These formulations were found to be more effective than a comparable dose of free monensin in Plasmodium falciparum (3D7) cultures and established mice models of Plasmodium berghei strains NK65 and ANKA. Parasite killing was determined by a radiolabeled [(3)H]hypoxanthine incorporation assay (in vitro) and microscopic counting of Giemsa-stained infected erythrocytes (in vivo). The enhancement of antimalarial activity was dependent on the liposomal lipid composition and preferential uptake by infected red blood cells (RBCs). The antiplasmodial activity of monensin in SA liposome (50% inhibitory concentration [IC50], 0.74 nM) and SPC:Chol-liposome with 5 mol% DSPE-mPEG 2000 (IC50, 0.39 nM) was superior to that of free monensin (IC50, 3.17 nM), without causing hemolysis of erythrocytes. Liposomes exhibited a spherical shape, with sizes ranging from 90 to 120 nm, as measured by dynamic light scattering and high-resolution electron microscopy. Monensin in long-circulating liposomes of stearylamine with 5 mol% DSPE-mPEG 2000 in combination with free artemisinin resulted in enhanced killing of parasites, prevented parasite recrudescence, and improved survival. This is the first report to demonstrate that monensin in PEGylated stearylamine (SA) liposome has therapeutic potential against malaria

  8. Mice lacking Programmed cell death-1 show a role for CD8(+) T cells in long-term immunity against blood-stage malaria.

    PubMed

    Horne-Debets, Joshua M; Karunarathne, Deshapriya S; Faleiro, Rebecca J; Poh, Chek Meng; Renia, Laurent; Wykes, Michelle N

    2016-01-01

    Even after years of experiencing malaria, caused by infection with Plasmodium species, individuals still have incomplete immunity and develop low-density parasitemia on re-infection. Previous studies using the P. chabaudi (Pch) mouse model to understand the reason for chronic malaria, found that mice with a deletion of programmed cell death-1 (PD-1KO) generate sterile immunity unlike wild type (WT) mice. Here we investigated if the mechanism underlying this defect during acute immunity also impacts on long-term immunity. We infected WT and PD-1KO mice with Pch-malaria and measured protection as well as immune responses against re-infections, 15 or 20 weeks after the original infection had cleared. WT mice showed approximately 1% parasitemia compared to sterile immunity in PD-1KO mice on re-infection. An examination of the mechanisms of immunity behind this long-term protection in PD-1KO mice showed a key role for parasite-specific CD8(+) T cells even when CD4(+) T cells and B cells responded to re-infection. These studies indicate that long-term CD8(+) T cell-meditated protection requires consideration for future malaria vaccine design, as part of a multi-cell type response. PMID:27217330

  9. Mice lacking Programmed cell death-1 show a role for CD8+ T cells in long-term immunity against blood-stage malaria

    PubMed Central

    Horne-Debets, Joshua M.; Karunarathne, Deshapriya S.; Faleiro, Rebecca J.; Poh, Chek Meng; Renia, Laurent; Wykes, Michelle N.

    2016-01-01

    Even after years of experiencing malaria, caused by infection with Plasmodium species, individuals still have incomplete immunity and develop low-density parasitemia on re-infection. Previous studies using the P. chabaudi (Pch) mouse model to understand the reason for chronic malaria, found that mice with a deletion of programmed cell death-1 (PD-1KO) generate sterile immunity unlike wild type (WT) mice. Here we investigated if the mechanism underlying this defect during acute immunity also impacts on long-term immunity. We infected WT and PD-1KO mice with Pch-malaria and measured protection as well as immune responses against re-infections, 15 or 20 weeks after the original infection had cleared. WT mice showed approximately 1% parasitemia compared to sterile immunity in PD-1KO mice on re-infection. An examination of the mechanisms of immunity behind this long-term protection in PD-1KO mice showed a key role for parasite-specific CD8+ T cells even when CD4+ T cells and B cells responded to re-infection. These studies indicate that long-term CD8+ T cell-meditated protection requires consideration for future malaria vaccine design, as part of a multi-cell type response. PMID:27217330

  10. A Phase 1 Trial of MSP2-C1, a Blood-Stage Malaria Vaccine Containing 2 Isoforms of MSP2 Formulated with Montanide® ISA 720

    PubMed Central

    McCarthy, James S.; Marjason, Joanne; Elliott, Suzanne; Fahey, Paul; Bang, Gilles; Malkin, Elissa; Tierney, Eveline; Aked-Hurditch, Hayley; Adda, Christopher; Cross, Nadia; Richards, Jack S.; Fowkes, Freya J. I.; Boyle, Michelle J.; Long, Carole; Druilhe, Pierre; Beeson, James G.; Anders, Robin F.

    2011-01-01

    Background In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naïve adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide® ISA 720 as a water-in-oil emulsion. Methodology/Principal Findings The trial was designed to include three dose cohorts (10, 40, and 80 µg), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide® ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 µg dose; no subjects received the 80 µg dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 µg and 40 µg dose cohorts, with antibody levels by ELISA higher in the 40 µg cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth. Conclusions/Significance As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further

  11. A Phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel with CPG 7909, using two different formulations and dosing intervals.

    PubMed

    Ellis, Ruth D; Mullen, Gregory E D; Pierce, Mark; Martin, Laura B; Miura, Kazutoyo; Fay, Michael P; Long, Carole A; Shaffer, Donna; Saul, Allan; Miller, Louis H; Durbin, Anna P

    2009-06-24

    A Phase 1 study was conducted in 24 malaria naïve adults to assess the safety and immunogenicity of the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with CPG 7909 in two different formulations (phosphate buffer and saline), and given at two different dosing schedules, 0 and 1 month or 0 and 2 months. Both formulations were well tolerated and frequency of local reactions and solicited adverse events was similar among the groups. Peak antibody levels in the groups receiving CPG 7909 in saline were not significantly different than those receiving CPG 7909 in phosphate. Peak antibody levels in the groups vaccinated at a 0,2 month interval were 2.52-fold higher than those vaccinated at a 0,1 month interval (p=0.037, 95% CI 1.03, 4.28). In vitro growth inhibition followed the antibody level: median inhibition was 51% (0,1 month interval) versus 85% (0,2 month interval) in antibody from samples taken 2 weeks post-second vaccination (p=0.056). PMID:19410624

  12. Malaria

    MedlinePlus

    Quartan malaria; Falciparum malaria; Biduoterian fever; Blackwater fever; Tertian malaria; Plasmodium ... Malaria is caused by a parasite that is passed to humans by the bite of infected Anopheles ...

  13. A review of malaria transmission dynamics in forest ecosystems

    PubMed Central

    2014-01-01

    Malaria continues to be a major health problem in more than 100 endemic countries located primarily in tropical and sub-tropical regions around the world. Malaria transmission is a dynamic process and involves many interlinked factors, from uncontrollable natural environmental conditions to man-made disturbances to nature. Almost half of the population at risk of malaria lives in forest areas. Forests are hot beds of malaria transmission as they provide conditions such as vegetation cover, temperature, rainfall and humidity conditions that are conducive to distribution and survival of malaria vectors. Forests often lack infrastructure and harbor tribes with distinct genetic traits, socio-cultural beliefs and practices that greatly influence malaria transmission dynamics. Here we summarize the various topographical, entomological, parasitological, human ecological and socio-economic factors, which are crucial and shape malaria transmission in forested areas. An in-depth understanding and synthesis of the intricate relationship of these parameters in achieving better malaria control in various types of forest ecosystems is emphasized. PMID:24912923

  14. Profoundly Reduced CD1c+ Myeloid Dendritic Cell HLA-DR and CD86 Expression and Increased Tumor Necrosis Factor Production in Experimental Human Blood-Stage Malaria Infection.

    PubMed

    Loughland, Jessica R; Minigo, Gabriela; Burel, Julie; Tipping, Peta E; Piera, Kim A; Amante, Fiona H; Engwerda, Christian R; Good, Michael F; Doolan, Denise L; Anstey, Nicholas M; McCarthy, James S; Woodberry, Tonia

    2016-05-01

    Dendritic cells (DCs) are sentinels of the immune system that uniquely prime naive cells and initiate adaptive immune responses. CD1c (BDCA-1) myeloid DCs (CD1c(+) mDCs) highly express HLA-DR, have a broad Toll-like receptor (TLR) repertoire, and secrete immune modulatory cytokines. To better understand immune responses to malaria, CD1c(+) mDC maturation and cytokine production were examined in healthy volunteers before and after experimental intravenous Plasmodium falciparum infection with 150- or 1,800-parasite-infected red blood cells (pRBCs). After either dose, CD1c(+) mDCs significantly reduced HLA-DR expression in prepatent infections. Circulating CD1c(+) mDCs did not upregulate HLA-DR after pRBC or TLR ligand stimulation and exhibited reduced CD86 expression. At peak parasitemia, CD1c(+) mDCs produced significantly more tumor necrosis factor (TNF), whereas interleukin-12 (IL-12) production was unchanged. Interestingly, only the 1,800-pRBC dose caused a reduction in the circulating CD1c(+) mDC count with evidence of apoptosis. The 1,800-pRBC dose produced no change in T cell IFN-γ or IL-2 production at peak parasitemia or at 3 weeks posttreatment. Overall, CD1c(+) mDCs are compromised by P. falciparum exposure, with impaired HLA-DR and CD86 expression, and have an increased capacity for TNF but not IL-12 production. A first prepatent P. falciparum infection is sufficient to modulate CD1c(+) mDC responsiveness, likely contributing to hampered effector T cell cytokine responses and assisting parasite immune evasion. PMID:26902728

  15. Malaria

    MedlinePlus

    MENU Return to Web version Malaria Overview What is malaria? Malaria is an infection of a part of the blood called the red blood cells. It is ... by mosquitoes that carry a parasite that causes malaria. If a mosquito carrying this parasite bites you, ...

  16. The Plasmodium falciparum blood stages acquire factor H family proteins to evade destruction by human complement.

    PubMed

    Rosa, Thiago F A; Flammersfeld, Ansgar; Ngwa, Che J; Kiesow, Meike; Fischer, Rainer; Zipfel, Peter F; Skerka, Christine; Pradel, Gabriele

    2016-04-01

    The acquisition of regulatory proteins is a means of blood-borne pathogens to avoid destruction by the human complement. We recently showed that the gametes of the human malaria parasite Plasmodium falciparum bind factor H (FH) from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. While these findings provided a first glimpse of a complex mechanism used by Plasmodium to control the host immune attack, it is hitherto not known, how the pathogenic blood stages of the malaria parasite evade destruction by the human complement. We now show that the human complement system represents a severe threat for the replicating blood stages, particularly for the reinvading merozoites, with complement factor C3b accumulating on the surfaces of the intraerythrocytic schizonts as well as of free merozoites. C3b accumulation initiates terminal complement complex formation, in consequence resulting in blood stage lysis. To inactivate C3b, the parasites bind FH as well as related proteins FHL-1 and CFHR-1 to their surface, and FH binding is trypsin-resistant. Schizonts acquire FH via two contact sites, which involve CCP modules 5 and 20. Blockage of FH-mediated protection via anti-FH antibodies results in significantly impaired blood stage replication, pointing to the plasmodial complement evasion machinery as a promising malaria vaccine target. PMID:26457721

  17. Malaria.

    ERIC Educational Resources Information Center

    Dupasquier, Isabelle

    1989-01-01

    Malaria, the greatest pandemia in the world, claims an estimated one million lives each year in Africa alone. While it may still be said that for the most part malaria is found in what is known as the world's poverty belt, cases are now frequently diagnosed in western countries. Due to resistant strains of malaria which have developed because of…

  18. Malaria

    MedlinePlus

    Malaria is a serious disease caused by a parasite. You get it when an infected mosquito bites you. Malaria is a major cause of death worldwide, but ... at risk. There are four different types of malaria caused by four related parasites. The most deadly ...

  19. Malaria

    PubMed Central

    Suh, Kathryn N.; Kain, Kevin C.; Keystone, Jay S.

    2004-01-01

    Malaria is a parasitic infection of global importance. Although relatively uncommon in developed countries, where the disease occurs mainly in travellers who have returned from endemic regions, it remains one of the most prevalent infections of humans worldwide. In endemic regions, malaria is a significant cause of morbidity and mortality and creates enormous social and economic burdens. Current efforts to control malaria focus on reducing attributable morbidity and mortality. Targeted chemoprophylaxis and use of insecticide-treated bed nets have been successful in some endemic areas. For travellers to malaria-endemic regions, personal protective measures and appropriate chemoprophylaxis can significantly reduce the risk of infection. Prompt evaluation of the febrile traveller, a high degree of suspicion of malaria, rapid and accurate diagnosis, and appropriate antimalarial therapy are essential in order to optimize clinical outcomes of infected patients. Additional approaches to malaria control, including genetic manipulation of mosquitoes and malaria vaccines, are areas of ongoing research. PMID:15159369

  20. Malaria

    MedlinePlus

    ... a parasite. You get it when an infected mosquito bites you. Malaria is a major cause of ... insect repellent with DEET Cover up Sleep under mosquito netting Centers for Disease Control and Prevention

  1. Malaria

    MedlinePlus

    ... Malaria can be carried by mosquitoes in temperate climates, but the parasite disappears over the winter. The ... a major disease hazard for travelers to warm climates. In some areas of the world, mosquitoes that ...

  2. Malaria.

    PubMed

    White, Nicholas J; Pukrittayakamee, Sasithon; Hien, Tran Tinh; Faiz, M Abul; Mokuolu, Olugbenga A; Dondorp, Arjen M

    2014-02-22

    Although global morbidity and mortality have decreased substantially, malaria, a parasite infection of red blood cells, still kills roughly 2000 people per day, most of whom are children in Africa. Two factors largely account for these decreases; increased deployment of insecticide-treated bednets and increased availability of highly effective artemisinin combination treatments. In large trials, parenteral artesunate (an artemisinin derivative) reduced severe malaria mortality by 22·5% in Africa and 34·7% in Asia compared with quinine, whereas adjunctive interventions have been uniformly unsuccessful. Rapid tests have been an important addition to microscopy for malaria diagnosis. Chemopreventive strategies have been increasingly deployed in Africa, notably intermittent sulfadoxine-pyrimethamine treatment in pregnancy, and monthly amodiaquine-sulfadoxine-pyrimethamine during the rainy season months in children aged between 3 months and 5 years across the sub-Sahel. Enthusiasm for malaria elimination has resurfaced. This ambitious but laudable goal faces many challenges, including the worldwide economic downturn, difficulties in elimination of vivax malaria, development of pyrethroid resistance in some anopheline mosquitoes, and the emergence of artemisinin resistance in Plasmodium falciparum in southeast Asia. We review the epidemiology, clinical features, pathology, prevention, and treatment of malaria. PMID:23953767

  3. Malaria transmission dynamics at a site in northern Ghana proposed for testing malaria vaccines.

    PubMed

    Appawu, Maxwell; Owusu-Agyei, Seth; Dadzie, Samuel; Asoala, Victor; Anto, Francis; Koram, Kwadwo; Rogers, William; Nkrumah, Francis; Hoffman, Stephen L; Fryauff, David J

    2004-01-01

    We studied the malaria transmission dynamics in Kassena Nankana district (KND), a site in northern Ghana proposed for testing malaria vaccines. Intensive mosquito sampling for 1 year using human landing catches in three micro-ecological sites (irrigated, lowland and rocky highland) yielded 18 228 mosquitoes. Anopheles gambiae s.l. and Anopheles funestus constituted 94.3% of the total collection with 76.8% captured from the irrigated communities. Other species collected but in relatively few numbers were Anopheles pharoensis (5.4%) and Anopheles rufipes (0.3%). Molecular analysis of 728 An. gambiae.s.l. identified Anopheles gambiae s.s. as the most dominant sibling species (97.7%) of the An. gambiae complex from the three ecological sites. Biting rates of the vectors (36.7 bites per man per night) were significantly higher (P<0.05) in the irrigated area than in the non-irrigated lowland (5.2) and rocky highlands (5.9). Plasmodium falciparum sporozoite rates of 7.2% (295/4075) and 7.1% (269/3773) were estimated for An. gambiae s.s. and An. funestus, respectively. Transmission was highly seasonal, and the heaviest transmission occurred from June to October. The intensity of transmission was higher for people in the irrigated communities than the non-irrigated ones. An overall annual entomological inoculation rate (EIR) of 418 infective bites was estimated in KND. There were micro-ecological variations in the EIRs, with values of 228 infective bites in the rocky highlands, 360 in the lowlands and 630 in the irrigated area. Approximately 60% of malaria transmission in KND occurred indoors during the second half of the night, peaking at daybreak between 04.00 and 06.00 hours. Vaccine trials could be conducted in this district, with timing dependent on the seasonal patterns and intensity of transmission taking into consideration the micro-geographical differences and vaccine trial objectives. PMID:14728621

  4. Population dynamics of a pathogen: the conundrum of vivax malaria.

    PubMed

    McQueen, Philip G

    2010-08-01

    Building a mathematical model of population dynamics of pathogens within their host involves considerations of factors similar to those in ecology, as pathogens can prey on cells in the host. But within the multicellular host, attacked cell types are integrated with other cellular systems, which in turn intervene in the infection. For example, immune responses attempt to sense and then eliminate or contain pathogens, and homeostatic mechanisms try to compensate for cell loss. This review focuses on modeling applied to malarias, diseases caused by single-cell eukaryote parasites that infect red blood cells, with special concern given to vivax malaria, a disease often thought to be benign (if sometimes incapacitating) because the parasite only attacks a small proportion of red blood cells, the very youngest ones. However, I will use mathematical modeling to argue that depletion of this pool of red blood cells can be disastrous to the host if growth of the parasite is not vigorously check by host immune responses. Also, modeling can elucidate aspects of new field observations that indicate that vivax malaria is more dangerous than previously thought. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12551-010-0034-3) contains supplementary material, which is available to authorized users. PMID:20730124

  5. Dynamics of Bacterial Community Composition in the Malaria Mosquito's Epithelia

    PubMed Central

    Tchioffo, Majoline T.; Boissière, Anne; Abate, Luc; Nsango, Sandrine E.; Bayibéki, Albert N.; Awono-Ambéné, Parfait H.; Christen, Richard; Gimonneau, Geoffrey; Morlais, Isabelle

    2016-01-01

    The Anopheles midgut hosts diverse bacterial communities and represents a complex ecosystem. Several evidences indicate that mosquito midgut microbiota interferes with malaria parasite transmission. However, the bacterial composition of salivary glands and ovaries, two other biologically important tissues, has not been described so far. In this study, we investigated the dynamics of the bacterial communities in the mosquito tissues from emerging mosquitoes until 8 days after a blood meal containing Plasmodium falciparum gametocytes and described the temporal colonization of the mosquito epithelia. Bacterial communities were identified in the midgut, ovaries, and salivary glands of individual mosquitoes using pyrosequencing of the 16S rRNA gene. We found that the mosquito epithelia share a core microbiota, but some bacteria taxa were more associated with one or another tissue at a particular time point. The bacterial composition in the tissues of emerging mosquitoes varied according to the breeding site, indicating that some bacteria are acquired from the environment. Our results revealed temporal variations in the bacterial community structure, possibly as a result of the mosquito physiological changes. The abundance of Serratia significantly correlated with P. falciparum infection both in the midgut and salivary glands of malaria challenged mosquitoes, which suggests that interactions occur between microbes and parasites. These bacteria may represent promising targets for vector control strategies. Overall, this study points out the importance of characterizing bacterial communities in malaria mosquito vectors. PMID:26779155

  6. Extreme Polymorphism in a Vaccine Antigen and Risk of Clinical Malaria: Implications for Vaccine Development

    PubMed Central

    Takala, Shannon L.; Coulibaly, Drissa; Thera, Mahamadou A.; Batchelor, Adrian H.; Cummings, Michael P.; Escalante, Ananias A.; Ouattara, Amed; Traoré, Karim; Niangaly, Amadou; Djimdé, Abdoulaye A.; Doumbo, Ogobara K.; Plowe, Christopher V.

    2010-01-01

    Vaccines directed against the blood stages of Plasmodium falciparum malaria are intended to prevent the parasite from invading and replicating within host cells. No blood-stage malaria vaccine has shown clinical efficacy in humans. Most malaria vaccine antigens are parasite surface proteins that have evolved extensive genetic diversity, and this diversity could allow malaria parasites to escape vaccine-induced immunity. We examined the extent and within-host dynamics of genetic diversity in the blood-stage malaria vaccine antigen apical membrane antigen–1 in a longitudinal study in Mali. Two hundred and fourteen unique apical membrane antigen–1 haplotypes were identified among 506 human infections, and amino acid changes near a putative invasion machinery binding site were strongly associated with the development of clinical symptoms, suggesting that these residues may be important to consider in designing polyvalent apical membrane antigen–1 vaccines and in assessing vaccine efficacy in field trials. This extreme diversity may pose a serious obstacle to an effective polyvalent recombinant subunit apical membrane antigen–1 vaccine. PMID:20165550

  7. Threshold dynamics of a malaria transmission model in periodic environment

    NASA Astrophysics Data System (ADS)

    Wang, Lei; Teng, Zhidong; Zhang, Tailei

    2013-05-01

    In this paper, we propose a malaria transmission model with periodic environment. The basic reproduction number R0 is computed for the model and it is shown that the disease-free periodic solution of the model is globally asymptotically stable when R0<1, that is, the disease goes extinct when R0<1, while the disease is uniformly persistent and there is at least one positive periodic solution when R0>1. It indicates that R0 is the threshold value determining the extinction and the uniform persistence of the disease. Finally, some examples are given to illustrate the main theoretical results. The numerical simulations show that, when the disease is uniformly persistent, different dynamic behaviors may be found in this model, such as the global attractivity and the chaotic attractor.

  8. Dynamical malaria models reveal how immunity buffers effect of climate variability

    PubMed Central

    Laneri, Karina; Paul, Richard E.; Tall, Adama; Faye, Joseph; Diene-Sarr, Fatoumata; Sokhna, Cheikh; Trape, Jean-François; Rodó, Xavier

    2015-01-01

    Assessing the influence of climate on the incidence of Plasmodium falciparum malaria worldwide and how it might impact local malaria dynamics is complex and extrapolation to other settings or future times is controversial. This is especially true in the light of the particularities of the short- and long-term immune responses to infection. In sites of epidemic malaria transmission, it is widely accepted that climate plays an important role in driving malaria outbreaks. However, little is known about the role of climate in endemic settings where clinical immunity develops early in life. To disentangle these differences among high- and low-transmission settings we applied a dynamical model to two unique adjacent cohorts of mesoendemic seasonal and holoendemic perennial malaria transmission in Senegal followed for two decades, recording daily P. falciparum cases. As both cohorts are subject to similar meteorological conditions, we were able to analyze the relevance of different immunological mechanisms compared with climatic forcing in malaria transmission. Transmission was first modeled by using similarly unique datasets of entomological inoculation rate. A stochastic nonlinear human–mosquito model that includes rainfall and temperature covariates, drug treatment periods, and population variability is capable of simulating the complete dynamics of reported malaria cases for both villages. We found that under moderate transmission intensity climate is crucial; however, under high endemicity the development of clinical immunity buffers any effect of climate. Our models open the possibility of forecasting malaria from climate in endemic regions but only after accounting for the interaction between climate and immunity. PMID:26124134

  9. Cross-stage immunity for malaria vaccine development.

    PubMed

    Nahrendorf, Wiebke; Scholzen, Anja; Sauerwein, Robert W; Langhorne, Jean

    2015-12-22

    A vaccine against malaria is urgently needed for control and eventual eradication. Different approaches are pursued to induce either sterile immunity directed against pre-erythrocytic parasites or to mimic naturally acquired immunity by controlling blood-stage parasite densities and disease severity. Pre-erythrocytic and blood-stage malaria vaccines are often seen as opposing tactics, but it is likely that they have to be combined into a multi-stage malaria vaccine to be optimally safe and effective. Since many antigenic targets are shared between liver- and blood-stage parasites, malaria vaccines have the potential to elicit cross-stage protection with immune mechanisms against both stages complementing and enhancing each other. Here we discuss evidence from pre-erythrocytic and blood-stage subunit and whole parasite vaccination approaches that show that protection against malaria is not necessarily stage-specific. Parasites arresting at late liver-stages especially, can induce powerful blood-stage immunity, and similarly exposure to blood-stage parasites can afford pre-erythrocytic immunity. The incorporation of a blood-stage component into a multi-stage malaria vaccine would hence not only combat breakthrough infections in the blood should the pre-erythrocytic component fail to induce sterile protection, but would also actively enhance the pre-erythrocytic potency of this vaccine. We therefore advocate that future studies should concentrate on the identification of cross-stage protective malaria antigens, which can empower multi-stage malaria vaccine development. PMID:26469724

  10. Seasonal dynamics and microgeographical spatial heterogeneity of malaria along the China-Myanmar border.

    PubMed

    Hu, Yue; Zhou, Guofa; Ruan, Yonghua; Lee, Ming-chieh; Xu, Xin; Deng, Shuang; Bai, Yao; Zhang, Jie; Morris, James; Liu, Huaie; Wang, Ying; Fan, Qi; Li, Peipei; Wu, Yanrui; Yang, Zhaoqing; Yan, Guiyun; Cui, Liwang

    2016-05-01

    Malaria transmission is heterogeneous in the Greater Mekong Subregion with most of the cases occurring along international borders. Knowledge of transmission hotspots is essential for targeted malaria control and elimination in this region. This study aimed to determine the dynamics of malaria transmission and possible existence of transmission hotspots on a microgeographical scale along the China-Myanmar border. Microscopically confirmed clinical malaria cases were recorded in five border villages through a recently established surveillance system between January 2011 and December 2014. A total of 424 clinical cases with confirmed spatial and temporal information were analyzed, of which 330 (77.8%) were Plasmodium vivax and 88 (20.8%) were Plasmodium falciparum, respectively. The P. vivax and P. falciparum case ratio increased dramatically from 2.2 in 2011 to 4.7 in 2014, demonstrating that P. vivax malaria has become the predominant parasite species. Clinical infections showed a strong bimodal seasonality. There were significant differences in monthly average incidence rates among the study villages with rates in a village in China being 3-8 folds lower than those in nearby villages in Myanmar. Spatial analysis revealed the presence of clinical malaria hotspots in four villages. This information on malaria seasonal dynamics and transmission hotspots should be harnessed for planning targeted control. PMID:26812008

  11. Transmission dynamics & epidemiology of malaria in two tribal districts in Madhya Pradesh, India

    PubMed Central

    Chand, Gyan; Chaudhary, N.K.; Soan, V.; Kaushal, L.S.; Sharma, R.K.; Singh, Neeru

    2015-01-01

    Background and objectives: Epidemiology and transmission of malaria vary within the tribal areas with the variation in topography, forest cover and type of forest. For the control of disease, understanding of the dynamics of transmission in the varied ecological situation is essential. This study was carried out in the two distinct tribal areas- Baiga Chak (thick forested area) of Dindori district and Bichhia block (forest fringe area) of Mandla district, Madhya Prasdesh, India, to understand the epidemiology and transmission dynamics of malaria. Methods: Mosquitoes were collected using hand catch and whole night collections to determine the proportion of vectors, their density and seasonality. Vector incrimination was done by sporozoite ELISA and feeding preferences of vector by gel diffusion method. Active fever surveys were carried out fortnightly to determine the age specific malaria parasite rates among the inhabitants of two areas. Results: Density of Anopheles culicifacies was significantly higher in Bichhia while the density of An. fluviatilis was higher in Baiga Chak. An. culicifacies was incriminated from both the areas while An. fluviatilis was incriminated from Baiga Chak only. Malaria slide positivity rate (SPR) was significantly higher (OR=3.7 95%CI, 3.1-4.4) in Baiga Chak (28.2%) than Bichhia (9.6%). Interpretation & conclusions: The features of malaria transmission in tribal areas differed from those reported in rural or semirural population. Site-specific and region-specific studies are required to develop appropriate intervention measures to control malaria. PMID:26139772

  12. Persistence and immunogenicity of chemically attenuated blood stage Plasmodium falciparum in Aotus monkeys.

    PubMed

    De, Sai Lata; Stanisic, Danielle I; van Breda, Karin; Bellete, Bernadette; Harris, Ivor; McCallum, Fiona; Edstein, Michael D; Good, Michael F

    2016-08-01

    Malaria is a disease caused by a protozoan of the Plasmodium genus and results in 0.5-0.7million deaths per year. Increasing drug resistance of the parasite and insecticide resistance of mosquitoes necessitate alternative control measures. Numerous vaccine candidates have been identified but none have been able to induce robust, long-lived protection when evaluated in malaria endemic regions. Rodent studies have demonstrated that chemically attenuated blood stage parasites can persist at sub-patent levels and induce homologous and heterologous protection against malaria. Parasite-specific cellular responses were detected, with protection dependent on CD4+ T cells. To investigate this vaccine approach for Plasmodium falciparum, we characterised the persistence and immunogenicity of chemically attenuated P. falciparum FVO strain parasites (CAPs) in non-splenectomised Aotus nancymaae monkeys following administration of a single dose. Control monkeys received either normal red blood cells or wild-type parasites followed by drug treatment. Chemical attenuation was performed using tafuramycin A, which irreversibly binds to DNA. CAPs were detected in the peripheral blood for up to 2days following inoculation as determined by thick blood smears, and for up to 8days as determined by quantitative PCR. Parasite-specific IgG was not detected in monkeys that received CAPs; however, in vitro parasite-specific T cell proliferation was observed. Following challenge, the CAP monkeys developed an infection; however, one CAP monkey and the infection and drug-cure monkeys showed partial or complete resistance. These experiments lay the groundwork for further assessment of CAPs as a potential vaccine against malaria. PMID:27238088

  13. The effect of temperature on Anopheles mosquito population dynamics and the potential for malaria transmission.

    PubMed

    Beck-Johnson, Lindsay M; Nelson, William A; Paaijmans, Krijn P; Read, Andrew F; Thomas, Matthew B; Bjørnstad, Ottar N

    2013-01-01

    The parasites that cause malaria depend on Anopheles mosquitoes for transmission; because of this, mosquito population dynamics are a key determinant of malaria risk. Development and survival rates of both the Anopheles mosquitoes and the Plasmodium parasites that cause malaria depend on temperature, making this a potential driver of mosquito population dynamics and malaria transmission. We developed a temperature-dependent, stage-structured delayed differential equation model to better understand how climate determines risk. Including the full mosquito life cycle in the model reveals that the mosquito population abundance is more sensitive to temperature than previously thought because it is strongly influenced by the dynamics of the juvenile mosquito stages whose vital rates are also temperature-dependent. Additionally, the model predicts a peak in abundance of mosquitoes old enough to vector malaria at more accurate temperatures than previous models. Our results point to the importance of incorporating detailed vector biology into models for predicting the risk for vector borne diseases. PMID:24244467

  14. Border Malaria Associated with Multidrug Resistance on Thailand-Myanmar and Thailand-Cambodia Borders: Transmission Dynamic, Vulnerability, and Surveillance

    PubMed Central

    Bhumiratana, Adisak; Intarapuk, Apiradee; Sorosjinda-Nunthawarasilp, Prapa; Maneekan, Pannamas; Koyadun, Surachart

    2013-01-01

    This systematic review elaborates the concepts and impacts of border malaria, particularly on the emergence and spread of Plasmodium falciparum and Plasmodium vivax multidrug resistance (MDR) malaria on Thailand-Myanmar and Thailand-Cambodia borders. Border malaria encompasses any complex epidemiological settings of forest-related and forest fringe-related malaria, both regularly occurring in certain transmission areas and manifesting a trend of increased incidence in transmission prone areas along these borders, as the result of interconnections of human settlements and movement activities, cross-border population migrations, ecological changes, vector population dynamics, and multidrug resistance. For regional and global perspectives, this review analyzes and synthesizes the rationales pertaining to transmission dynamics and the vulnerabilities of border malaria that constrain surveillance and control of the world's most MDR falciparum and vivax malaria on these chaotic borders. PMID:23865048

  15. Dynamic alteration in splenic function during acute falciparum malaria

    SciTech Connect

    Looareesuwan, S.; Ho, M.; Wattanagoon, Y.; White, N.J.; Warrell, D.A.; Bunnag, D.; Harinasuta, T.; Wyler, D.J.

    1987-09-10

    Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated /sup 51/Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes (mean +/- SD) vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.

  16. The Implications of HIV Treatment on the HIV-Malaria Coinfection Dynamics: A Modeling Perspective.

    PubMed

    Nyabadza, F; Bekele, B T; Rúa, M A; Malonza, D M; Chiduku, N; Kgosimore, M

    2015-01-01

    Most hosts harbor multiple pathogens at the same time in disease epidemiology. Multiple pathogens have the potential for interaction resulting in negative impacts on host fitness or alterations in pathogen transmission dynamics. In this paper we develop a mathematical model describing the dynamics of HIV-malaria coinfection. Additionally, we extended our model to examine the role treatment (of malaria and HIV) plays in altering populations' dynamics. Our model consists of 13 interlinked equations which allow us to explore multiple aspects of HIV-malaria transmission and treatment. We perform qualitative analysis of the model that includes positivity and boundedness of solutions. Furthermore, we evaluate the reproductive numbers corresponding to the submodels and investigate the long term behavior of the submodels. We also consider the qualitative dynamics of the full model. Sensitivity analysis is done to determine the impact of some chosen parameters on the dynamics of malaria. Finally, numerical simulations illustrate the potential impact of the treatment scenarios and confirm our analytical results. PMID:26425549

  17. Chemically Attenuated Blood-Stage Plasmodium yoelii Parasites Induce Long-Lived and Strain-Transcending Protection

    PubMed Central

    Raja, Amber I.; Cai, Yeping; Reiman, Jennifer M.; Groves, Penny; Chakravarty, Sumana; McPhun, Virginia; Doolan, Denise L.; Cockburn, Ian; Hoffman, Stephen L.; Stanisic, Danielle I.

    2016-01-01

    The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuated Plasmodium yoelii 17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4+ and CD8+ T cells was shown after vaccination; however, in vivo studies demonstrated a pivotal role for both CD4+ T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8+ T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8+ T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4+ and CD8+ T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans. PMID:27245410

  18. Implementation of malaria dynamic models in municipality level early warning systems in Colombia. Part I: description of study sites.

    PubMed

    Ruiz, Daniel; Cerón, Viviana; Molina, Adriana M; Quiñónes, Martha L; Jiménez, Mónica M; Ahumada, Martha; Gutiérrez, Patricia; Osorio, Salua; Mantilla, Gilma; Connor, Stephen J; Thomson, Madeleine C

    2014-07-01

    As part of the Integrated National Adaptation Pilot project and the Integrated Surveillance and Control System, the Colombian National Institute of Health is working on the design and implementation of a Malaria Early Warning System framework, supported by seasonal climate forecasting capabilities, weather and environmental monitoring, and malaria statistical and dynamic models. In this report, we provide an overview of the local ecoepidemiologic settings where four malaria process-based mathematical models are currently being implemented at a municipal level. The description includes general characteristics, malaria situation (predominant type of infection, malaria-positive cases data, malaria incidence, and seasonality), entomologic conditions (primary and secondary vectors, mosquito densities, and feeding frequencies), climatic conditions (climatology and long-term trends), key drivers of epidemic outbreaks, and non-climatic factors (populations at risk, control campaigns, and socioeconomic conditions). Selected pilot sites exhibit different ecoepidemiologic settings that must be taken into account in the development of the integrated surveillance and control system. PMID:24891460

  19. Implementation of Malaria Dynamic Models in Municipality Level Early Warning Systems in Colombia. Part I: Description of Study Sites

    PubMed Central

    Ruiz, Daniel; Cerón, Viviana; Molina, Adriana M.; Quiñónes, Martha L.; Jiménez, Mónica M.; Ahumada, Martha; Gutiérrez, Patricia; Osorio, Salua; Mantilla, Gilma; Connor, Stephen J.; Thomson, Madeleine C.

    2014-01-01

    As part of the Integrated National Adaptation Pilot project and the Integrated Surveillance and Control System, the Colombian National Institute of Health is working on the design and implementation of a Malaria Early Warning System framework, supported by seasonal climate forecasting capabilities, weather and environmental monitoring, and malaria statistical and dynamic models. In this report, we provide an overview of the local ecoepidemiologic settings where four malaria process-based mathematical models are currently being implemented at a municipal level. The description includes general characteristics, malaria situation (predominant type of infection, malaria-positive cases data, malaria incidence, and seasonality), entomologic conditions (primary and secondary vectors, mosquito densities, and feeding frequencies), climatic conditions (climatology and long-term trends), key drivers of epidemic outbreaks, and non-climatic factors (populations at risk, control campaigns, and socioeconomic conditions). Selected pilot sites exhibit different ecoepidemiologic settings that must be taken into account in the development of the integrated surveillance and control system. PMID:24891460

  20. On the study of the dynamical aspects of parasitemia in the blood cycle of malaria

    NASA Astrophysics Data System (ADS)

    Zorzenon Dos Santos, R. M.; Pinho, S. T. R.; Ferreira, C. P.; da Silva, P. C. A.

    2007-04-01

    Malaria is an important cause of morbidity and mortality worldwide. One striking aspect regarding malaria is the fact that individuals living in endemic areas do not develop immunity against the parasite, falling ill whenever they are exposed to the parasite. The understanding of why immunity is not developed in the usual way against Plasmodium is crucial to the improvement of treatment and prevention. In this work, we study some aspects of the dynamics of the blood cycle of malaria using both modelling and data analysis of observed case-histories described by parasitemia time series. By comparing our simulations with experimental results we have shown that the different behaviour observed among patients may be associated to differences in the efficiency of the immune system to control the infection.

  1. The dynamics, transmission, and population impacts of avian malaria in native hawaiian birds: A modeling approach

    USGS Publications Warehouse

    Samuel, M.D.; Hobbelen, P.H.F.; Decastro, F.; Ahumada, J.A.; Lapointe, D.A.; Atkinson, C.T.; Woodworth, B.L.; Hart, P.J.; Duffy, D.C.

    2011-01-01

    We developed an epidemiological model of avian malaria (Plasmodium relictum) across an altitudinal gradient on the island of Hawaii that includes the dynamics of the host, vector, and parasite. This introduced mosquito-borne disease is hypothesized to have contributed to extinctions and major shifts in the altitudinal distribution of highly susceptible native forest birds. Our goal was to better understand how biotic and abiotic factors influence the intensity of malaria transmission and impact on susceptible populations of native Hawaiian forest birds. Our model illustrates key patterns in the malaria-forest bird system: high malaria transmission in low-elevation forests with minor seasonal or annual variation in infection;episodic transmission in mid-elevation forests with site-to-site, seasonal, and annual variation depending on mosquito dynamics;and disease refugia in high-elevation forests with only slight risk of infection during summer. These infection patterns are driven by temperature and rainfall effects on parasite incubation period and mosquito dynamics across an elevational gradient and the availability of larval habitat, especially in mid-elevation forests. The results from our model suggest that disease is likely a key factor in causing population decline or restricting the distribution of many susceptible Hawaiian species and preventing the recovery of other vulnerable species. The model also provides a framework for the evaluation of factors influencing disease transmission and alternative disease control programs, and to evaluate the impact of climate change on disease cycles and bird populations. ??2011 by the Ecological Society of America.

  2. Dynamic linear models using the Kalman filter for early detection and early warning of malaria outbreaks

    NASA Astrophysics Data System (ADS)

    Merkord, C. L.; Liu, Y.; DeVos, M.; Wimberly, M. C.

    2015-12-01

    Malaria early detection and early warning systems are important tools for public health decision makers in regions where malaria transmission is seasonal and varies from year to year with fluctuations in rainfall and temperature. Here we present a new data-driven dynamic linear model based on the Kalman filter with time-varying coefficients that are used to identify malaria outbreaks as they occur (early detection) and predict the location and timing of future outbreaks (early warning). We fit linear models of malaria incidence with trend and Fourier form seasonal components using three years of weekly malaria case data from 30 districts in the Amhara Region of Ethiopia. We identified past outbreaks by comparing the modeled prediction envelopes with observed case data. Preliminary results demonstrated the potential for improved accuracy and timeliness over commonly-used methods in which thresholds are based on simpler summary statistics of historical data. Other benefits of the dynamic linear modeling approach include robustness to missing data and the ability to fit models with relatively few years of training data. To predict future outbreaks, we started with the early detection model for each district and added a regression component based on satellite-derived environmental predictor variables including precipitation data from the Tropical Rainfall Measuring Mission (TRMM) and land surface temperature (LST) and spectral indices from the Moderate Resolution Imaging Spectroradiometer (MODIS). We included lagged environmental predictors in the regression component of the model, with lags chosen based on cross-correlation of the one-step-ahead forecast errors from the first model. Our results suggest that predictions of future malaria outbreaks can be improved by incorporating lagged environmental predictors.

  3. History, Dynamics, and Public Health Importance of Malaria Parasite Resistance

    PubMed Central

    Talisuna, Ambrose O.; Bloland, Peter; D’Alessandro, Umberto

    2004-01-01

    Despite considerable efforts, malaria is still one of the most devastating infectious diseases in the tropics. The rapid spread of antimalarial drug resistance currently compounds this grim picture. In this paper, we review the history of antimalarial drug resistance and the methods for monitoring it and assess the current magnitude and burden of parasite resistance to two commonly used drugs: chloroquine and sulfadoxine-pyrimethamine. Furthermore, we review the factors involved in the emergence and spread of drug resistance and highlight its public health importance. Finally, we discuss ways of dealing with such a problem by using combination therapy and suggest some of the research themes needing urgent answers. PMID:14726463

  4. Dissecting the determinants of malaria chronicity: why within-host models struggle to reproduce infection dynamics.

    PubMed

    Childs, Lauren M; Buckee, Caroline O

    2015-03-01

    The duration of infection is fundamental to the epidemiological behaviour of any infectious disease, but remains one of the most poorly understood aspects of malaria. In endemic areas, the malaria parasite Plasmodium falciparum can cause both acute, severe infections and asymptomatic, chronic infections through its interaction with the host immune system. Frequent superinfection and massive parasite genetic diversity make it extremely difficult to accurately measure the distribution of infection lengths, complicating the estimation of basic epidemiological parameters and the prediction of the impact of interventions. Mathematical models have qualitatively reproduced parasite dynamics early during infection, but reproducing long-lived chronic infections remains much more challenging. Here, we construct a model of infection dynamics to examine the consequences of common biological assumptions for the generation of chronicity and the impact of co-infection. We find that although a combination of host and parasite heterogeneities are capable of generating chronic infections, they do so only under restricted parameter choices. Furthermore, under biologically plausible assumptions, co-infection of parasite genotypes can alter the course of infection of both the resident and co-infecting strain in complex non-intuitive ways. We outline the most important puzzles for within-host models of malaria arising from our analysis, and their implications for malaria epidemiology and control. PMID:25673299

  5. Vivax malaria

    PubMed Central

    Price, Ric N; Tjitra, Emiliana; Guerra, Carlos A; Yeung, Shunmay; White, Nicholas J; Anstey, Nicholas M

    2009-01-01

    Plasmodium vivax threatens almost 40% of the world’s population, resulting in 132 - 391 million clinical infections each year. Most of these cases originate from South East Asia and the Western Pacific, although a significant number also occur in Africa and South America. Although often regarded as causing a benign and self-limiting infection, there is increasing evidence that the overall burden, economic impact and severity of disease from P. vivax have been underestimated. Malaria control strategies have had limited success and are confounded by the lack of access to reliable diagnosis, emergence of multidrug resistant isolates and the parasite’s ability to transmit early in the course of disease and relapse from dormant liver stages at varying time intervals after the initial infection. Progress in reducing the burden of disease will require improved access to reliable diagnosis and effective treatment of both blood-stage and latent parasites, and more detailed characterization of the epidemiology, morbidity and economic impact of vivax malaria. Without these, vivax malaria will continue to be neglected by ministries of health, policy makers, researchers and funding bodies. PMID:18165478

  6. Dynamics of Forest Malaria Transmission in Balaghat District, Madhya Pradesh, India

    PubMed Central

    Singh, Neeru; Chand, Sunil K.; Bharti, Praveen K.; Singh, Mrigendra P.; Chand, Gyan; Mishra, Ashok K.; Shukla, Man M.; Mahulia, Man M.; Sharma, Ravendra K.

    2013-01-01

    Background An epidemiological and entomological study was carried out in Balaghat district, Madhya Pradesh, India to understand the dynamics of forest malaria transmission in a difficult and hard to reach area where indoor residual spray and insecticide treated nets were used for vector control. Methods This community based cross-sectional study was undertaken from January 2010 to December 2012 in Baihar and Birsa Community Health Centres of district Balaghat for screening malaria cases. Entomological surveillance included indoor resting collections, pyrethrum spray catches and light trap catches. Anophelines were assayed by ELISA for detection of Plasmodium circumsporozoite protein. Findings Plasmodium falciparum infection accounted for >80% of all infections. P. vivax 16.5%, P. malariae 0.75% and remaining were mixed infections of P. falciparum, P. vivax and P. malariae. More than, 30% infections were found in infants under 6 months of age. Overall, an increasing trend in malaria positivity was observed from 2010 to 2012 (chi-square for trend  =  663.55; P<0.0001). Twenty five Anopheles culicifacies (sibling species C, D and E) were positive for circumsporozoite protein of P. falciparum (44%) and P. vivax (56%). Additionally, 2 An. fluviatilis, were found positive for P. falciparum and 1 for P. vivax (sibling species S and T). An. fluviatilis sibling species T was found as vector in forest villages for the first time in India. Conclusion These results showed that the study villages are experiencing almost perennial malaria transmission inspite of indoor residual spray and insecticide treated nets. Therefore, there is a need for new indoor residual insecticides which has longer residual life or complete coverage of population with long lasting insecticide treated nets or both indoor residual spray and long lasting bed nets for effective vector control. There is a need to undertake a well designed case control study to evaluate the efficacy of these

  7. Plasmodium vivax: N-terminal diversity in the blood stage SERA genes from Indian isolates.

    PubMed

    Rahul, C N; Shiva Krishna, K; Meera, M; Phadke, Sandhya; Rajesh, Vidya

    2015-06-01

    Worldwide malaria risk due to Plasmodium vivax makes development of vaccine against P. vivax, a high priority. Serine Repeat Antigen of P. vivax (PvSERA) is a multigene family of blood stage proteins with 12 homologues. Sequence diversity studies are important for understanding them as potential vaccine candidates. No information on N-terminal diversity of these genes is available in literature. In this paper, we evaluate the genetic polymorphism of N-terminal regions of the highly expressed member PvSERA4 and PvSERA5 genes from Indian field isolates. Our results show that PvSERA4 has deletions and insertions in Glutamine rich tetrameric repeat units contributing to its diversity. PvSERA5 also exhibits high genetic diversity with non-synonymous substitutions leading to identification of novel haplotypes from India. Our first report helps in elucidating the allelic variants of PvSERA genes in this region and contributes to evaluating their efficacy as vaccine candidates. PMID:25976464

  8. A regional-scale, high resolution dynamical malaria model that accounts for population density, climate and surface hydrology

    PubMed Central

    2013-01-01

    Background The relative roles of climate variability and population related effects in malaria transmission could be better understood if regional-scale dynamical malaria models could account for these factors. Methods A new dynamical community malaria model is introduced that accounts for the temperature and rainfall influences on the parasite and vector life cycles which are finely resolved in order to correctly represent the delay between the rains and the malaria season. The rainfall drives a simple but physically based representation of the surface hydrology. The model accounts for the population density in the calculation of daily biting rates. Results Model simulations of entomological inoculation rate and circumsporozoite protein rate compare well to data from field studies from a wide range of locations in West Africa that encompass both seasonal endemic and epidemic fringe areas. A focus on Bobo-Dioulasso shows the ability of the model to represent the differences in transmission rates between rural and peri-urban areas in addition to the seasonality of malaria. Fine spatial resolution regional integrations for Eastern Africa reproduce the malaria atlas project (MAP) spatial distribution of the parasite ratio, and integrations for West and Eastern Africa show that the model grossly reproduces the reduction in parasite ratio as a function of population density observed in a large number of field surveys, although it underestimates malaria prevalence at high densities probably due to the neglect of population migration. Conclusions A new dynamical community malaria model is publicly available that accounts for climate and population density to simulate malaria transmission on a regional scale. The model structure facilitates future development to incorporate migration, immunity and interventions. PMID:23419192

  9. Malaria control under unstable dynamics: reactive vs. climate-based strategies.

    PubMed

    Baeza, Andres; Bouma, Menno J; Dhiman, Ramesh; Pascual, Mercedes

    2014-01-01

    In areas of the world where malaria prevails under unstable conditions, attacking the adult vector population through insecticide-based Indoor Residual Spraying (IRS) is the most common method for controlling epidemics. Defined in policy guidance, the use of Annual Parasitic Incidence (API) is an important tool for assessing the effectiveness of control and for planning new interventions. To investigate the consequences that a policy based on API in previous seasons might have on the population dynamics of the disease and on control itself in regions of low and seasonal transmission, we formulate a mathematical malaria model that couples epidemiologic and vector dynamics with IRS intervention. This model is parameterized for a low transmission and semi-arid region in northwest India, where epidemics are driven by high rainfall variability. We show that this type of feedback mechanism in control strategies can generate transient cycles in malaria even in the absence of environmental variability, and that this tendency to cycle can in turn limit the effectiveness of control in the presence of such variability. Specifically, for realistic rainfall conditions and over a range of control intensities, the effectiveness of such 'reactive' intervention is compared to that of an alternative strategy based on rainfall and therefore vector variability. Results show that the efficacy of intervention is strongly influenced by rainfall variability and the type of policy implemented. In particular, under an API 'reactive' policy, high vector populations can coincide more frequently with low control coverage, and in so doing generate large unexpected epidemics and decrease the likelihood of elimination. These results highlight the importance of incorporating information on climate variability, rather than previous incidence, in planning IRS interventions in regions of unstable malaria. These findings are discussed in the more general context of elimination and other low

  10. Arm-specific dynamics of chromosome evolution in malaria mosquitoes

    PubMed Central

    2011-01-01

    Background The malaria mosquito species of subgenus Cellia have rich inversion polymorphisms that correlate with environmental variables. Polymorphic inversions tend to cluster on the chromosomal arms 2R and 2L but not on X, 3R and 3L in Anopheles gambiae and homologous arms in other species. However, it is unknown whether polymorphic inversions on homologous chromosomal arms of distantly related species from subgenus Cellia nonrandomly share similar sets of genes. It is also unclear if the evolutionary breakage of inversion-poor chromosomal arms is under constraints. Results To gain a better understanding of the arm-specific differences in the rates of genome rearrangements, we compared gene orders and established syntenic relationships among Anopheles gambiae, Anopheles funestus, and Anopheles stephensi. We provided evidence that polymorphic inversions on the 2R arms in these three species nonrandomly captured similar sets of genes. This nonrandom distribution of genes was not only a result of preservation of ancestral gene order but also an outcome of extensive reshuffling of gene orders that created new combinations of homologous genes within independently originated polymorphic inversions. The statistical analysis of distribution of conserved gene orders demonstrated that the autosomal arms differ in their tolerance to generating evolutionary breakpoints. The fastest evolving 2R autosomal arm was enriched with gene blocks conserved between only a pair of species. In contrast, all identified syntenic blocks were preserved on the slowly evolving 3R arm of An. gambiae and on the homologous arms of An. funestus and An. stephensi. Conclusions Our results suggest that natural selection favors specific gene combinations within polymorphic inversions when distant species are exposed to similar environmental pressures. This knowledge could be useful for the discovery of genes responsible for an association of inversion polymorphisms with phenotypic variations in

  11. Plasmodium falciparum SERA5 plays a non-enzymatic role in the malarial asexual blood-stage lifecycle

    PubMed Central

    Stallmach, Robert; Kavishwar, Manoli; Withers-Martinez, Chrislaine; Hackett, Fiona; Collins, Christine R; Howell, Steven A; Yeoh, Sharon; Knuepfer, Ellen; Atid, Avshalom J; Holder, Anthony A; Blackman, Michael J

    2015-01-01

    The malaria parasite Plasmodium falciparum replicates in an intraerythrocytic parasitophorous vacuole (PV). The most abundant P. falciparum PV protein, called SERA5, is essential in blood stages and possesses a papain-like domain, prompting speculation that it functions as a proteolytic enzyme. Unusually however, SERA5 possesses a Ser residue (Ser596) at the position of the canonical catalytic Cys of papain-like proteases, and the function of SERA5 or whether it performs an enzymatic role is unknown. In this study, we failed to detect proteolytic activity associated with the Ser596-containing parasite-derived or recombinant protein. However, substitution of Ser596 with a Cys residue produced an active recombinant enzyme with characteristics of a cysteine protease, demonstrating that SERA5 can bind peptides. Using targeted homologous recombination in P. falciparum, we substituted Ser596 with Ala with no phenotypic consequences, proving that SERA5 does not perform an essential enzymatic role in the parasite. We could also replace an internal segment of SERA5 with an affinity-purification tag. In contrast, using almost identical targeting constructs, we could not truncate or C-terminally tag the SERA5 gene, or replace Ser596 with a bulky Arg residue. Our findings show that SERA5 plays an indispensable but non-enzymatic role in the P. falciparum blood-stage life cycle. PMID:25599609

  12. In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

    PubMed Central

    Cabrera, Mynthia

    2015-01-01

    Currently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) for Plasmodium falciparum malaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes of in vitro-cultured P. falciparum strains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages of P. falciparum laboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ-naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ-chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem). PMID:26416869

  13. In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum.

    PubMed

    Cabrera, Mynthia; Cui, Liwang

    2015-12-01

    Currently, the World Health Organization recommends addition of a 0.25-mg base/kg single dose of primaquine (PQ) to artemisinin combination therapies (ACTs) for Plasmodium falciparum malaria as a gametocytocidal agent for reducing transmission. Here, we investigated the potential interactions of PQ with the long-lasting components of the ACT drugs for eliminating the asexual blood stages and gametocytes of in vitro-cultured P. falciparum strains. Using the SYBR green I assay for asexual parasites and a flow cytometry-based assay for gametocytes, we determined the interactions of PQ with the schizonticides chloroquine, mefloquine, piperaquine, lumefantrine, and naphthoquine. With the sums of fractional inhibitory concentrations and isobolograms, we were able to determine mostly synergistic interactions for the various PQ and schizonticide combinations on the blood stages of P. falciparum laboratory strains. The synergism in inhibiting asexual stages and gametocytes was highly evident with PQ-naphthoquine, whereas synergism was moderate for the PQ-piperaquine, PQ-chloroquine, and PQ-mefloquine combinations. We have detected potentially antagonistic interactions between PQ and lumefantrine under certain drug combination ratios, suggesting that precautions might be needed when PQ is added as the gametocytocide to the artemether-lumefantrine ACT (Coartem). PMID:26416869

  14. Spatial and temporal dynamics of malaria transmission in rural Western Kenya

    PubMed Central

    2012-01-01

    Background Understanding the relationship between Plasmodium falciparum malaria transmission and health outcomes requires accurate estimates of exposure to infectious mosquitoes. However, measures of exposure such as mosquito density and entomological inoculation rate (EIR) are generally aggregated over large areas and time periods, biasing the outcome-exposure relationship. There are few studies examining the extent and drivers of local variation in malaria exposure in endemic areas. Methods We describe the spatio-temporal dynamics of malaria transmission intensity measured by mosquito density and EIR in the KEMRI/CDC health and demographic surveillance system using entomological data collected during 2002–2004. Geostatistical zero inflated binomial and negative binomial models were applied to obtain location specific (house) estimates of sporozoite rates and mosquito densities respectively. Model-based predictions were multiplied to estimate the spatial pattern of annual entomological inoculation rate, a measure of the number of infective bites a person receive per unit of time. The models included environmental and climatic predictors extracted from satellite data, harmonic seasonal trends and parameters describing space-time correlation. Results Anopheles gambiae s.l was the main vector species accounting for 86 % (n = 2309) of the total mosquitoes collected with the remainder being Anopheles funestus. Sixty eight percent (757/1110) of the surveyed houses had no mosquitoes. Distance to water bodies, vegetation and day temperature were strongly associated with mosquito density. Overall annual point estimates of EIR were 6.7, 9.3 and 9.6 infectious bites per annum for 2002, 2003 and 2004 respectively. Monthly mosquito density and EIR varied over the study period peaking in May during the wet season each year. The predicted and observed densities of mosquitoes and EIR showed a strong seasonal and spatial pattern over the study area. Conclusions Spatio

  15. Static and dynamic light scattering of healthy and malaria-parasite invaded red blood cells

    NASA Astrophysics Data System (ADS)

    Park, Yongkeun; Diez-Silva, Monica; Fu, Dan; Popescu, Gabriel; Choi, Wonshik; Barman, Ishan; Suresh, Subra; Feld, Michael S.

    2010-03-01

    We present the light scattering of individual Plasmodium falciparum-parasitized human red blood cells (Pf-RBCs), and demonstrate progressive alterations to the scattering signal arising from the development of malaria-inducing parasites. By selectively imaging the electric fields using quantitative phase microscopy and a Fourier transform light scattering technique, we calculate the light scattering maps of individual Pf-RBCs. We show that the onset and progression of pathological states of the Pf-RBCs can be clearly identified by the static scattering maps. Progressive changes to the biophysical properties of the Pf-RBC membrane are captured from dynamic light scattering.

  16. Dynamic and Combinatorial Landscape of Histone Modifications during the Intraerythrocytic Developmental Cycle of the Malaria Parasite.

    PubMed

    Saraf, Anita; Cervantes, Serena; Bunnik, Evelien M; Ponts, Nadia; Sardiu, Mihaela E; Chung, Duk-Won D; Prudhomme, Jacques; Varberg, Joseph M; Wen, Zhihui; Washburn, Michael P; Florens, Laurence; Le Roch, Karine G

    2016-08-01

    A major obstacle in understanding the complex biology of the malaria parasite remains to discover how gene transcription is controlled during its life cycle. Accumulating evidence indicates that the parasite's epigenetic state plays a fundamental role in gene expression and virulence. Using a comprehensive and quantitative mass spectrometry approach, we determined the global and dynamic abundance of histones and their covalent post-transcriptional modifications throughout the intraerythrocytic developmental cycle of Plasmodium falciparum. We detected a total of 232 distinct modifications, of which 160 had never been detected in Plasmodium and 88 had never been identified in any other species. We further validated over 10% of the detected modifications and their expression patterns by multiple reaction monitoring assays. In addition, we uncovered an unusual chromatin organization with parasite-specific histone modifications and combinatorial dynamics that may be directly related to transcriptional activity, DNA replication, and cell cycle progression. Overall, our data suggest that the malaria parasite has a unique histone modification signature that correlates with parasite virulence. PMID:27291344

  17. Modeling the role of environmental variables on the population dynamics of the malaria vector Anopheles gambiae sensu stricto

    PubMed Central

    2012-01-01

    Background The impact of weather and climate on malaria transmission has attracted considerable attention in recent years, yet uncertainties around future disease trends under climate change remain. Mathematical models provide powerful tools for addressing such questions and understanding the implications for interventions and eradication strategies, but these require realistic modeling of the vector population dynamics and its response to environmental variables. Methods Published and unpublished field and experimental data are used to develop new formulations for modeling the relationships between key aspects of vector ecology and environmental variables. These relationships are integrated within a validated deterministic model of Anopheles gambiae s.s. population dynamics to provide a valuable tool for understanding vector response to biotic and abiotic variables. Results A novel, parsimonious framework for assessing the effects of rainfall, cloudiness, wind speed, desiccation, temperature, relative humidity and density-dependence on vector abundance is developed, allowing ease of construction, analysis, and integration into malaria transmission models. Model validation shows good agreement with longitudinal vector abundance data from Tanzania, suggesting that recent malaria reductions in certain areas of Africa could be due to changing environmental conditions affecting vector populations. Conclusions Mathematical models provide a powerful, explanatory means of understanding the role of environmental variables on mosquito populations and hence for predicting future malaria transmission under global change. The framework developed provides a valuable advance in this respect, but also highlights key research gaps that need to be resolved if we are to better understand future malaria risk in vulnerable communities. PMID:22877154

  18. Numerical modelling of a healthy/malaria-infected erythrocyte in shear flow using dissipative particle dynamics method

    NASA Astrophysics Data System (ADS)

    Ye, Ting; Phan-Thien, Nhan; Cheong Khoo, Boo; Teck Lim, Chwee

    2014-06-01

    In the present paper, the dynamics of healthy and malaria-infected erythrocytes in the shear flow are investigated using dissipative particle dynamics (DPD), a particle-based method. A discrete model is developed, where the computational domain is discretized into a set of particles to represent the suspending liquid, as well as erythrocytes as suspended deformable particles. The particles on an erythrocyte surface are connected into a triangular network to represent the membrane. The interaction between any two particles is modelled by the DPD method, which conserves both mass and momentum. In order to validate this model, the deformation of a spherical capsule in the shear flow is firstly simulated, and a good agreement is found with previously published works. Then, the dynamics of a healthy biconcave erythrocyte in a shear flow is investigated. The results demonstrate that a healthy erythrocyte undergoes a tank-treading motion at a high capillary number, and a tumbling motion at a low capillary number or at a high viscosity ratio, internal (erythrocyte) to external fluids. Two other types of trembling motions, breathing with tumbling and swinging with tank-treading, are also found at an intermediate capillary number or viscosity ratio. Finally, the dynamics of malaria-infected erythrocyte in a shear flow is studied. At the same shear rate, if the healthy erythrocyte undergoes a tumbling motion, the malaria-infected one will exhibit a tumbling motion only. If the healthy erythrocyte undergoes a trembling motion, the malaria-infected one cannot exhibit tank-treading motion. If the healthy erythrocyte undergoes a tank-treading motion, the malaria-infected one will exhibit one of three dynamic motions: tumbling, trembling or tank-treading motion.

  19. RALP1 Is a Rhoptry Neck Erythrocyte-Binding Protein of Plasmodium falciparum Merozoites and a Potential Blood-Stage Vaccine Candidate Antigen

    PubMed Central

    Ito, Daisuke; Hasegawa, Tomoyuki; Miura, Kazutoyo; Yamasaki, Tsutomu; Arumugam, Thangavelu U.; Thongkukiatkul, Amporn; Takeo, Satoru; Takashima, Eizo; Sattabongkot, Jetsumon; Han, Eun-Taek; Long, Carole A.; Torii, Motomi

    2013-01-01

    Erythrocyte invasion by merozoites is an obligatory stage of Plasmodium infection and is essential to disease progression. Proteins in the apical organelles of merozoites mediate the invasion of erythrocytes and are potential malaria vaccine candidates. Rhoptry-associated, leucine zipper-like protein 1 (RALP1) of Plasmodium falciparum was previously found to be specifically expressed in schizont stages and localized to the rhoptries of merozoites by immunofluorescence assay (IFA). Also, RALP1 has been refractory to gene knockout attempts, suggesting that it is essential for blood-stage parasite survival. These characteristics suggest that RALP1 can be a potential blood-stage vaccine candidate antigen, and here we assessed its potential in this regard. Antibodies were raised against recombinant RALP1 proteins synthesized by using the wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that RALP1 is a rhoptry neck protein of merozoites. Moreover, our IFA data showed that RALP1 translocates from the rhoptry neck to the moving junction during merozoite invasion. Growth and invasion inhibition assays revealed that anti-RALP1 antibodies inhibit the invasion of erythrocytes by merozoites. The findings that RALP1 possesses an erythrocyte-binding epitope in the C-terminal region and that anti-RALP1 antibodies disrupt tight-junction formation, are evidence that RALP1 plays an important role during merozoite invasion of erythrocytes. In addition, human sera collected from areas in Thailand and Mali where malaria is endemic recognized this protein. Overall, our findings indicate that RALP1 is a rhoptry neck erythrocyte-binding protein and that it qualifies as a potential blood-stage vaccine candidate. PMID:24002067

  20. Dynamics of Plasmodium falciparum Parasitemia Regarding Combined Treatment Regimens for Acute Uncomplicated Malaria, Antioquia, Colombia

    PubMed Central

    Álvarez, Gonzalo; Tobón, Alberto; Piñeros, Juan-Gabriel; Ríos, Alexandra; Blair, Silvia

    2010-01-01

    Selecting suitable anti-malarial treatment represents one of the best tools for reducing morbidity and mortality caused by this disease. Sexual and asexual parasite dynamics were thus evaluated in patients involved in antimalarial drug efficacy studies by using combined treatment with and without artemisinin derivatives for treating uncomplicated acute Plasmodium falciparum malaria in Antioquia, Colombia. All treatment doses were supervised and administered according to patients' weight; sexual and asexual parasitemia were evaluated during 28- or 42-days follow-up in 468 patients. Artemisinin-based combination therapy showed greater parasiticidal ability, showing a mean asexual parasitemia survival rate of one day and mean gametocyte survival rate of 1–2 days. Sexual and asexual parasitemias were eliminated more quickly and effectively in the group receiving artemisinin-based combination therapy. Adding 45 mg of primaquine to treatment with artesunate and mefloquine reduced gametocyte and asexual parasite survival by one day. PMID:20595483

  1. Malaria Research

    MedlinePlus

    ... Malaria > Research Malaria Understanding Research NIAID Role Basic Biology Prevention and Control Strategies Strategic Partnerships and Research ... the malaria parasite. Related Links Global Research​ Vector Biology International Centers of Excellence for Malaria Research (ICEMR) ...

  2. A dynamic model of some malaria-transmitting anopheline mosquitoes of the Afrotropical region. I. Model description and sensitivity analysis

    PubMed Central

    2013-01-01

    Background Most of the current biophysical models designed to address the large-scale distribution of malaria assume that transmission of the disease is independent of the vector involved. Another common assumption in these type of model is that the mortality rate of mosquitoes is constant over their life span and that their dispersion is negligible. Mosquito models are important in the prediction of malaria and hence there is a need for a realistic representation of the vectors involved. Results We construct a biophysical model including two competing species, Anopheles gambiae s.s. and Anopheles arabiensis. Sensitivity analysis highlight the importance of relative humidity and mosquito size, the initial conditions and dispersion, and a rarely used parameter, the probability of finding blood. We also show that the assumption of exponential mortality of adult mosquitoes does not match the observed data, and suggest that an age dimension can overcome this problem. Conclusions This study highlights some of the assumptions commonly used when constructing mosquito-malaria models and presents a realistic model of An. gambiae s.s. and An. arabiensis and their interaction. This new mosquito model, OMaWa, can improve our understanding of the dynamics of these vectors, which in turn can be used to understand the dynamics of malaria. PMID:23342980

  3. Climatic variables and malaria transmission dynamics in Jimma town, South West Ethiopia

    PubMed Central

    2011-01-01

    Background:- In Ethiopia, malaria is seasonal and unstable, causing frequent epidemics. It usually occurs at altitudes < 2,000 m above sea level. Occasionally, transmission of malaria occurs in areas previously free of malaria, including areas > 2,000 m above sea level. For transmission of malaria parasite, climatic factors are important determinants as well as non-climatic factors that can negate climatic influences. Indeed, there is a scarcity of information on the correlation between climatic variability and malaria transmission risk in Ethiopia in general and in the study area in particular. Therefore, the aim of this study was to determine the level of correlation between meteorological variables and malaria cases. Methods: - Time-series analysis was conducted using data on monthly meteorological variables and monthly total malaria in Jimma town, south west Ethiopia, for the period 2000-2009. All the data were entered and analyzed using SPSS-15 database program. Spearman correlation and linear regression analysis were used to asses association between the variables. Results: - During last ten years (2000-2009), a fluctuating trend of malaria transmission was observed with P.vivax becoming predominant species. Spearman correlation analysis showed that monthly minimum temperature, total rainfall and two measures of relative humidity were positively related with malaria but monthly maximum temperature negatively related. Also regression analysis suggested that monthly minimum (p = 0.008), monthly maximum temperature (p = 0.013) and monthly total rainfall (p = 0.040), at one month lagged effect, were significant meteorological factors for transmission of malaria in the study area. Conclusion: - Malaria incidences in the last decade seem to have a significant association with meteorological variables. In future, prospective and multidisciplinary cooperative research involving researchers from the fields of parasitology, epidemiology, botany, agriculture and

  4. Dynamics of Socioeconomic Risk Factors for Neglected Tropical Diseases and Malaria in an Armed Conflict

    PubMed Central

    Fürst, Thomas; Raso, Giovanna; Acka, Cinthia A.; Tschannen, Andres B.; N'Goran, Eliézer K.; Utzinger, Jürg

    2009-01-01

    Background Armed conflict and war are among the leading causes of disability and premature death, and there is a growing share of civilians killed or injured during armed conflicts. A major part of the civilian suffering stems from indirect effects or collateral impact such as changing risk profiles for infectious diseases. We focused on rural communities in the western part of Côte d'Ivoire, where fighting took place during the Ivorian civil war in 2002/2003, and assessed the dynamics of socioeconomic risk factors for neglected tropical diseases (NTDs) and malaria. Methodology The same standardized and pre-tested questionnaires were administered to the heads of 182 randomly selected households in 25 villages in the region of Man, western Côte d'Ivoire, shortly before and after the 2002/2003 armed conflict. Principal Findings There was no difference in crowding as measured by the number of individuals per sleeping room, but the inadequate sanitation infrastructure prior to the conflict further worsened, and the availability and use of protective measures against mosquito bites and accessibility to health care infrastructure deteriorated. Although the direct causal chain between these findings and the conflict are incomplete, partially explained by the very nature of working in conflict areas, the timing and procedures of the survey, other sources and anecdotal evidence point toward a relationship between an increased risk of suffering from NTDs and malaria and armed conflict. Conclusion New research is needed to deepen our understanding of the often diffuse and neglected indirect effects of armed conflict and war, which may be worse than the more obvious, direct effects. PMID:19907632

  5. When climate change couples social neglect: malaria dynamics in Panamá

    PubMed Central

    Hurtado, Lisbeth Amarilis; Cáceres, Lorenzo; Chaves, Luis Fernando; Calzada, José E

    2014-01-01

    A major challenge of infectious disease elimination is the need to interrupt pathogen transmission across all vulnerable populations. Ethnic minorities are among the key vulnerable groups deserving special attention in disease elimination initiatives, especially because their lifestyle might be intrinsically linked to locations with high transmission risk. There has been a renewed interest in malaria elimination, which has ignited a quest to understand factors necessary for sustainable malaria elimination, highlighting the need for diverse approaches to address epidemiological heterogeneity across malaria transmission settings. An analysis of malaria incidence among the Guna Amerindians of Panamá over the last 34 years showed that this ethnic minority was highly vulnerable to changes that were assumed to not impact malaria transmission. Epidemic outbreaks were linked with El Niño Southern Oscillations and were sensitive to political instability and policy changes that did not ensure adequate attention to the malaria control needs of the Gunas. Our results illustrate how the neglect of minorities poses a threat to the sustainable control and eventual elimination of malaria in Central America and other areas where ethnic minorities do not share the benefits of malaria control strategies intended for dominant ethnic groups. PMID:26038518

  6. When climate change couples social neglect: malaria dynamics in Panamá.

    PubMed

    Hurtado, Lisbeth Amarilis; Cáceres, Lorenzo; Chaves, Luis Fernando; Calzada, José E

    2014-04-01

    A major challenge of infectious disease elimination is the need to interrupt pathogen transmission across all vulnerable populations. Ethnic minorities are among the key vulnerable groups deserving special attention in disease elimination initiatives, especially because their lifestyle might be intrinsically linked to locations with high transmission risk. There has been a renewed interest in malaria elimination, which has ignited a quest to understand factors necessary for sustainable malaria elimination, highlighting the need for diverse approaches to address epidemiological heterogeneity across malaria transmission settings. An analysis of malaria incidence among the Guna Amerindians of Panamá over the last 34 years showed that this ethnic minority was highly vulnerable to changes that were assumed to not impact malaria transmission. Epidemic outbreaks were linked with El Niño Southern Oscillations and were sensitive to political instability and policy changes that did not ensure adequate attention to the malaria control needs of the Gunas. Our results illustrate how the neglect of minorities poses a threat to the sustainable control and eventual elimination of malaria in Central America and other areas where ethnic minorities do not share the benefits of malaria control strategies intended for dominant ethnic groups. PMID:26038518

  7. MicroRNAs and Malaria – A Dynamic Interaction Still Incompletely Understood

    PubMed Central

    Cohen, Amy; Combes, Valéry; Grau, Georges ER

    2015-01-01

    Malaria is a mosquito-borne infectious disease caused by parasitic protozoa of the genus Plasmodium. It remains a major problem affecting humans today, especially children. However, the pathogenesis of malaria, especially severe malaria, remains incompletely understood, hindering our ability to treat this disease. Of recent interest is the role that small, non-coding RNAs play in the progression, pathogenesis of, and resistance to, malaria. Independent studies have now revealed the presence of microRNA (miRNA) in the malaria parasite, vector, and host, though these studies are relatively few. Here, we review these studies, focusing on the roles specific miRNA have in the disease, and how they may be harnessed for therapeutic purposes. PMID:26005686

  8. Contrasting Transmission Dynamics of Co-endemic Plasmodium vivax and P. falciparum: Implications for Malaria Control and Elimination

    PubMed Central

    Noviyanti, Rintis; Coutrier, Farah; Utami, Retno A. S.; Trimarsanto, Hidayat; Tirta, Yusrifar K.; Trianty, Leily; Kusuma, Andreas; Sutanto, Inge; Kosasih, Ayleen; Kusriastuti, Rita; Hawley, William A.; Laihad, Ferdinand; Lobo, Neil; Marfurt, Jutta; Clark, Taane G.; Price, Ric N.; Auburn, Sarah

    2015-01-01

    Background Outside of Africa, P. falciparum and P. vivax usually coexist. In such co-endemic regions, successful malaria control programs have a greater impact on reducing falciparum malaria, resulting in P. vivax becoming the predominant species of infection. Adding to the challenges of elimination, the dormant liver stage complicates efforts to monitor the impact of ongoing interventions against P. vivax. We investigated molecular approaches to inform the respective transmission dynamics of P. falciparum and P. vivax and how these could help to prioritize public health interventions. Methodology/ Principal Findings Genotype data generated at 8 and 9 microsatellite loci were analysed in 168 P. falciparum and 166 P. vivax isolates, respectively, from four co-endemic sites in Indonesia (Bangka, Kalimantan, Sumba and West Timor). Measures of diversity, linkage disequilibrium (LD) and population structure were used to gauge the transmission dynamics of each species in each setting. Marked differences were observed in the diversity and population structure of P. vivax versus P. falciparum. In Bangka, Kalimantan and Timor, P. falciparum diversity was low, and LD patterns were consistent with unstable, epidemic transmission, amenable to targeted intervention. In contrast, P. vivax diversity was higher and transmission appeared more stable. Population differentiation was lower in P. vivax versus P. falciparum, suggesting that the hypnozoite reservoir might play an important role in sustaining local transmission and facilitating the spread of P. vivax infections in different endemic settings. P. vivax polyclonality varied with local endemicity, demonstrating potential utility in informing on transmission intensity in this species. Conclusions/ Significance Molecular approaches can provide important information on malaria transmission that is not readily available from traditional epidemiological measures. Elucidation of the transmission dynamics circulating in a given

  9. Hypothesis: dynamics of classical malaria epidemics show Plasmodium falciparum's survival strategy.

    PubMed

    Shanks, G Dennis

    2015-03-01

    Areas of marginal transmission can generate enormous lethal falciparum malaria epidemics when factors favoring the parasite shift only slightly. Although usually described in terms of vectorial capacity, medical scientists working in India in the early 20th century came to the conclusion that "an epidemic of relapses" was the key triggering event of malaria epidemics. This explanation has been largely discarded, because the biology of Plasmodium falciparum recrudescence has since been differentiated from P. vivax relapse. Using data from the Punjab in 1908 and Ceylon in 1934-1935, the genesis of malaria epidemics has been re-examined to inform current control efforts. The epidemics were focused geographically depending on recent rainfall or drought. Epidemics arose very suddenly and simultaneously in several places. Malaria spleen surveys indicated very little recent malaria transmission, and blood smears showed very few gametocytes just before the epidemic. Population stress as indicated by high grain prices because of a poor harvest caused by drought the previous year was a risk factor for malaria epidemics. Although increased female Anopheline survival because of increased humidity played an important part in the magnification of the epidemic, it does not explain its genesis. Human population stress triggering a shift toward gametocytogenesis is hypothesized as the key initiation factor for malaria epidemics. Its evolutionary significance may be that it allows the parasite to match the tropical agricultural cycle. PMID:25624407

  10. Hypothesis: Dynamics of Classical Malaria Epidemics Show Plasmodium falciparum's Survival Strategy

    PubMed Central

    Shanks, G. Dennis

    2015-01-01

    Areas of marginal transmission can generate enormous lethal falciparum malaria epidemics when factors favoring the parasite shift only slightly. Although usually described in terms of vectorial capacity, medical scientists working in India in the early 20th century came to the conclusion that “an epidemic of relapses” was the key triggering event of malaria epidemics. This explanation has been largely discarded, because the biology of Plasmodium falciparum recrudescence has since been differentiated from P. vivax relapse. Using data from the Punjab in 1908 and Ceylon in 1934–1935, the genesis of malaria epidemics has been re-examined to inform current control efforts. The epidemics were focused geographically depending on recent rainfall or drought. Epidemics arose very suddenly and simultaneously in several places. Malaria spleen surveys indicated very little recent malaria transmission, and blood smears showed very few gametocytes just before the epidemic. Population stress as indicated by high grain prices because of a poor harvest caused by drought the previous year was a risk factor for malaria epidemics. Although increased female Anopheline survival because of increased humidity played an important part in the magnification of the epidemic, it does not explain its genesis. Human population stress triggering a shift toward gametocytogenesis is hypothesized as the key initiation factor for malaria epidemics. Its evolutionary significance may be that it allows the parasite to match the tropical agricultural cycle. PMID:25624407

  11. The Dynamics of Transmission and Spatial Distribution of Malaria in Riverside Areas of Porto Velho, Rondônia, in the Amazon Region of Brazil

    PubMed Central

    Katsuragawa, Tony Hiroshi; Gil, Luiz Herman Soares; Tada, Mauro Shugiro; de Almeida e Silva, Alexandre; Costa, Joana D'Arc Neves; da Silva Araújo, Maisa; Escobar, Ana Lúcia; Pereira da Silva, Luiz Hildebrando

    2010-01-01

    The study area in Rondônia was the site of extensive malaria epidemic outbreaks in the 19th and 20th centuries related to environmental impacts, with large immigration flows. The present work analyzes the transmission dynamics of malaria in these areas to propose measures for avoiding epidemic outbreaks due to the construction of two Hydroelectric Power Plants. A population based baseline demographic census and a malaria prevalence follow up were performed in two river side localities in the suburbs of Porto Velho city and in its rural vicinity. The quantification and nature of malaria parasites in clinical patients and asymptomatic parasite carriers were performed using microscopic and Real Time PCR methodologies. Anopheles densities and their seasonal variation were done by monthly captures for defining HBR (hourly biting rate) values. Main results: (i) malaria among residents show the riverside profile, with population at risk represented by children and young adults; (ii) asymptomatic vivax and falciparum malaria parasite carriers correspond to around 15% of adults living in the area; (iii) vivax malaria relapses were responsible for 30% of clinical cases; (iv) malaria risk for the residents was evaluated as 20–25% for vivax and 5–7% for falciparum malaria; (v) anopheline densities shown outdoors HBR values 5 to 10 fold higher than indoors and reach 10.000 bites/person/year; (vi) very high incidence observed in one of the surveyed localities was explained by a micro epidemic outbreak affecting visitors and temporary residents. Temporary residents living in tents or shacks are accessible to outdoors transmission. Seasonal fishermen were the main group at risk in the study and were responsible for a 2.6 fold increase in the malaria incidence in the locality. This situation illustrates the danger of extensive epidemic outbreaks when thousands of workers and secondary immigrant population will arrive attracted by opportunities opened by the Hydroelectric Power

  12. Molecular dynamics simulation of soft grains: Malaria-infected red blood cells motion within obstructed 2-D capillary vessel

    NASA Astrophysics Data System (ADS)

    Haris, L.; Khotimah, S. N.; Haryanto, F.; Viridi, S.

    2014-02-01

    Molecular dynamics has been widely used to numerically solve equation of motion of classical many-particle system. It can be used to simulate many systems including biophysics, whose complexity level is determined by the involved elements. Based on this method, a numerical model had been constructed to mimic the behaviour of malaria-infected red blood cells within capillary vessel. The model was governed by three forces namely Coulomb force, normal force, and Stokes force. By utilizing two dimensional four-cells scheme, theoretical observation was carried out to test its capability. Although the parameters were chosen deliberately, all of the quantities were given arbitrary value. Despite this fact, the results were quite satisfactory. Combined with the previous results, it can be said that the proposed model were sufficient enough to mimic the malaria-infected red blood cells motion within obstructed capillary vessel.

  13. Recent advances in malaria drug discovery

    PubMed Central

    Biamonte, Marco A.; Wanner, Jutta; Le Roch, Karine G.

    2013-01-01

    This digest covers some of the most relevant progress in malaria drug disco very published betwe en 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug disco very efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria. PMID:23587422

  14. CD8+ T Cells Mediate Robust Stage-Specific Immunity to P. berghei under Chemoprophylaxis and This Protective Environment Is Not Downregulated by the Presence of Blood-Stage Infection

    PubMed Central

    Heiss, Kirsten; Mueller, Ann-Kristin

    2014-01-01

    Sterile protection against malaria infection can be achieved by the inoculation of intact sporozoites while treating concomitantly with the 4-aminoquinoline chloroquine. We present an analysis of protective immunity elicited by successive immunization with Plasmodium berghei sporozoites under chemoprophylaxis. Immunization resulted in a protective, stage-specific immune response. Protection appeared to be mediated by CD8+ T cells and was abrogated upon their specific depletion. Adoptive transfer of splenocytes rendered recipient animals resistant to sporozoite infection, but not to blood-stage challenge. Immunization with sporozoites under chemoprophylaxis results in robust immunity, and the presence of blood-stage infection at sporozoite immunization had no downregulating effect on the protective immune response. PMID:24516592

  15. Dynamic Epigenetic Regulation of Gene Expression during the Life Cycle of Malaria Parasite Plasmodium falciparum

    PubMed Central

    Gupta, Archna P.; Chin, Wai Hoe; Zhu, Lei; Mok, Sachel; Luah, Yen-Hoon; Lim, Eng-How; Bozdech, Zbynek

    2013-01-01

    Epigenetic mechanisms are emerging as one of the major factors of the dynamics of gene expression in the human malaria parasite, Plasmodium falciparum. To elucidate the role of chromatin remodeling in transcriptional regulation associated with the progression of the P. falciparum intraerythrocytic development cycle (IDC), we mapped the temporal pattern of chromosomal association with histone H3 and H4 modifications using ChIP-on-chip. Here, we have generated a broad integrative epigenomic map of twelve histone modifications during the P. falciparum IDC including H4K5ac, H4K8ac, H4K12ac, H4K16ac, H3K9ac, H3K14ac, H3K56ac, H4K20me1, H4K20me3, H3K4me3, H3K79me3 and H4R3me2. While some modifications were found to be associated with the vast majority of the genome and their occupancy was constant, others showed more specific and highly dynamic distribution. Importantly, eight modifications displaying tight correlations with transcript levels showed differential affinity to distinct genomic regions with H4K8ac occupying predominantly promoter regions while others occurred at the 5′ ends of coding sequences. The promoter occupancy of H4K8ac remained unchanged when ectopically inserted at a different locus, indicating the presence of specific DNA elements that recruit histone modifying enzymes regardless of their broad chromatin environment. In addition, we showed the presence of multivalent domains on the genome carrying more than one histone mark, highlighting the importance of combinatorial effects on transcription. Overall, our work portrays a substantial association between chromosomal locations of various epigenetic markers, transcriptional activity and global stage-specific transitions in the epigenome. PMID:23468622

  16. Rapid transdermal bloodless and reagent-free malaria detection

    NASA Astrophysics Data System (ADS)

    Lukianova-Hleb, Ekaterina Y.; Campbell, Kelly M.; Constantinou, Pamela E.; Braam, Janet; Olson, John S.; Ware, Russell E.; Sullivan, David S.; Lapotko, Dmitri

    2014-02-01

    Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. Such diagnostic methods are not currently available. Here we show that the high optical absorbance and nanosize of endogenous heme nanoparticles called hemozoin, a unique component of all blood-stage malaria parasites, generate a transient vapor nanobubble around hemozoin in response to a short and safe near-infrared picosecond laser pulse. The acoustic signals of these malaria-specific nanobubbles provided the first transdermal non-invasive and rapid detection of a malaria infection as low as 0.00034% in animals without using any reagents or drawing blood. These on-demand transient events have no analogs among current malaria markers and probes, can detect and screen malaria in seconds and can be realized as a compact, easy to use, inexpensive and safe field technology.

  17. Malaria biology and disease pathogenesis: insights for new treatments

    PubMed Central

    Miller, Louis H; Ackerman, Hans C; Su, Xin-zhuan; Wellems, Thomas E

    2016-01-01

    Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast Asia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials, including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Our current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the high mortality of severe malaria. An understanding of the pathophysiology of severe disease may identify rational targets for drugs that improve survival. PMID:23389616

  18. Induction of cell death on Plasmodium falciparum asexual blood stages by Solanum nudum steroids.

    PubMed

    López, Mary Luz; Vommaro, Rossiane; Zalis, Mariano; de Souza, Wanderley; Blair, Silvia; Segura, Cesar

    2010-06-01

    Solanum nudum Dunal (Solanaceae) is a plant used in traditional medicine in Colombian Pacific Coast, from which five steroids denominated SNs have been isolated. The SNs compounds have antiplasmodial activity against asexual blood stages of Plasmodium falciparum strain 7G8 with an IC(50) between 20-87microM. However, their mode of action is unknown. Steroids regulate important cellular functions including cell growth, differentiation and death. Thus, the aim of this work was to determine the effects of S. nudum compounds on P. falciparum asexual blood stages and their association with cell death. We found that trophozoite and schizont stages were the most sensitive to SNs. By Giemsa-stained smears, induction of crisis forms was observed. Transmission electron microscopy of treated parasites showed morphological abnormalities such as a cytoplasm rich in vesicles and myelinic figures. The Mitochondria presented no morphological alterations and the nuclei showed no abnormal chromatin condensation. By the use of S. nudum compounds, cell death in P. falciparum was evident by a decrease in mitochondrial membrane potential, DNA fragmentation and cytoplasmic acidification. The asexual blood stages of P. falciparum showed some apoptotic-like and autophagic-like cell death characteristics induced by SNs treatment. PMID:20153445

  19. Climate and Population Immunity in Malaria Dynamics: Harnessing Information from Endemicity Gradients.

    PubMed

    Pascual, Mercedes

    2015-11-01

    It is clear that climate variability and climate change influence malaria in low transmission regions. Much less understood is how climate forcing interacts with population immunity as one moves towards higher transmission intensity. The same transmission model confronted to time series data from two contrasting intensities helps unravel this interaction. PMID:26422773

  20. Iron, anemia and hepcidin in malaria

    PubMed Central

    Spottiswoode, Natasha; Duffy, Patrick E.; Drakesmith, Hal

    2014-01-01

    Malaria and iron have a complex but important relationship. Plasmodium proliferation requires iron, both during the clinically silent liver stage of growth and in the disease-associated phase of erythrocyte infection. Precisely how the protozoan acquires its iron from its mammalian host remains unclear, but iron chelators can inhibit pathogen growth in vitro and in animal models. In humans, iron deficiency appears to protect against severe malaria, while iron supplementation increases risks of infection and disease. Malaria itself causes profound disturbances in physiological iron distribution and utilization, through mechanisms that include hemolysis, release of heme, dyserythropoiesis, anemia, deposition of iron in macrophages, and inhibition of dietary iron absorption. These effects have significant consequences. Malarial anemia is a major global health problem, especially in children, that remains incompletely understood and is not straightforward to treat. Furthermore, the changes in iron metabolism during a malaria infection may modulate susceptibility to co-infections. The release of heme and accumulation of iron in granulocytes may explain increased vulnerability to non-typhoidal Salmonella during malaria. The redistribution of iron away from hepatocytes and into macrophages may confer host resistance to superinfection, whereby blood-stage parasitemia prevents the development of a second liver-stage Plasmodium infection in the same organism. Key to understanding the pathophysiology of iron metabolism in malaria is the activity of the iron regulatory hormone hepcidin. Hepcidin is upregulated during blood-stage parasitemia and likely mediates much of the iron redistribution that accompanies disease. Understanding the regulation and role of hepcidin may offer new opportunities to combat malaria and formulate better approaches to treat anemia in the developing world. PMID:24910614

  1. Comparison of mathematical frameworks for modeling erythropoiesis in the context of malaria infection.

    PubMed

    Fonseca, Luis L; Voit, Eberhard O

    2015-12-01

    Malaria is an infectious disease present all around the globe and responsible for half a million deaths per year. A within-host model of this infection requires a framework capable of properly approximating not only the blood stage of the infection but also the erythropoietic process that is in charge of overcoming the malaria induced anemia. Within this context, we compare ordinary differential equations (ODEs) with and without age classes, delayed differential equations (DDEs), and discrete recursive equations (DREs) with age classes. Results show that ODEs without age classes are fair approximations that do not provide a crisp temporal representation of the processes involved, and inclusion of age classes only mitigates the problem to some degree. DDEs perform well with respect to generating the essentially fixed delay between cell production and cell removal due to age, but the inclusion of any other processes, such as sudden blood loss, becomes cumbersome. The framework that was found to perform best in representing the dynamics of red blood cells during malaria infection is a DRE with age classes. In this model structure, the amount of time a cell remains alive is easily controlled, and the addition of age dependent or independent processes is straightforward. All events that populations of cells face during their lifespan, like growth or adaptation in differentiation or maturation rate, are properly represented in this framework. PMID:26362230

  2. Association of temperature and historical dynamics of malaria in the Republic of Korea, including reemergence in 1993

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasmodium vivax malaria reemerged in the Republic of Korea (ROK) in 1993 after it had been declared malaria free in 1979. Malaria rapidly increased and peaked in 2000 with 4,142 cases. Lower but variable numbers of cases were reported through 2011. We examined the association of regional climate tr...

  3. Malaria Facts

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  4. Development of vaccines for Plasmodium vivax malaria.

    PubMed

    Mueller, Ivo; Shakri, Ahmad Rushdi; Chitnis, Chetan E

    2015-12-22

    Plasmodium vivax continues to cause significant morbidity outside Africa with more than 50% of malaria cases in many parts of South and South-east Asia, Pacific islands, Central and South America being attributed to P. vivax infections. The unique biology of P. vivax, including its ability to form latent hypnozoites that emerge months to years later to cause blood stage infections, early appearance of gametocytes before clinical symptoms are apparent and a shorter development cycle in the vector makes elimination of P. vivax using standard control tools difficult. The availability of an effective vaccine that provides protection and prevents transmission would be a valuable tool in efforts to eliminate P. vivax. Here, we review the latest developments related to P. vivax malaria vaccines and discuss the challenges as well as directions toward the goal of developing highly efficacious vaccines against P. vivax malaria. PMID:26428453

  5. Temporal dynamics of the ABC transporter response to insecticide treatment: insights from the malaria vector Anopheles stephensi

    PubMed Central

    Epis, Sara; Porretta, Daniele; Mastrantonio, Valentina; Urbanelli, Sandra; Sassera, Davide; De Marco, Leone; Mereghetti, Valeria; Montagna, Matteo; Ricci, Irene; Favia, Guido; Bandi, Claudio

    2014-01-01

    In insects, ABC transporters have been shown to contribute to defence/resistance to insecticides by reducing toxic concentrations in cells/tissues. Despite the extensive studies about this detoxifying mechanism, the temporal patterns of ABC transporter activation have been poorly investigated. Using the malaria vector Anopheles stephensi as a study system, we investigated the expression profile of ABC genes belonging to different subfamilies in permethrin-treated larvae at different time points (30 min to 48 h). Our results showed that the expression of ABCB and ABCG subfamily genes was upregulated at 1 h after treatment, with the highest expression observed at 6 h. Therefore, future investigations on the temporal dynamics of ABC gene expression will allow a better implementation of insecticide treatment regimens, including the use of specific inhibitors of ABC efflux pumps. PMID:25504146

  6. Temporal dynamics of the ABC transporter response to insecticide treatment: insights from the malaria vector Anopheles stephensi.

    PubMed

    Epis, Sara; Porretta, Daniele; Mastrantonio, Valentina; Urbanelli, Sandra; Sassera, Davide; De Marco, Leone; Mereghetti, Valeria; Montagna, Matteo; Ricci, Irene; Favia, Guido; Bandi, Claudio

    2014-01-01

    In insects, ABC transporters have been shown to contribute to defence/resistance to insecticides by reducing toxic concentrations in cells/tissues. Despite the extensive studies about this detoxifying mechanism, the temporal patterns of ABC transporter activation have been poorly investigated. Using the malaria vector Anopheles stephensi as a study system, we investigated the expression profile of ABC genes belonging to different subfamilies in permethrin-treated larvae at different time points (30 min to 48 h). Our results showed that the expression of ABCB and ABCG subfamily genes was upregulated at 1 h after treatment, with the highest expression observed at 6 h. Therefore, future investigations on the temporal dynamics of ABC gene expression will allow a better implementation of insecticide treatment regimens, including the use of specific inhibitors of ABC efflux pumps. PMID:25504146

  7. Temporal dynamics of the ABC transporter response to insecticide treatment: insights from the malaria vector Anopheles stephensi

    NASA Astrophysics Data System (ADS)

    Epis, Sara; Porretta, Daniele; Mastrantonio, Valentina; Urbanelli, Sandra; Sassera, Davide; De Marco, Leone; Mereghetti, Valeria; Montagna, Matteo; Ricci, Irene; Favia, Guido; Bandi, Claudio

    2014-12-01

    In insects, ABC transporters have been shown to contribute to defence/resistance to insecticides by reducing toxic concentrations in cells/tissues. Despite the extensive studies about this detoxifying mechanism, the temporal patterns of ABC transporter activation have been poorly investigated. Using the malaria vector Anopheles stephensi as a study system, we investigated the expression profile of ABC genes belonging to different subfamilies in permethrin-treated larvae at different time points (30 min to 48 h). Our results showed that the expression of ABCB and ABCG subfamily genes was upregulated at 1 h after treatment, with the highest expression observed at 6 h. Therefore, future investigations on the temporal dynamics of ABC gene expression will allow a better implementation of insecticide treatment regimens, including the use of specific inhibitors of ABC efflux pumps.

  8. Prospect of vaccination in human malaria*

    PubMed Central

    Corradetti, A.

    1974-01-01

    Rodents have been successfully protected against a challenge of viable Plasmodium berghei by employing as vaccine: (1) the irradiated blood stages of the same parasite, or (2) the water-insoluble fraction of the blood stages, or (3) irradiated sporozoites; all these vaccines were shown to be stage-specific. A method is outlined for testing in the field, in the absence of any risks, the efficacy of analogous vaccines against falciparum malaria in man. It is emphasized that: (1) the efficacy of the vaccines can be tested in no model but only against P. falciparum in man; (2) the protection should be measured in terms of (a) prevention of morbidity, and (b) prevention of mortality; and (3) research must be intensified in order to meet, as needed, the requirements of mass production of merozoites and/or sporozoites, and to find ways to increase the human immune response to a higher level of protection against P. falciparum. PMID:4216411

  9. Malaria vectors and transmission dynamics in Goulmoun, a rural city in south-western Chad

    PubMed Central

    2009-01-01

    Background Knowledge of some baseline entomological data such as Entomological Inoculation Rates (EIR) is crucially needed to assess the epidemiological impact of malaria control activities directed either against parasites or vectors. In Chad, most published surveys date back to the 1960's. In this study, anopheline species composition and their relation to malaria transmission were investigated in a dry Sudanian savannas area of Chad. Methods A 12-month longitudinal survey was conducted in the irrigated rice-fields area of Goulmoun in south western Chad. Human landing catches were performed each month from July 2006 to June 2007 in three compounds (indoors and outdoors) and pyrethrum spray collections were conducted in July, August and October 2006 in 10 randomly selected rooms. Mosquitoes belonging to the Anopheles gambiae complex and to the An. funestus group were identified by molecular diagnostic tools. Plasmodium falciparum infection and blood meal sources were detected by ELISA. Results Nine anopheline species were collected by the two sampling methods. The most aggressive species were An. arabiensis (51 bites/human/night), An. pharoensis (12.5 b/h/n), An. funestus (1.5 b/h/n) and An. ziemanni (1.3 b/h/n). The circumsporozoite protein rate was 1.4% for An. arabiensis, 1.4% for An. funestus, 0.8% for An. pharoensis and 0.5% for An. ziemanni. Malaria transmission is seasonal, lasting from April to December. However, more than 80% of the total EIR was concentrated in the period from August to October. The overall annual EIR was estimated at 311 bites of infected anophelines/human/year, contributed mostly by An. arabiensis (84.5%) and An. pharoensis (12.2%). Anopheles funestus and An. ziemanni played a minor role. Parasite inoculation occurred mostly after 22:00 hours but around 20% of bites of infected anophelines were distributed earlier in the evening. Conclusion The present study revealed the implication of An. pharoensis in malaria transmission in the

  10. Advances and challenges in malaria vaccine development

    PubMed Central

    Wang, Ruobing; Smith, Joseph D.; Kappe, Stefan H.I.

    2010-01-01

    Malaria remains one of the most devastating infectious diseases that threaten humankind. Human malaria is caused by five different species of Plasmodium parasites, each transmitted by the bite of female Anopheles mosquitoes. Plasmodia are eukaryotic protozoans with more than 5000 genes and a complex life cycle that takes place in the mosquito vector and the human host. The life cycle can be divided into pre-erythrocytic stages, erythrocytic stages and mosquito stages. Malaria vaccine research and development faces formidable obstacles because many vaccine candidates will probably only be effective in a specific species at a specific stage. In addition, Plasmodium actively subverts and escapes immune responses, possibly foiling vaccine-induced immunity. Although early successful vaccinations with irradiated, live-attenuated malaria parasites suggested that a vaccine is possible, until recently, most efforts have focused on subunit vaccine approaches. Blood-stage vaccines remain a primary research focus, but real progress is evident in the development of a partially efficacious recombinant pre-erythrocytic subunit vaccine and a live-attenuated sporozoite vaccine. It is unlikely that partially effective vaccines will eliminate malaria; however, they might prove useful in combination with existing control strategies. Elimination of malaria will probably ultimately depend on the development of highly effective vaccines. PMID:20003658

  11. Malaria (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Malaria KidsHealth > For Parents > Malaria Print A A A ... Prevention Diagnosis and Treatment en español Malaria About Malaria Malaria is a common infection in hot, tropical ...

  12. Malaria transmission dynamics in central Côte d'Ivoire: the influence of changing patterns of irrigated rice agriculture.

    PubMed

    Koudou, B G; Tano, Y; Doumbia, M; Nsanzabana, C; Cissé, G; Girardin, O; Dao, D; N'Goran, E K; Vounatsou, P; Bordmann, G; Keiser, J; Tanner, M; Utzinger, J

    2005-03-01

    The dynamics of malaria transmission was studied comparatively in the villages of Zatta and Tiemelekro, central Cote d'Ivoire, from February 2002 to August 2003. Prominent agroecosystems in these villages are irrigated rice growing and vegetable farming, respectively. Mosquitoes (Diptera: Culicidae) were collected on human bait at night and by pyrethrum knock-down spray sheet collections at four randomly selected sentinel sites in each village. In 2002, for a total of 96 man-nights per village, 7716 mosquitoes were collected in Zatta and 3308 in Tiemelekro. In 2003, with half the sampling effort, 859 and 2056 mosquitoes were collected in Zatta and Tiemelekro, respectively. Anopheles gambiae Giles s.l. was the predominant mosquito and the key malaria vector throughout, followed by An. funestus Giles. Anthropophily among adult female Anopheles exceeded 95% in both villages. Comparison between years revealed that the biting rate of An. gambiae s.l. in Zatta decreased several-fold from 49.3 bites per person per night (b/p/n) in 2002 to 7.9 b/p/n in 2003 (likelihood ratio test (LRT) = 1072.66; P < 0.001). Although the biting rate remained fairly constant in Tiemelekro, the difference between years was significant (16.1 vs. 18.2 b/p/n; LRT = 148.06; P < 0.001). These observations were paralleled by a marked decrease in the infective rate of An. gambiae s.l. in Zatta (4.6-1.2%), and an increase in Tiemelekro (3.1-7.6%). Meanwhile, the entomological inoculation rate of An. gambiae s.l. decreased 21-fold in Zatta, from 789 to 38 infective bites per person per year (ib/p/y), whereas it remained high in Tiemelekro (233 vs. 342 ib/p/y). The interruption of irrigated rice growing in Zatta in 2003, consequential to a farmers' conflict over land, might be the underlying cause for the significant reduction in malaria transmission, whereas more stable conditions occurred in Tiemelekro. PMID:15752174

  13. Association of temperature and historical dynamics of malaria in the Republic of Korea, including reemergence in 1993.

    PubMed

    Linthicum, Kenneth J; Anyamba, Assaf; Killenbeck, Bradley; Lee, Won-Ja; Lee, Hee Choon S; Klein, Terry A; Kim, Heung-Chul; Pavlin, Julie A; Britch, Seth C; Small, Jennifer; Tucker, Compton J; Gaydos, Joel C

    2014-07-01

    Plasmodium vivax malaria reemerged in the Republic of Korea in 1993 after it had been declared malaria free in 1979. Malaria rapidly increased and peaked in 2000 with 4,142 cases with lower but variable numbers of cases reported through 2011. We examined the association of regional climate trends over the Korean Peninsula relative to malaria cases in U.S. military and Republic of Korea soldiers, veterans, and civilians from 1950 to 2011. Temperatures and anomaly trends in air temperature associated with satellite remotely sensed outgoing long-wave radiation were used to observe temporal changes. These changes, particularly increasing air temperatures, in combination with moderate rains throughout the malaria season, and distribution of malaria vectors, likely supported the 1993 reemergence and peaks in malaria incidence that occurred through 2011 by accelerating the rate of parasite development in mosquitoes and increased numbers as a result of an expansion of larval habitat, thereby increasing the vectorial capacity of Anopheles vectors. High malaria rates associated with a favorable climate were similarly observed during the Korean War. These findings support the need for increased investigations into malaria predictive models using climate-related variables. PMID:25003869

  14. Malaria parasite epigenetics: when virulence and romance collide.

    PubMed

    Flueck, Christian; Baker, David A

    2014-08-13

    Blood-stage malaria parasites evade the immune system by switching the protein exposed at the surface of the infected erythrocyte. A small proportion of these parasites commits to sexual development to mediate mosquito transmission. Two studies in this issue (Brancucci et al., 2014; Coleman et al., 2014) shed light on shared epigenetic machinery underlying both of these events. PMID:25121742

  15. A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys

    PubMed Central

    Douglas, Alexander D.; Baldeviano, G. Christian; Lucas, Carmen M.; Lugo-Roman, Luis A.; Crosnier, Cécile; Bartholdson, S. Josefin; Diouf, Ababacar; Miura, Kazutoyo; Lambert, Lynn E.; Ventocilla, Julio A.; Leiva, Karina P.; Milne, Kathryn H.; Illingworth, Joseph J.; Spencer, Alexandra J.; Hjerrild, Kathryn A.; Alanine, Daniel G.W.; Turner, Alison V.; Moorhead, Jeromy T.; Edgel, Kimberly A.; Wu, Yimin; Long, Carole A.; Wright, Gavin J.; Lescano, Andrés G.; Draper, Simon J.

    2015-01-01

    Summary Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans. PMID:25590760

  16. The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites.

    PubMed

    Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H; Bagrel, Denyse; Blandin, Stephanie; Lanzer, Michael; Davioud-Charvet, Elisabeth

    2016-09-01

    Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. PMID:27297478

  17. Dendritic cell function and antigen presentation in malaria.

    PubMed

    Cockburn, Ian A; Zavala, Fidel

    2016-06-01

    Due to the diverse roles T cells play in protection against malaria as well as pathogenesis it is critical to know which cells present antigen and the nature of the antigens they present. During pre-erythrocytic stages of infection, cutting-edge imaging studies have shown how Plasmodium antigens are presented during both the priming and effector phases of the protective CD8+ T cell response. During blood stages, pathology is in part due to the loss of DC function and the action of pathogenic T cells in the brain. Recently endothelial cells presenting malaria antigen to cognate T cells have emerged as critical players in malaria pathogenesis. Manipulating these processes may inform both vaccine design and the development of therapies for cerebral malaria. PMID:26845735

  18. Use of Integrated Malaria Management Reduces Malaria in Kenya

    PubMed Central

    Okech, Bernard A.; Mwobobia, Isaac K.; Kamau, Anthony; Muiruri, Samuel; Mutiso, Noah; Nyambura, Joyce; Mwatele, Cassian; Amano, Teruaki; Mwandawiro, Charles S.

    2008-01-01

    Background During an entomological survey in preparation for malaria control interventions in Mwea division, the number of malaria cases at the Kimbimbi sub-district hospital was in a steady decline. The underlying factors for this reduction were unknown and needed to be identified before any malaria intervention tools were deployed in the area. We therefore set out to investigate the potential factors that could have contributed to the decline of malaria cases in the hospital by analyzing the malaria control knowledge, attitudes and practices (KAP) that the residents in Mwea applied in an integrated fashion, also known as integrated malaria management (IMM). Methods Integrated Malaria Management was assessed among community members of Mwea division, central Kenya using KAP survey. The KAP study evaluated community members' malaria disease management practices at the home and hospitals, personal protection measures used at the household level and malaria transmission prevention methods relating to vector control. Concurrently, we also passively examined the prevalence of malaria parasite infection via outpatient admission records at the major referral hospital in the area. In addition we studied the mosquito vector population dynamics, the malaria sporozoite infection status and entomological inoculation rates (EIR) over an 8 month period in 6 villages to determine the risk of malaria transmission in the entire division. Results A total of 389 households in Mwea division were interviewed in the KAP study while 90 houses were surveyed in the entomological study. Ninety eight percent of the households knew about malaria disease while approximately 70% of households knew its symptoms and methods to manage it. Ninety seven percent of the interviewed households went to a health center for malaria diagnosis and treatment. Similarly a higher proportion (81%) used anti-malarial medicines bought from local pharmacies. Almost 90% of households reported owning and using an

  19. Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria

    PubMed Central

    Lukianova-Hleb, Ekaterina Y.; Campbell, Kelly M.; Constantinou, Pamela E.; Braam, Janet; Olson, John S.; Ware, Russell E.; Sullivan, David J.; Lapotko, Dmitri O.

    2014-01-01

    Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. Such diagnostic methods are not currently available. Here we show that the high optical absorbance and nanosize of endogenous heme nanoparticles called “hemozoin,” a unique component of all blood-stage malaria parasites, generates a transient vapor nanobubble around hemozoin in response to a short and safe near-infrared picosecond laser pulse. The acoustic signals of these malaria-specific nanobubbles provided transdermal noninvasive and rapid detection of a malaria infection as low as 0.00034% in animals without using any reagents or drawing blood. These on-demand transient events have no analogs among current malaria markers and probes, can detect and screen malaria in seconds, and can be realized as a compact, easy-to-use, inexpensive, and safe field technology. PMID:24379385

  20. Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria.

    PubMed

    Lukianova-Hleb, Ekaterina Y; Campbell, Kelly M; Constantinou, Pamela E; Braam, Janet; Olson, John S; Ware, Russell E; Sullivan, David J; Lapotko, Dmitri O

    2014-01-21

    Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. Such diagnostic methods are not currently available. Here we show that the high optical absorbance and nanosize of endogenous heme nanoparticles called "hemozoin," a unique component of all blood-stage malaria parasites, generates a transient vapor nanobubble around hemozoin in response to a short and safe near-infrared picosecond laser pulse. The acoustic signals of these malaria-specific nanobubbles provided transdermal noninvasive and rapid detection of a malaria infection as low as 0.00034% in animals without using any reagents or drawing blood. These on-demand transient events have no analogs among current malaria markers and probes, can detect and screen malaria in seconds, and can be realized as a compact, easy-to-use, inexpensive, and safe field technology. PMID:24379385

  1. Linking individual phenotype to density-dependent population growth: the influence of body size on the population dynamics of malaria vectors

    PubMed Central

    Russell, Tanya L.; Lwetoijera, Dickson W.; Knols, Bart G. J.; Takken, Willem; Killeen, Gerry F.; Ferguson, Heather M.

    2011-01-01

    Understanding the endogenous factors that drive the population dynamics of malaria mosquitoes will facilitate more accurate predictions about vector control effectiveness and our ability to destabilize the growth of either low- or high-density insect populations. We assessed whether variation in phenotypic traits predict the dynamics of Anopheles gambiae sensu lato mosquitoes, the most important vectors of human malaria. Anopheles gambiae dynamics were monitored over a six-month period of seasonal growth and decline. The population exhibited density-dependent feedback, with the carrying capacity being modified by rainfall (97% wAICc support). The individual phenotypic expression of the maternal (p = 0.0001) and current (p = 0.040) body size positively influenced population growth. Our field-based evidence uniquely demonstrates that individual fitness can have population-level impacts and, furthermore, can mitigate the impact of exogenous drivers (e.g. rainfall) in species whose reproduction depends upon it. Once frontline interventions have suppressed mosquito densities, attempts to eliminate malaria with supplementary vector control tools may be attenuated by increased population growth and individual fitness. PMID:21389034

  2. Eradicating malaria.

    PubMed

    Breman, Joel G

    2009-01-01

    The renewed interest in malaria research and control is based on the intolerable toll this disease takes on young children and pregnant women in Africa and other vulnerable populations; 150 to 300 children die each hour from malaria amounting to 1 to 2 million deaths yearly. Malaria-induced neurologic impairment, anemia, hypoglycemia, and low birth weight imperil normal development and survival. Resistance of Plasmodium falciparum to drugs and Anopheles mosquitoes to insecticides has stimulated discovery and development of artemisinin-based combination treatments (ACTs) and other drugs, long-lasting insecticide-treated bednets (with synthetic pyrethroids) and a search for non-toxic, long-lasting, affordable insecticides for indoor residual spraying (IRS). Malaria vaccine development and testing are progressing rapidly and a recombinant protein (RTS,S/AS02A) directed against the circumsporozoite protein is soon to be in Phase 3 trials. Support for malaria control, research, and advocacy through the Global Fund for HIV/AIDS, Tuberculosis and Malaria, the U.S. President's Malaria Initiative, the Bill & Melinda Gates Foundation, WHO and other organizations is resulting in decreasing morbidity and mortality in many malarious countries. Sustainability of effective programs through training and institution strengthening will be the key to malaria elimination coupled with improved surveillance and targeted research. PMID:19544698

  3. A breeding site model for regional, dynamical malaria simulations evaluated using in situ temporary ponds observations.

    PubMed

    Asare, Ernest O; Tompkins, Adrian M; Amekudzi, Leonard K; Ermert, Volker

    2016-01-01

    Daily observations of potential mosquito developmental habitats in a suburb of Kumasi in central Ghana reveal a strong variability in their water persistence times, which ranged between 11 and 81 days. The persistence of the ponds was strongly tied with rainfall, location and size of the puddles. A simple power-law relationship is found to fit the relationship between the average pond depth and area well. A prognostic water balance model is derived that describes the temporal evolution of the pond area and depth, incorporating the power-law geometrical relation. Pond area increases in response to rainfall, while evaporation and infiltration act as sink terms. Based on a range of evaluation metrics, the prognostic model is judged to provide a good representation of the pond coverage evolution at most sites. Finally, we demonstrate that the prognostic equation can be generalised and equally applied to a grid-cell to derive a fractional pond coverage, and thus can be implemented in spatially distributed models for relevant vector- borne diseases such as malaria. PMID:27063734

  4. Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum

    PubMed Central

    2014-01-01

    Background In view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty. Methods The selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as ‘signposts’ in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay. Results This screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series. Conclusion A selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical

  5. Mitochondrial oxygen consumption in asexual and sexual blood stages of the human malarial parasite, Plasmodium falciparum.

    PubMed

    Krungkrai, J; Burat, D; Kudan, S; Krungkrai, S; Prapunwattana, P

    1999-12-01

    The two developmental stages of human malarial parasite Plasmodium falciparum, asexual and sexual blood stages, were continuously cultivated in vitro. Both asexual and sexual stages of the parasites were assayed for mitochondrial oxygen consumption by using a polarographic assay. The rate of oxygen consumption by both stages was found to be relatively low, and was not much different. Furthermore, the mitochondrial oxygen consumption by both stages was inhibited to various degrees by mammalian mitochondrial inhibitors that targeted each component of complexes I- IV of the respiratory system. The oxygen consumption by both stages was also affected by 5-fluoroorotate, a known inhibitor of enzyme dihydroorotate dehydrogenase of the pyrimidine pathway and by an antimalarial drug atovaquone that acted specifically on mitochondrial complex III of the parasite. Moreover, antimalarials primaquine and artemisinin had inhibitory effects on the oxygen consumption by both stages of the parasites. Our results suggest that P. falciparum in both developmental stages have functional mitochondria that operate a classical electron transport system, containing complexes I-IV, and linked to the pyrimidine biosynthetic pathway. PMID:10928353

  6. CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.

    PubMed

    Ng, Caroline L; Siciliano, Giulia; Lee, Marcus C S; de Almeida, Mariana J; Corey, Victoria C; Bopp, Selina E; Bertuccini, Lucia; Wittlin, Sergio; Kasdin, Rachel G; Le Bihan, Amélie; Clozel, Martine; Winzeler, Elizabeth A; Alano, Pietro; Fidock, David A

    2016-08-01

    Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials. PMID:27073104

  7. Gametocyte clearance dynamics following oral artesunate treatment of uncomplicated falciparum malaria in Malian children

    PubMed Central

    Djimde, Abdoulaye A.; Maiga, Amelia W.; Ouologuem, Dinkorma; Fofana, Bakary; Sagara, Issaka; Dembele, Demba; Toure, Sekou; Sanogo, Kassim; Dama, Souleymane; Sidibe, Bakary; Doumbo, Ogobara K.

    2016-01-01

    Artemisinin-based combination therapies decrease Plasmodium gametocyte carriage. However, the role of artesunate in monotherapy in vivo, the mechanisms involved, and the utility of gametocyte carriage as a potential tool for the surveillance of antimalarial resistance are poorly understood. In 2010–2011, we conducted an open-label, prospective efficacy study of artesunate as monotherapy in children 1–10 years of age with uncomplicated falciparum malaria in Bougoula-Hameau, Mali. Standard oral doses of artesunate were administered for 7 days and patients were followed up for 28 days. The data were compared to a similar study conducted in 2002–2004. Of 100 children enrolled in the 2010–2011 study, 92 were analyzed and compared to 217 children enrolled in the 2002–2004 study. The proportion of gametocyte carriers was unchanged at the end of treatment (23% at baseline vs. 24% on day 7, p = 1.0) and did not significantly decline until day 21 of follow-up (23% vs. 6%, p = 0.003). The mean gametocyte density at inclusion remained unchanged at the end of treatment (12 gametocytes/μL vs. 16 gametocytes/μL, p = 0.6). Overall, 46% of the 71 initial non-carriers had gametocytes detected by day 7. Similar results were found in the 2002–2004 study. In both studies, although gametocyte carriage significantly decreased by the end of the 28-day follow-up, artesunate did not clear mature gametocytes during treatment and did not prevent the appearance of new stage V gametocytes as assessed by light microscopy. Baseline gametocyte carriage was significantly higher 6 years after the deployment of artemisinin-based combination therapies in this setting. PMID:26839003

  8. Gametocyte clearance dynamics following oral artesunate treatment of uncomplicated falciparum malaria in Malian children.

    PubMed

    Djimde, Abdoulaye A; Maiga, Amelia W; Ouologuem, Dinkorma; Fofana, Bakary; Sagara, Issaka; Dembele, Demba; Toure, Sekou; Sanogo, Kassim; Dama, Souleymane; Sidibe, Bakary; Doumbo, Ogobara K

    2016-01-01

    Artemisinin-based combination therapies decrease Plasmodium gametocyte carriage. However, the role of artesunate in monotherapy in vivo, the mechanisms involved, and the utility of gametocyte carriage as a potential tool for the surveillance of antimalarial resistance are poorly understood. In 2010-2011, we conducted an open-label, prospective efficacy study of artesunate as monotherapy in children 1-10 years of age with uncomplicated falciparum malaria in Bougoula-Hameau, Mali. Standard oral doses of artesunate were administered for 7 days and patients were followed up for 28 days. The data were compared to a similar study conducted in 2002-2004. Of 100 children enrolled in the 2010-2011 study, 92 were analyzed and compared to 217 children enrolled in the 2002-2004 study. The proportion of gametocyte carriers was unchanged at the end of treatment (23% at baseline vs. 24% on day 7, p = 1.0) and did not significantly decline until day 21 of follow-up (23% vs. 6%, p = 0.003). The mean gametocyte density at inclusion remained unchanged at the end of treatment (12 gametocytes/μL vs. 16 gametocytes/μL, p = 0.6). Overall, 46% of the 71 initial non-carriers had gametocytes detected by day 7. Similar results were found in the 2002-2004 study. In both studies, although gametocyte carriage significantly decreased by the end of the 28-day follow-up, artesunate did not clear mature gametocytes during treatment and did not prevent the appearance of new stage V gametocytes as assessed by light microscopy. Baseline gametocyte carriage was significantly higher 6 years after the deployment of artemisinin-based combination therapies in this setting. PMID:26839003

  9. Discovery of Dual-Stage Malaria Inhibitors with New Targets.

    PubMed

    Raphemot, Rene; Lafuente-Monasterio, Maria J; Gamo-Benito, Francisco Javier; Clardy, Jon; Derbyshire, Emily R

    2015-01-01

    Malaria remains a major global health problem, with more than half of the world population at risk of contracting the disease and nearly a million deaths each year. Here, we report the discovery of inhibitors that target multiple stages of malaria parasite growth. To identify these inhibitors, we took advantage of the Tres Cantos Antimalarial Compound Set (TCAMS) small-molecule library, which is comprised of diverse and potent chemical scaffolds with activities against the blood stage of the malaria parasite, and investigated their effects against the elusive liver stage of the malaria parasite using a forward chemical screen. From a screen of nearly 14,000 compounds, we identified and confirmed 103 compounds as dual-stage malaria inhibitors. Interestingly, these compounds show preferential inhibition of parasite growth in liver- versus blood-stage malaria parasite assays, highlighting the drug susceptibility of this parasite form. Mode-of-action studies were completed using genetically modified and drug-resistant Plasmodium parasite strains. While we identified some compound targets as classical antimalarial pathways, such as the mitochondrial electron transport chain through cytochrome bc1 complex inhibition or the folate biosynthesis pathway, most compounds induced parasite death through as yet unknown mechanisms of action. Importantly, the identification of new chemotypes with different modes of action in killing Plasmodium parasites represents a promising opportunity for probing essential and novel molecular processes that remain to be discovered. The chemical scaffolds identified with activity against drug-resistant Plasmodium parasites represent starting points for dual-stage antimalarial development to surmount the threat of malaria parasite drug resistance. PMID:26666931

  10. Malaria vaccine.

    PubMed

    1994-05-01

    Some have argued that the vaccine against malaria developed by Manuel Pattaroyo, a Colombian scientist, is being tested prematurely in humans and that it is unlikely to be successful. While the Pattaroyo vaccine has been shown to confer protection against the relatively mild malaria found in Colombia, doubts exist over whether it will be effective in Africa. Encouraging first results, however, are emerging from field tests in Tanzania. The vaccine triggered a strong new immune response, even in individuals previously exposed to malaria. Additional steps must be taken to establish its impact upon mortality and morbidity. Five major trials are underway around the world. The creator estimates that the first ever effective malaria vaccine could be available for widespread use within five years and he has no intention of securing a patent for the discovery. In another development, malaria specialists from 35 African countries convened at an international workshop in Zimbabwe to compare notes. Participants disparaged financial outlays for the fight against malaria equivalent to 2% of total AIDS funding as insufficient; noted intercountry differences in prevention, diagnosis, and treatment; and found information exchange between anglophone and francophone doctors to be generally poor. PMID:12287671

  11. Gene gun immunization to combat malaria.

    PubMed

    Bergmann-Leitner, Elke S; Leitner, Wolfgang W

    2013-01-01

    DNA immunization by gene gun against a variety of infectious diseases has yielded promising results in animal models. Skin-based DNA vaccination against these diseases is not only an attractive option for the clinic but can aid in the discovery and optimization of vaccine candidates. Vaccination against the protozoan parasite Plasmodium presents unique challenges: (a) most parasite-associated antigens are stage-specific; (b) antibodies capable of neutralizing the parasite during the probing of the mosquitoes have to be available at high titers in order to prevent infection of the liver; (c) immunity to liver-stage infection needs to be absolute in order to prevent subsequent blood-stage parasitemia. Gene gun vaccination has successfully been used to prevent the infection of mice with the rodent malaria strain P. berghei and has been employed in a macaque model of human P. falciparum. DNA plasmid delivery by gene gun offers the opportunity to economically and efficiently test novel malaria vaccine candidates and vaccination strategies, which include the evaluation of novel molecular adjuvant strategies. Here we describe the procedures involved in making and delivering a pre-clinical malaria DNA vaccine by gene gun as well as the correct approach for the in vivo evaluation of the vaccine. Furthermore, we discuss various approaches that either have already been tested or could be employed to improve DNA vaccines against malaria. PMID:23104349

  12. Artemisinin combination therapy for vivax malaria?

    PubMed Central

    Douglas, Nicholas M.; Anstey, Nicholas M.; Angus, Brian J.; Nosten, Francois; Price, Ric N.

    2012-01-01

    Early parasitological diagnosis and treatment with artemisinin-based combination therapies (ACT) are seen as key components of global malaria elimination programmes. In general, use of ACTs has been limited to patients with falciparum malaria whereas blood-stage P. vivax infections are mostly still treated with chloroquine. We review the evidence for the relative benefits and disadvantages of the existing ‘separate’ treatment approach versus a ‘unified’ ACT-based strategy for treating P. falciparum and P. vivax infections in regions where both species are endemic (co-endemic). The ‘separate’ treatment scenario is justifiable where P. vivax remains sensitive to chloroquine and providing that diagnostic tests reliably distinguish P. vivax from P. falciparum. However, with the high frequency of misdiagnosis in routine practice and the rise and spread of chloroquine-resistant P. vivax, there may be a compelling rationale for a unified ACT-based strategy for vivax and falciparum malaria in all co-endemic areas. Analyses of the cost-effectiveness of ACTs for both Plasmodium species are required to assess the role of these drugs in vivax malaria control and elimination efforts. PMID:20510281

  13. MALVAC 2012 scientific forum: accelerating development of second-generation malaria vaccines

    PubMed Central

    2012-01-01

    The World Health Organization (WHO) convened a malaria vaccines committee (MALVAC) scientific forum from 20 to 21 February 2012 in Geneva, Switzerland, to review the global malaria vaccine portfolio, to gain consensus on approaches to accelerate second-generation malaria vaccine development, and to discuss the need to update the vision and strategic goal of the Malaria Vaccine Technology Roadmap. This article summarizes the forum, which included reviews of leading Plasmodium falciparum vaccine candidates for pre-erythrocytic vaccines, blood-stage vaccines, and transmission-blocking vaccines. Other major topics included vaccine candidates against Plasmodium vivax, clinical trial site capacity development in Africa, trial design considerations for a second-generation malaria vaccine, adjuvant selection, and regulatory oversight functions including vaccine licensure. PMID:23140365

  14. The Structure of Plasmodium falciparum Blood-Stage 6-Cys Protein Pf41 Reveals an Unexpected Intra-Domain Insertion Required for Pf12 Coordination.

    PubMed

    Parker, Michelle L; Peng, Fangni; Boulanger, Martin J

    2015-01-01

    Plasmodium falciparum is an apicomplexan parasite and the etiological agent of severe human malaria. The complex P. falciparum life cycle is supported by a diverse repertoire of surface proteins including the family of 6-Cys s48/45 antigens. Of these, Pf41 is localized to the surface of the blood-stage merozoite through its interaction with the glycophosphatidylinositol-anchored Pf12. Our recent structural characterization of Pf12 revealed two juxtaposed 6-Cys domains (D1 and D2). Pf41, however, contains an additional segment of 120 residues predicted to form a large spacer separating its two 6-Cys domains. To gain insight into the assembly mechanism and overall architecture of the Pf12-Pf41 complex, we first determined the 2.45 Å resolution crystal structure of Pf41 using zinc single-wavelength anomalous dispersion. Structural analysis revealed an unexpected domain organization where the Pf41 6-Cys domains are, in fact, intimately associated and the additional residues instead map predominately to an inserted domain-like region (ID) located between two β-strands in D1. Notably, the ID is largely proteolyzed in the final structure suggesting inherent flexibility. To assess the contribution of the ID to complex formation, we engineered a form of Pf41 where the ID was replaced by a short glycine-serine linker and showed by isothermal titration calorimetry that binding to Pf12 was abrogated. Finally, protease protection assays showed that the proteolytic susceptibility of the ID was significantly reduced in the complex, consistent with the Pf41 ID directly engaging Pf12. Collectively, these data establish the architectural organization of Pf41 and define an essential role for the Pf41 ID in promoting assembly of the Pf12-Pf41 heterodimeric complex. PMID:26414347

  15. Blood Stage Plasmodium falciparum Exhibits Biological Responses to Direct Current Electric Fields

    PubMed Central

    Coronado, Lorena M.; Montealegre, Stephania; Chaverra, Zumara; Mojica, Luis; Espinosa, Carlos; Almanza, Alejandro; Correa, Ricardo; Stoute, José A.; Gittens, Rolando A.

    2016-01-01

    The development of resistance to insecticides by the vector of malaria and the increasingly faster appearance of resistance to antimalarial drugs by the parasite can dangerously hamper efforts to control and eradicate the disease. Alternative ways to treat this disease are urgently needed. Here we evaluate the in vitro effect of direct current (DC) capacitive coupling electrical stimulation on the biology and viability of Plasmodium falciparum. We designed a system that exposes infected erythrocytes to different capacitively coupled electric fields in order to evaluate their effect on P. falciparum. The effect on growth of the parasite, replication of DNA, mitochondrial membrane potential and level of reactive oxygen species after exposure to electric fields demonstrate that the parasite is biologically able to respond to stimuli from DC electric fields involving calcium signaling pathways. PMID:27537497

  16. Blood Stage Plasmodium falciparum Exhibits Biological Responses to Direct Current Electric Fields.

    PubMed

    Coronado, Lorena M; Montealegre, Stephania; Chaverra, Zumara; Mojica, Luis; Espinosa, Carlos; Almanza, Alejandro; Correa, Ricardo; Stoute, José A; Gittens, Rolando A; Spadafora, Carmenza

    2016-01-01

    The development of resistance to insecticides by the vector of malaria and the increasingly faster appearance of resistance to antimalarial drugs by the parasite can dangerously hamper efforts to control and eradicate the disease. Alternative ways to treat this disease are urgently needed. Here we evaluate the in vitro effect of direct current (DC) capacitive coupling electrical stimulation on the biology and viability of Plasmodium falciparum. We designed a system that exposes infected erythrocytes to different capacitively coupled electric fields in order to evaluate their effect on P. falciparum. The effect on growth of the parasite, replication of DNA, mitochondrial membrane potential and level of reactive oxygen species after exposure to electric fields demonstrate that the parasite is biologically able to respond to stimuli from DC electric fields involving calcium signaling pathways. PMID:27537497

  17. Plasmepsin 4-Deficient Plasmodium berghei Are Virulence Attenuated and Induce Protective Immunity against Experimental Malaria

    PubMed Central

    Spaccapelo, Roberta; Janse, Chris J.; Caterbi, Sara; Franke-Fayard, Blandine; Bonilla, J. Alfredo; Syphard, Luke M.; Di Cristina, Manlio; Dottorini, Tania; Savarino, Andrea; Cassone, Antonio; Bistoni, Francesco; Waters, Andrew P.; Dame, John B.; Crisanti, Andrea

    2010-01-01

    Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei Δpm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant mice were able to clear infections. Furthermore, after a single infection, all convalescent mice were protected against subsequent parasite challenge for at least 1 year. Real-time in vivo parasite imaging and splenectomy experiments demonstrated that protective immunity acted through antibody-mediated parasite clearance in the spleen. This work demonstrates, for the first time, that a single Plasmodium gene disruption can generate virulence-attenuated parasites that do not induce cerebral complications and, moreover, are able to stimulate strong protective immunity against subsequent challenge with wild-type parasites. Parasite blood-stage attenuation should help identify protective immune responses against malaria, unravel parasite-derived factors involved in malarial pathologies, such as cerebral malaria, and potentially pave the way for blood-stage whole organism vaccines. PMID:20019192

  18. Standardization of the antibody-dependent respiratory burst assay with human neutrophils and Plasmodium falciparum malaria

    PubMed Central

    Llewellyn, David; Miura, Kazutoyo; Fay, Michael P.; Williams, Andrew R.; Murungi, Linda M.; Shi, Jianguo; Hodgson, Susanne H.; Douglas, Alexander D.; Osier, Faith H.; Fairhurst, Rick M.; Diakite, Mahamadou; Pleass, Richard J.; Long, Carole A.; Draper, Simon J.

    2015-01-01

    The assessment of naturally-acquired and vaccine-induced immunity to blood-stage Plasmodium falciparum malaria is of long-standing interest. However, the field has suffered from a paucity of in vitro assays that reproducibly measure the anti-parasitic activity induced by antibodies in conjunction with immune cells. Here we optimize the antibody-dependent respiratory burst (ADRB) assay, which assesses the ability of antibodies to activate the release of reactive oxygen species from human neutrophils in response to P. falciparum blood-stage parasites. We focus particularly on assay parameters affecting serum preparation and concentration, and importantly assess reproducibility. Our standardized protocol involves testing each serum sample in singlicate with three independent neutrophil donors, and indexing responses against a standard positive control of pooled hyper-immune Kenyan sera. The protocol can be used to quickly screen large cohorts of samples from individuals enrolled in immuno-epidemiological studies or clinical vaccine trials, and requires only 6 μL of serum per sample. Using a cohort of 86 samples, we show that malaria-exposed individuals induce higher ADRB activity than malaria-naïve individuals. The development of the ADRB assay complements the use of cell-independent assays in blood-stage malaria, such as the assay of growth inhibitory activity, and provides an important standardized cell-based assay in the field. PMID:26373337

  19. Application of Serological Tools and Spatial Analysis to Investigate Malaria Transmission Dynamics in Highland Areas of Southwest Uganda

    PubMed Central

    Lynch, Caroline A.; Cook, Jackie; Nanyunja, Sarah; Bruce, Jane; Bhasin, Amit; Drakeley, Chris; Roper, Cally; Pearce, Richard; Rwakimari, John B.; Abeku, Tarekegn A.; Corran, Patrick; Cox, Jonathan

    2016-01-01

    Serological markers, combined with spatial analysis, offer a comparatively more sensitive means by which to measure and detect foci of malaria transmission in highland areas than traditional malariometric indicators. Plasmodium falciparum parasite prevalence, seroprevalence, and seroconversion rate to P. falciparum merozoite surface protein-119 (MSP-119) were measured in a cross-sectional survey to determine differences in transmission between altitudinal strata. Clusters of P. falciparum parasite prevalence and high antibody responses to MSP-119 were detected and compared. Results show that P. falciparum prevalence and seroprevalence generally decreased with increasing altitude. However, transmission was heterogeneous with hotspots of prevalence and/or seroprevalence detected in both highland and highland fringe altitudes, including a serological hotspot at 2,200 m. Results demonstrate that seroprevalence can be used as an additional tool to identify hotspots of malaria transmission that might be difficult to detect using traditional cross-sectional parasite surveys or through vector studies. Our study findings identify ways in which malaria prevention and control can be more effectively targeted in highland or low transmission areas via serological measures. These tools will become increasingly important for countries with an elimination agenda and/or where malaria transmission is becoming patchy and focal, but receptivity to malaria transmission remains high. PMID:27022156

  20. Application of Serological Tools and Spatial Analysis to Investigate Malaria Transmission Dynamics in Highland Areas of Southwest Uganda.

    PubMed

    Lynch, Caroline A; Cook, Jackie; Nanyunja, Sarah; Bruce, Jane; Bhasin, Amit; Drakeley, Chris; Roper, Cally; Pearce, Richard; Rwakimari, John B; Abeku, Tarekegn A; Corran, Patrick; Cox, Jonathan

    2016-06-01

    Serological markers, combined with spatial analysis, offer a comparatively more sensitive means by which to measure and detect foci of malaria transmission in highland areas than traditional malariometric indicators. Plasmodium falciparum parasite prevalence, seroprevalence, and seroconversion rate to P. falciparum merozoite surface protein-119 (MSP-119) were measured in a cross-sectional survey to determine differences in transmission between altitudinal strata. Clusters of P. falciparum parasite prevalence and high antibody responses to MSP-119 were detected and compared. Results show that P. falciparum prevalence and seroprevalence generally decreased with increasing altitude. However, transmission was heterogeneous with hotspots of prevalence and/or seroprevalence detected in both highland and highland fringe altitudes, including a serological hotspot at 2,200 m. Results demonstrate that seroprevalence can be used as an additional tool to identify hotspots of malaria transmission that might be difficult to detect using traditional cross-sectional parasite surveys or through vector studies. Our study findings identify ways in which malaria prevention and control can be more effectively targeted in highland or low transmission areas via serological measures. These tools will become increasingly important for countries with an elimination agenda and/or where malaria transmission is becoming patchy and focal, but receptivity to malaria transmission remains high. PMID:27022156

  1. Spatio-temporal Dynamics of Wetlands and Malaria in the Ethiopian Highlands Using Multi-sensor Satellite Observations

    NASA Astrophysics Data System (ADS)

    Midekisa, A. A.; Wimberly, M. C.; Senay, G. B.

    2013-12-01

    Tropical wetlands provide various beneficial ecosystem services; however, they can also facilitate the transmission of vector-borne diseases. Because wetlands serve as breeding habitats for Anopheles mosquitoes, particularly during the dry season, they are critical eco-hydrologic elements for malaria transmission. The overarching hypothesis of this study is that landscape and regional patterns of wetlands are associated with malaria risk in the Amhara region of Ethiopia. To test this hypothesis, we developed a random forest decision tree model to map seasonal and permanent wetlands in the Amhara region. Wetland training and validation data were acquired from high-resolution imagery in Google Earth and ground surveys. We evaluated the effectiveness of three random forest models using the following sets of predictor variables: (1) topographical indices from 30 m SRTM data, (2) individual reflectance bands and multispectral wetness indices from Landsat TM/ETM+ imagery, and (3) combined spectral and topographic data. The combined model produced the most accurate wetland maps, and we used it to map wetlands across the study area for 2000, 2005, and 2010. We found spatial associations between indicators of malaria risk from historical surveillance data and metrics of wetland cover at a district level. We also quantified seasonal moisture variability among three different land use land cover types (permanent wetland, seasonal wetland, and cropland) using Actual Evapotranspiration (ETa) over a ten year period (2001-2010) derived from MODIS imagery. We found that permanent and seasonal wetlands have peak moisture during the major malaria transmission season (September-November), whereas the permanent wetlands retain moisture and potentially sustain mosquito populations during the low transmission season (December-March). These findings about the spatial and temporal associations of malaria risk and wetlands can help to highlight areas that likely sustain transmission during

  2. Design and Synthesis of Novel Hybrid Molecules against Malaria

    PubMed Central

    Lödige, Melanie; Hiersch, Luisa

    2015-01-01

    The effective treatment of malaria can be very complex: Plasmodium parasites develop in multiple stages within a complex life cycle between mosquitoes as vectors and vertebrates as hosts. For the full and effective elimination of parasites, an effective drug should be active against the earliest stages of the Plasmodium infection: liver stages (reduce the progress of the infection), blood stages (cure the clinical symptoms), and gametocytes (inhibit the transmission cycle). Towards this goal, here we report the design, the synthetic methodology, and the characterization of novel hybrid agents with combined activity against Plasmodium liver stages and blood stages and gametocytes. The divergent synthetic approach allows the access to differently linked primaquine-chloroquine hybrid templates in up to eight steps. PMID:25734014

  3. Vivax malaria.

    PubMed

    Baker, P B; Dronen, S C

    1986-01-01

    Malaria occurs in the United States infrequently and is found exclusively among immigrants and travelers returning from areas where the disease is endemic. Cases of acute relapses of Plasmodium vivax infection can present to the emergency department. Patients are often immigrants from developing countries who were symptom-free in this country for weeks or months preceding their illness. The clinical presentation and current treatment of malaria are reviewed. Malarial infection may become apparent months after leaving endemic areas despite adherence to prophylactic regimens. The disease usually responds to appropriate drug therapy with rapid and often dramatic results, but it can be fatal if unrecognized. PMID:3511922

  4. Coadaptation and malaria control.

    PubMed

    Tosta, Carlos Eduardo

    2007-06-01

    Malaria emerges from a disequilibrium of the system 'human-plasmodium-mosquito' (HPM). If the equilibrium is maintained, malaria does not ensue and the result is asymptomatic plasmodium infection. The relationships among the components of the system involve coadaptive linkages that lead to equilibrium. A vast body of evidence supports this assumption, including the strategies involved in the relationships between plasmodium and human and mosquito immune systems, and the emergence of resistance of plasmodia to antimalarial drugs and of mosquitoes to insecticides. Coadaptive strategies for malaria control are based on the following principles: (1) the system HPM is composed of three highly complex and dynamic components, whose interplay involves coadaptive linkages that tend to maintain the equilibrium of the system; (2) human and mosquito immune systems play a central role in the coadaptive interplay with plasmodium, and hence, in the maintenance of the system's equilibrium; the under- or overfunction of human immune system may result in malaria and influence its severity; (3) coadaptation depends on genetic and epigenetic phenomena occurring at the interfaces of the components of the system, and may involve exchange of infectrons (genes or gene fragments) between the partners; (4) plasmodia and mosquitoes have been submitted to selective pressures, leading to adaptation, for an extremely long while and are, therefore, endowed with the capacity to circumvent both natural (immunity) and artificial (drugs, insecticides, vaccines) measures aiming at destroying them; (5) since malaria represents disequilibrium of the system HPM, its control should aim at maintaining or restoring this equilibrium; (6) the disequilibrium of integrated systems involves the disequilibrium of their components, therefore the maintenance or restoration of the system's equilibrium depend on the adoption of integrated and coordinated measures acting on all components, that means, panadaptive

  5. Cellular and humoral immune responses against the Plasmodium vivax MSP-119 malaria vaccine candidate in individuals living in an endemic area in north-eastern Amazon region of Brazil

    PubMed Central

    2013-01-01

    Background Plasmodium vivax merozoite surface protein-1 (MSP-1) is an antigen considered to be one of the leading malaria vaccine candidates. PvMSP-1 is highly immunogenic and evidences suggest that it is target for protective immunity against asexual blood stages of malaria parasites. Thus, this study aims to evaluate the acquired cellular and antibody immune responses against PvMSP-1 in individuals naturally exposed to malaria infections in a malaria-endemic area in the north-eastern Amazon region of Brazil. Methods The study was carried out in Paragominas, Pará State, in the Brazilian Amazon. Blood samples were collected from 35 individuals with uncomplicated malaria. Peripheral blood mononuclear cells were isolated and the cellular proliferation and activation was analysed in presence of 19 kDa fragment of MSP-1 (PvMSP-119) and Plasmodium falciparum PSS1 crude antigen. Antibodies IgE, IgM, IgG and IgG subclass and the levels of TNF, IFN-γ and IL-10 were measured by enzyme-linked immunosorbent assay. Results The prevalence of activated CD4+ was greater than CD8+ T cells, in both ex-vivo and in 96 h culture in presence of PvMSP-119 and PSS1 antigen. A low proliferative response against PvMSP-119 and PSS1 crude antigen after 96 h culture was observed. High plasmatic levels of IFN-γ and IL-10 as well as lower TNF levels were also detected in malaria patients. However, in the 96 h supernatant culture, the dynamics of cytokine responses differed from those depicted on plasma assays; in presence of PvMSP-119 stimulus, higher levels of TNF were noted in supernatant 96 h culture of malaria patient’s cells while low levels of IFN-γ and IL-10 were verified. High frequency of malaria patients presenting antibodies against PvMSP-119 was evidenced, regardless class or IgG subclass.PvMSP-119-induced antibodies were predominantly on non-cytophilic subclasses. Conclusions The results presented here shows that PvMSP-119 was able to induce a high cellular activation

  6. Reflections on Early Malaria Vaccine Studies, the First Successful Human Malaria Vaccination, and Beyond✰

    PubMed Central

    Vanderberg, Jerome P.

    2009-01-01

    Advances towards protective vaccines against malaria were made feasible by the development of a rodent model of mammalian malaria that allowed production of all stages of the malaria parasite for study. Investigations with sporozoites (the stage transmitted by mosquitoes in their saliva) demonstrated that immunization with radiation-attenuated sporozoites could produce a solid, sterile immunity, first shown in studies with mice and later with human volunteers. Protective immune mechanisms involve anti-sporozoite antibodies that immobilize sporozoites injected into the skin by mosquitoes, followed by CD4+ and CD8+ T-cells acting against liver stage parasites produced by sporozoites that have escaped antibody-based immunity and invaded hepatocytes. Two alternative approaches now being used in human trials are immunization with intact, attenuated sporozoites vs. immunization with “sub-unit” vaccines based on immunogenic components of sporozoites or liver stage parasites. In addition to immunization against these pre-erythrocytic stages, encouraging progress is being made on immunization against blood stage parasites and on immunization for production of transmission-blocking antibodies. There is reason to be optimistic that one or more of the approaches will work on a large scale, and that a multi-stage vaccine may be able to combine several of these approaches in a sequential immunological assault against the malaria parasite as it progresses through its stages. PMID:18973784

  7. Liver-stage malaria parasites vulnerable to diverse chemical scaffolds

    PubMed Central

    Derbyshire, Emily R.; Prudêncio, Miguel; Mota, Maria M.; Clardy, Jon

    2012-01-01

    Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite’s life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents. PMID:22586124

  8. Malaria vaccines and human immune responses.

    PubMed

    Long, Carole A; Zavala, Fidel

    2016-08-01

    Despite reductions in malaria episodes and deaths over the past decade, there is still significant need for more effective tools to combat this serious global disease. The positive results with the Phase III trial of RTS,S directed to the circumsporozoite protein of Plasmodium falciparum have established that a vaccine against malaria can provide partial protection to children in endemic areas, but its limited efficacy and relatively short window of protection mandate that new generations of more efficacious vaccines must be sought. Evidence shows that anti-parasite immune responses can control infection against other stages as well, but translating these experimental findings into vaccines for blood stages has been disappointing and clinical efforts to test a transmission blocking vaccine are just beginning. Difficulties include the biological complexity of the organism with a large array of stage-specific genes many of which in the erythrocytic stages are antigenically diverse. In addition, it appears necessary to elicit high and long-lasting antibody titers, address the redundant pathways of merozoite invasion, and still seek surrogate markers of protective immunity. Most vaccine studies have focused on a single or a few antigens with an apparent functional role, but this is likely to be too restrictive, and broad, multi-antigen, multi-stage vaccines need further investigation. Finally, novel tools and biological insights involving parasite sexual stages and the mosquito vector will provide new avenues for reducing or blocking malaria transmission. PMID:27262417

  9. Malaria and global change: Insights, uncertainties and possible surprises

    SciTech Connect

    Martin, P.H.; Steel, A.

    1996-12-31

    Malaria may change with global change. Indeed, global change may affect malaria risk and malaria epidemiology. Malaria risk may change in response to a greenhouse warming; malaria epidemiology, in response to the social, economic, and political developments which a greenhouse warming may trigger. To date, malaria receptivity and epidemiology futures have been explored within the context of equilibrium studies. Equilibrium studies of climate change postulate an equilibrium present climate (the starting point) and a doubled-carbon dioxide climate (the end point), simulate conditions in both instances, and compare the two. What happens while climate changes, i.e., between the starting point and the end point, is ignored. The present paper focuses on malaria receptivity and addresses what equilibrium studies miss, namely transient malaria dynamics.

  10. Clinical implications of a gradual dormancy concept in malaria.

    PubMed

    Richter, Joachim; Franken, Gabriele; Holtfreter, Martha C; Walter, Susanne; Labisch, Alfons; Mehlhorn, Heinz

    2016-06-01

    Malaria recurrences after an initially successful therapy and malarial fever occurring a long time after infection are well-known problems in malariology. Currently, two distinct types of malaria recurrences are defined: recrudescence and relapse. A recrudescence is thought to originate from circulating Plasmodium blood stages which do not cause fever before a certain level of a microscopically detectable parasitemia is reached. Contrary, a relapse is thought to originate from quiescent intracellular hepatic parasite stages called hypnozoites. Recrudescences would typically occur in infections due to Plasmodium falciparum. Plasmodium knowlesi, and Plasmodium malariae, whereas relapses would be caused exclusively by Plasmodium vivax and Plasmodium ovale. This schematic view is, however, insufficiently supported by experimental evidence. For instance, hypnozoites of P. ovale have never been experimentally documented. On the other hand, the nonfinding of P. malariae hypnozoites turned into the proof for the nonexistence of P. malariae hypnozoites. Clinical relapse-type recurrences have been observed in both P. ovale and P. malariae infections, and decade-long incubation times have also been reported in P. falciparum infections. We propose a gradual hypothesis in accordance with the continuity concept of biological evolution: both, relapse and recrudescence may be potentially caused by all Plasmodium spp. We hypothesize that the difference between the various Plasmodium spp. is quantitative rather than qualitative: there are Plasmodium spp. which frequently cause relapses such as P. vivax, particularly the P.v. Chesson strain, species which cause relapses less frequently, such as P. ovale and sometimes P. malariae, and species which may exceptionally cause relapses such as P. falciparum. All species may cause recrudescences. As clinical consequences, we propose that 8-aminquinolines may be considered in a relapse-type recrudescence regardless of the causal Plasmodium

  11. Flow cytometric readout based on Mitotracker Red CMXRos staining of live asexual blood stage malarial parasites reliably assesses antibody dependent cellular inhibition

    PubMed Central

    2012-01-01

    Background Functional in vitro assays could provide insights into the efficacy of malaria vaccine candidates. For estimating the anti-parasite effect induced by a vaccine candidate, an accurate determination of live parasite count is an essential component of most in vitro bioassays. Although traditionally parasites are counted microscopically, a faster, more accurate and less subjective method for counting parasites is desirable. In this study mitochondrial dye (Mitotracker Red CMXRos) was used for obtaining reliable live parasite counts through flow cytometry. Methods Both asynchronous and tightly synchronized asexual blood stage cultures of Plasmodium falciparum were stained with CMXRos and subjected to detection by flow cytometry and fluorescence microscopy. The parasite counts obtained by flow cytometry were compared to standard microscopic counts obtained through examination of Giemsa-stained thin smears. A comparison of the ability of CMXRos to stain live and compromised parasites (induced by either medium starvation or by anti-malarial drug treatment) was carried out. Finally, parasite counts obtained by CMXRos staining through flow cytometry were used to determine specific growth inhibition index (SGI) in an antibody-dependent cellular inhibition (ADCI) assay. Results Mitotracker Red CMXRos can reliably detect live intra-erythrocytic stages of P. falciparum. Comparison between staining of live with compromised parasites shows that CMXRos predominantly stains live parasites with functional mitochondria. Parasite counts obtained by CMXRos staining and flow cytometry were highly reproducible and can reliably determine the ability of IgG from hyper-immune individuals to inhibit parasite growth in presence of monocytes in ADCI assay. Further, a dose-dependent parasite growth inhibitory effect could be detected for both total IgG purified from hyper-immune sera and affinity purified IgGs against the N-terminal non-repeat region of GLURP in ADCI assays coupled

  12. Is there an efficient trap or collection method for sampling Anopheles darlingi and other malaria vectors that can describe the essential parameters affecting transmission dynamics as effectively as human landing catches? - A Review

    PubMed Central

    Lima, José Bento Pereira; Rosa-Freitas, Maria Goreti; Rodovalho, Cynara Melo; Santos, Fátima; Lourenço-de-Oliveira, Ricardo

    2014-01-01

    Distribution, abundance, feeding behaviour, host preference, parity status and human-biting and infection rates are among the medical entomological parameters evaluated when determining the vector capacity of mosquito species. To evaluate these parameters, mosquitoes must be collected using an appropriate method. Malaria is primarily transmitted by anthropophilic and synanthropic anophelines. Thus, collection methods must result in the identification of the anthropophilic species and efficiently evaluate the parameters involved in malaria transmission dynamics. Consequently, human landing catches would be the most appropriate method if not for their inherent risk. The choice of alternative anopheline collection methods, such as traps, must consider their effectiveness in reproducing the efficiency of human attraction. Collection methods lure mosquitoes by using a mixture of olfactory, visual and thermal cues. Here, we reviewed, classified and compared the efficiency of anopheline collection methods, with an emphasis on Neotropical anthropophilic species, especially Anopheles darlingi, in distinct malaria epidemiological conditions in Brazil. PMID:25185008

  13. Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c▿

    PubMed Central

    Olugbile, S.; Kulangara, C.; Bang, G.; Bertholet, S.; Suzarte, E.; Villard, V.; Frank, G.; Audran, R.; Razaname, A.; Nebie, I.; Awobusuyi, O.; Spertini, F.; Kajava, A. V.; Felger, I.; Druilhe, P.; Corradin, G.

    2009-01-01

    We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the Plasmodium falciparum genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria. Within the predicted open reading frame of P. falciparum hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in P. falciparum-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate. PMID:19786562

  14. Vaccine potentials of an intrinsically unstructured fragment derived from the blood stage-associated Plasmodium falciparum protein PFF0165c.

    PubMed

    Olugbile, S; Kulangara, C; Bang, G; Bertholet, S; Suzarte, E; Villard, V; Frank, G; Audran, R; Razaname, A; Nebie, I; Awobusuyi, O; Spertini, F; Kajava, A V; Felger, I; Druilhe, P; Corradin, G

    2009-12-01

    We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the Plasmodium falciparum genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria. Within the predicted open reading frame of P. falciparum hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in P. falciparum-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate. PMID:19786562

  15. An ecohydrological model of malaria outbreaks

    NASA Astrophysics Data System (ADS)

    Montosi, E.; Manzoni, S.; Porporato, A.; Montanari, A.

    2012-08-01

    Malaria is a geographically widespread infectious disease that is well known to be affected by climate variability at both seasonal and interannual timescales. In an effort to identify climatic factors that impact malaria dynamics, there has been considerable research focused on the development of appropriate disease models for malaria transmission driven by climatic time series. These analyses have focused largely on variation in temperature and rainfall as direct climatic drivers of malaria dynamics. Here, we further these efforts by considering additionally the role that soil water content may play in driving malaria incidence. Specifically, we hypothesize that hydro-climatic variability should be an important factor in controlling the availability of mosquito habitats, thereby governing mosquito growth rates. To test this hypothesis, we reduce a nonlinear ecohydrological model to a simple linear model through a series of consecutive assumptions and apply this model to malaria incidence data from three South African provinces. Despite the assumptions made in the reduction of the model, we show that soil water content can account for a significant portion of malaria's case variability beyond its seasonal patterns, whereas neither temperature nor rainfall alone can do so. Future work should therefore consider soil water content as a simple and computable variable for incorporation into climate-driven disease models of malaria and other vector-borne infectious diseases.

  16. Insights Into Circulating Cytokine Dynamics During Pregnancy in HIV-Infected Beninese Exposed to Plasmodium falciparum Malaria.

    PubMed

    Ibitokou, Samad A; Denoeud-Ndam, Lise; Ezinmegnon, Sèm; Ladékpo, Rodolphe; Zannou, Djimon-Marcel; Massougbodji, Achille; Girard, Pierre-Marie; Cot, Michel; Luty, Adrian J F; Ndam, Nicaise Tuikue

    2015-08-01

    We investigated the circulating plasma levels of Th1- (Interleukin-2 [IL-2], tumor necrosis factor-α [TNF-α], interferon-gamma [IFN-γ]) and Th2-type (IL-4, IL-5, IL-10) cytokines in human immunodeficiency virus (HIV)-infected pregnant women living in a malaria-endemic area. We analyzed samples from 200 pregnant women included in the prevention of pregnancy-associated malaria in HIV-infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) clinical trial who were followed until delivery. Cytokine concentrations were measured by flow cytometry-based multiplex bead array. Significantly elevated levels of IL-10 and lower levels of TNF-α were observed at delivery compared with inclusion (P = 0.005). At inclusion, the presence of circulating IFN-γ, a higher CD4(+) T cell count and having initiated intermittent preventive treatment of malaria with sulfadoxine pyrimethamine (SP-IPTp) were all associated with a lower likelihood of Plasmodium falciparum infection. At delivery, the inverse relationship between the presence of infection and circulating IFN-γ persisted, although there was a positive association between the likelihood of infection and the presence of circulating TNF-α. Initiation of antiretroviral therapy was associated with elevated IL-5 production. Consistent with our own and others' observations in HIV seronegative subjects, this study shows circulating IL-10 to be a marker of infection with P. falciparum during pregnancy even in HIV-infected women, although plasma IFN-γ may be a marker of anti-malarial protection in such women. PMID:26101276

  17. Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort

    PubMed Central

    Malhotra, Indu; Wang, Xuelie; Babineau, Denise; Yeo, Kee Thai; Anderson, Timothy; Kimmel, Rhonda J.; Angov, Evelina; Lanar, David E.; Narum, David; Dutta, Sheetij; Richards, Jack; Beeson, James G.; Crabb, Brendan S.; Cowman, Alan F.; Horii, Toshihiro; Muchiri, Eric; Mungai, Peter L.; King, Christopher L.; Kazura, James W.

    2015-01-01

    IgG antibodies to Plasmodium falciparum are transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. We examined the dynamics of malaria antibody responses of 84 Kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (VSA) assay, (iii) growth inhibitory activity (GIA), and (iv) invasion inhibition assays (IIA) specific for merozoite surface protein 1 (MSP1) and sialic acid-dependent invasion pathway. Maternal antibodies in each of these four categories were detected in cord blood and decreased to their lowest level by approximately 6 months of age. Serologic antibodies to 3 preerythrocytic and 10 blood-stage antigens subsequently increased, reaching peak prevalence by 36 months. In contrast, antibodies measured by VSA, GIA, and IIA remained low even up to 36 months. Infants sensitized to P. falciparum in utero, defined by cord blood lymphocyte recall responses to malaria antigens, acquired antimalarial antibodies at the same rate as those who were not sensitized in utero, indicating that fetal exposure to malaria antigens did not affect subsequent infant antimalarial responses. Infants with detectable serologic antibodies at 12 months of age had an increased risk of P. falciparum infection during the subsequent 24 months. We conclude that serologic measures of antimalarial antibodies in children 36 months of age or younger represent biomarkers of malaria exposure rather than protection and that functional antibodies develop after 36 months of age in this population. PMID:26656119

  18. Malaria zoonoses.

    PubMed

    Baird, J Kevin

    2009-09-01

    The genus Plasmodium includes many species that naturally cause malaria among apes and monkeys. The 2004 discovery of people infected by Plasmodium knowlesi in Malaysian Borneo alerted to the potential for non-human species of plasmodia to cause human morbidity and mortality. Subsequent work revealed what appears to be a surprisingly high risk of infection and relatively severe disease, including among travelers to Southeast Asia. The biology and medicine of this zoonosis is reviewed here, along with an examination of the spectrum of Plasmodium species that may cause infection of humans. PMID:19747661

  19. Cerebral malaria.

    PubMed

    Postels, Douglas G; Birbeck, Gretchen L

    2013-01-01

    Malaria, the most significant parasitic disease of man, kills approximately one million people per year. Half of these deaths occur in those with cerebral malaria (CM). The World Health Organization (WHO) defines CM as an otherwise unexplained coma in a patient with malarial parasitemia. Worldwide, CM occurs primarily in African children and Asian adults, with the vast majority (greater than 90%) of cases occurring in children 5 years old or younger in sub-Saharan Africa. The pathophysiology of the disease is complex and involves infected erythrocyte sequestration, cerebral inflammation, and breakdown of the blood-brain barrier. A recently characterized malarial retinopathy is visual evidence of Plasmodium falciparum's pathophysiological processes occurring in the affected patient. Treatment consists of supportive care and antimalarial administration. Thus far, adjuvant therapies have not been shown to improve mortality rates or neurological outcomes in children with CM. For those who survive CM, residual neurological abnormalities are common. Epilepsy, cognitive impairment, behavioral disorders, and gross neurological deficits which include motor, sensory, and language impairments are frequent sequelae. Primary prevention strategies, including bed nets, vaccine development, and chemoprophylaxis, are in varied states of development and implementation. Continuing efforts to find successful primary prevention options and strategies to decrease neurological sequelae are needed. PMID:23829902

  20. The complexities of malaria disease manifestations with a focus on asymptomatic malaria

    PubMed Central

    2012-01-01

    Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted. PMID:22289302

  1. Prophylaxis of Malaria

    PubMed Central

    Schwartz, Eli

    2012-01-01

    Malaria prevention in travelers to endemic areas remains dependent principally on chemoprophylaxis. Although malaria chemoprophylaxis refers to all malaria species, a distinction should be drawn between falciparum malaria prophylaxis and the prophylaxis of the relapsing malaria species (vivax & ovale). While the emergence of drug resistant strains, as well as the costs and adverse reactions to medications, complicate falciparum prophylaxis use, there are virtually no drugs available for vivax prophylaxis, beside of primaquine. Based on traveler’s malaria data, a revised recommendation for using chemoprophylaxis in low risk areas should be considered. PMID:22811794

  2. Malaria and Travelers

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  3. Malaria Treatment (United States)

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  4. Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design.

    PubMed

    Flanagan, Katie L; Wilson, Kirsty L; Plebanski, Magdalena

    2016-03-01

    The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes. PMID:26610026

  5. Hemiparesis post cerebral malaria

    PubMed Central

    Taiaa, Oumkaltoum; Amil, Touriya; Darbi, Abdelatif

    2015-01-01

    Cerebral malaria is one of the most serious complications in the Plasmodium falciparum infection. In endemic areas, the cerebral malaria interested mainly children. The occurrence in adults is very rare and most interested adult traveling in tropical zones. This case report describes a motor deficit post cerebral malaria in a young adult traveling in malaria endemic area. This complication has been reported especially in children and seems very rare in adults. PMID:25995798

  6. Hydrological and geomorphological controls of malaria transmission

    NASA Astrophysics Data System (ADS)

    Smith, M. W.; Macklin, M. G.; Thomas, C. J.

    2013-01-01

    Malaria risk is linked inextricably to the hydrological and geomorphological processes that form vector breeding sites. Yet environmental controls of malaria transmission are often represented by temperature and rainfall amounts, ignoring hydrological and geomorphological influences altogether. Continental-scale studies incorporate hydrology implicitly through simple minimum rainfall thresholds, while community-scale coupled hydrological and entomological models do not represent the actual diversity of the mosquito vector breeding sites. The greatest range of malaria transmission responses to environmental factors is observed at the catchment scale where seemingly contradictory associations between rainfall and malaria risk can be explained by hydrological and geomorphological processes that govern surface water body formation and persistence. This paper extends recent efforts to incorporate ecological factors into malaria-risk models, proposing that the same detailed representation be afforded to hydrological and, at longer timescales relevant for predictions of climate change impacts, geomorphological processes. We review existing representations of environmental controls of malaria and identify a range of hydrologically distinct vector breeding sites from existing literature. We illustrate the potential complexity of interactions among hydrology, geomorphology and vector breeding sites by classifying a range of water bodies observed in a catchment in East Africa. Crucially, the mechanisms driving surface water body formation and destruction must be considered explicitly if we are to produce dynamic spatial models of malaria risk at catchment scales.

  7. Spatiotemporal dynamics of gene flow and hybrid fitness between the M and S forms of the malaria mosquito, Anopheles gambiae

    PubMed Central

    Lee, Yoosook; Marsden, Clare D.; Norris, Laura C.; Collier, Travis C.; Main, Bradley J.; Fofana, Abdrahamane; Cornel, Anthony J.; Lanzaro, Gregory C.

    2013-01-01

    The M and S forms of Anopheles gambiae have been the focus of intense study by malaria researchers and evolutionary biologists interested in ecological speciation. Divergence occurs at three discrete islands in genomes that are otherwise nearly identical. An “islands of speciation” model proposes that diverged regions contain genes that are maintained by selection in the face of gene flow. An alternative “incidental island” model maintains that gene flow between M and S is effectively zero and that divergence islands are unrelated to speciation. A “divergence island SNP” assay was used to explore the spatial and temporal distributions of hybrid genotypes. Results revealed that hybrid individuals occur at frequencies ranging between 5% and 97% in every population examined. A temporal analysis revealed that assortative mating is unstable and periodically breaks down, resulting in extensive hybridization. Results suggest that hybrids suffer a fitness disadvantage, but at least some hybrid genotypes are viable. Stable introgression of the 2L speciation island occurred at one site following a hybridization event. PMID:24248386

  8. Frequent Malaria Drives Progressive Vδ2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood.

    PubMed

    Farrington, Lila A; Jagannathan, Prasanna; McIntyre, Tara I; Vance, Hilary M; Bowen, Katherine; Boyle, Michelle J; Nankya, Felistas; Wamala, Samuel; Auma, Ann; Nalubega, Mayimuna; Sikyomu, Esther; Naluwu, Kate; Bigira, Victor; Kapisi, James; Dorsey, Grant; Kamya, Moses R; Feeney, Margaret E

    2016-05-01

    γδ T cells expressing Vδ2 may be instrumental in the control of malaria, because they inhibit the replication of blood-stage parasites in vitro and expand during acute malaria infection. However, Vδ2 T-cell frequencies and function are lower among children with heavy prior malaria exposure. It remains unclear whether malaria itself is driving this loss. Here we measure Vδ2 T-cell frequency, cytokine production, and degranulation longitudinally in Ugandan children enrolled in a malaria chemoprevention trial from 6 to 36 months of age. We observed a progressive attenuation of the Vδ2 response only among children incurring high rates of malaria. Unresponsive Vδ2 T cells were marked by expression of CD16, which was elevated in the setting of high malaria transmission. Moreover, chemoprevention during early childhood prevented the development of dysfunctional Vδ2 T cells. These observations provide insight into the role of Vδ2 T cells in the immune response to chronic malaria. PMID:26667315

  9. Malaria transmission in Tripura: disease distribution & determinants

    PubMed Central

    Dev, Vas; Adak, Tridibes; Singh, Om P.; Nanda, Nutan; Baidya, Bimal K.

    2015-01-01

    Background & objectives: Malaria is a major public health problem in Tripura and focal disease outbreaks are of frequent occurrence. The State is co-endemic for both Plasmodium falciparum and P. vivax and transmission is perennial and persistent. The present study was aimed to review data on disease distribution to prioritize high-risk districts, and to study seasonal prevalence of disease vectors and their bionomical characteristics to help formulate vector species-specific interventions for malaria control. Methods: Data on malaria morbidity in the State were reviewed retrospectively (2008-2012) for understanding disease distribution and transmission dynamics. Cross-sectional mass blood surveys were conducted in malaria endemic villages of South Tripura district to ascertain the prevalence of malaria and proportions of parasite species. Mosquito collections were made in human dwellings of malaria endemic villages aiming at vector incrimination and to study relative abundance, resting and feeding preferences, and their present susceptibility status to DDT. Results: The study showed that malaria was widely prevalent and P. falciparum was the predominant infection (>90%), the remaining were P. vivax cases. The disease distribution, however, was uneven with large concentration of cases in districts of South Tripura and Dhalai coinciding with vast forest cover and tribal populations. Both Anopheles minimus s.s. and An. baimaii were recorded to be prevalent and observed to be highly anthropophagic and susceptible to DDT. Of these, An. minimus was incriminated (sporozoite infection rate 4.92%), and its bionomical characteristics revealed this species to be largely indoor resting and endophagic. Interpretation & conclusions: For effective control of malaria in the State, it is recommended that diseases surveillance should be robust, and vector control interventions including DDT spray coverage, mass distribution of insecticide-treated nets/long-lasting insecticidal nets

  10. Mixed-genotype infections of malaria parasites: within-host dynamics and transmission success of competing clones.

    PubMed Central

    Taylor, L H; Walliker, D; Read, A F

    1997-01-01

    Mixed-genotype infections of microparasites are common, but almost nothing is known about how competitive interactions within hosts affect the subsequent transmission success of individual genotypes. We investigated changes in the composition of mixed-genotype infections of the rodent malaria Plasmodium chabaudi clones CR and ER by monoclonal antibody analysis of the asexual infection in mice, and by PCR amplification of clone-specific alleles in oocysts sampled from mosquitoes which had fed on these mice. Mixed-clone infections were initiated with a 9:1 ratio of the two clones, with ER as the minority in the first experiment and CR as the minority in the second experiment. When beginning as the majority, clones achieved parasite densities in mice comparable to those achieved in control (single-clone) infections. When they began as the minority, clones were suppressed to less than 10% of control parasitaemias during the early part of the infections. However, in mosquitoes, the frequency of the initially rare clone was substantially greater than it was in mice at the start of the infection or four days prior to the feed. In both experiments, the minority clone in the inocula produced as many, or more, oocysts than it did as a single-clone infection. These experiments show that asexual dominance during most of the infection is poorly correlated to transmission probability, and therefore that the assumption that within-host population size correlates to transmission probability may not be warranted. They also raise the fundamental question of why transmission rates of individual genotypes are often higher from mixed than single-clone infections. PMID:9225482

  11. Quantifying the impact of human mobility on malaria.

    PubMed

    Wesolowski, Amy; Eagle, Nathan; Tatem, Andrew J; Smith, David L; Noor, Abdisalan M; Snow, Robert W; Buckee, Caroline O

    2012-10-12

    Human movements contribute to the transmission of malaria on spatial scales that exceed the limits of mosquito dispersal. Identifying the sources and sinks of imported infections due to human travel and locating high-risk sites of parasite importation could greatly improve malaria control programs. Here, we use spatially explicit mobile phone data and malaria prevalence information from Kenya to identify the dynamics of human carriers that drive parasite importation between regions. Our analysis identifies importation routes that contribute to malaria epidemiology on regional spatial scales. PMID:23066082

  12. Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria

    PubMed Central

    Beeson, James G.; Drew, Damien R.; Boyle, Michelle J.; Feng, Gaoqian; Fowkes, Freya J.I.; Richards, Jack S.

    2016-01-01

    Malaria accounts for an enormous burden of disease globally, with Plasmodium falciparum accounting for the majority of malaria, and P. vivax being a second important cause, especially in Asia, the Americas and the Pacific. During infection with Plasmodium spp., the merozoite form of the parasite invades red blood cells and replicates inside them. It is during the blood-stage of infection that malaria disease occurs and, therefore, understanding merozoite invasion, host immune responses to merozoite surface antigens, and targeting merozoite surface proteins and invasion ligands by novel vaccines and therapeutics have been important areas of research. Merozoite invasion involves multiple interactions and events, and substantial processing of merozoite surface proteins occurs before, during and after invasion. The merozoite surface is highly complex, presenting a multitude of antigens to the immune system. This complexity has proved challenging to our efforts to understand merozoite invasion and malaria immunity, and to developing merozoite antigens as malaria vaccines. In recent years, there has been major progress in this field, and several merozoite surface proteins show strong potential as malaria vaccines. Our current knowledge on this topic is reviewed, highlighting recent advances and research priorities. PMID:26833236

  13. Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria.

    PubMed

    Beeson, James G; Drew, Damien R; Boyle, Michelle J; Feng, Gaoqian; Fowkes, Freya J I; Richards, Jack S

    2016-05-01

    Malaria accounts for an enormous burden of disease globally, with Plasmodium falciparum accounting for the majority of malaria, and P. vivax being a second important cause, especially in Asia, the Americas and the Pacific. During infection with Plasmodium spp., the merozoite form of the parasite invades red blood cells and replicates inside them. It is during the blood-stage of infection that malaria disease occurs and, therefore, understanding merozoite invasion, host immune responses to merozoite surface antigens, and targeting merozoite surface proteins and invasion ligands by novel vaccines and therapeutics have been important areas of research. Merozoite invasion involves multiple interactions and events, and substantial processing of merozoite surface proteins occurs before, during and after invasion. The merozoite surface is highly complex, presenting a multitude of antigens to the immune system. This complexity has proved challenging to our efforts to understand merozoite invasion and malaria immunity, and to developing merozoite antigens as malaria vaccines. In recent years, there has been major progress in this field, and several merozoite surface proteins show strong potential as malaria vaccines. Our current knowledge on this topic is reviewed, highlighting recent advances and research priorities. PMID:26833236

  14. New insight-guided approaches to detect, cure, prevent and eliminate malaria.

    PubMed

    Kumar, Sushil; Kumari, Renu; Pandey, Richa

    2015-05-01

    New challenges posed by the development of resistance against artemisinin-based combination therapies (ACTs) as well as previous first-line therapies, and the continuing absence of vaccine, have given impetus to research in all areas of malaria control. This review portrays the ongoing progress in several directions of malaria research. The variants of RTS,S and apical membrane antigen 1 (AMA1) are being developed and test adapted as multicomponent and multistage malaria control vaccines, while many other vaccine candidates and methodologies to produce antigens are under experimentation. To track and prevent the spread of artemisinin resistance from Southeast Asia to other parts of the world, rolling circle-enhanced enzyme activity detection (REEAD), a time- and cost-effective malaria diagnosis in field conditions, and a DNA marker associated with artemisinin resistance have become available. Novel mosquito repellents and mosquito trapping and killing techniques much more effective than the prevalent ones are undergoing field testing. Mosquito lines stably infected with their symbiotic wild-type or genetically engineered bacteria that kill sympatric malaria parasites are being constructed and field tested for stopping malaria transmission. A complementary approach being pursued is the addition of ivermectin-like drug molecules to ACTs to cure malaria and kill mosquitoes. Experiments are in progress to eradicate malaria mosquito by making it genetically male sterile. High-throughput screening procedures are being developed and used to discover molecules that possess long in vivo half life and are active against liver and blood stages for the fast cure of malaria symptoms caused by simple or relapsing and drug-sensitive and drug-resistant types of varied malaria parasites, can stop gametocytogenesis and sporogony and could be given in one dose. Target-based antimalarial drug designing has begun. Some of the putative next-generation antimalarials that possess in their

  15. Placental Malaria: Decreased Transfer of Maternal Antibodies Directed to Plasmodium falciparum and Impact on the Incidence of Febrile Infections in Infants

    PubMed Central

    Dechavanne, Celia; Cottrell, Gilles; Garcia, André; Migot-Nabias, Florence

    2015-01-01

    The efficacy of mother-to-child placental transfer of antibodies specific to malaria blood stage antigens was investigated in the context of placental malaria infection, taking into account IgG specificity and maternal hypergammaglobulinemia. The impact of the resulting maternal antibody transfer on infections in infants up to the age of 6 months was also explored. This study showed that i) placental malaria was associated with a reduced placental transfer of total and specific IgG, ii) antibody placental transfer varied according to IgG specificity and iii) cord blood malaria IgG levels were similar in infants born to mothers with or without placental malaria. The number of malaria infections was negatively associated with maternal age, whereas it was not associated with the transfer of any malaria-specific IgG from the mother to the fetus. These results suggest that i) malaria-specific IgG may serve as a marker of maternal exposure but not as a useful marker of infant protection from malaria and ii) increasing maternal age contributes to diminishing febrile infections diagnosed in infants, perhaps by means of the transmission of an effective antibody response. PMID:26698578

  16. Landscape Ecology and Epidemiology of Malaria Associated with Rubber Plantations in Thailand: Integrated Approaches to Malaria Ecotoping

    PubMed Central

    Kaewwaen, Wuthichai

    2015-01-01

    The agricultural land use changes that are human-induced changes in agroforestry ecosystems and in physical environmental conditions contribute substantially to the potential risks for malaria transmission in receptive areas. Due to the pattern and extent of land use change, the risks or negatively ecosystemic outcomes are the results of the dynamics of malaria transmission, the susceptibility of human populations, and the geographical distribution of malaria vectors. This review focused basically on what are the potential effects of agricultural land use change as a result of the expansion of rubber plantations in Thailand and how significant the ecotopes of malaria-associated rubber plantations (MRP) are. More profoundly, this review synthesized the novel concepts and perspectives on applied landscape ecology and epidemiology of malaria, as well as approaches to determine the degree to which an MRP ecotope as fundamental landscape scale can establish malaria infection pocket(s). Malaria ecotoping encompasses the integrated approaches and tools applied to or used in modeling malaria transmission. The scalability of MRP ecotope depends upon its unique landscape structure as it is geographically associated with the infestation or reinfestation of Anopheles vectors, along with the attributes that are epidemiologically linked with the infections. The MRP ecotope can be depicted as the hotspot such that malaria transmission is modeled upon the MRP factors underlying human settlements and movement activities, health behaviors, land use/land cover change, malaria vector population dynamics, and agrienvironmental and climatic conditions. The systemic and uniform approaches to malaria ecotoping underpin the stratification of the potential risks for malaria transmission by making use of remotely sensed satellite imagery or landscape aerial photography using unmanned aerial vehicle (UAV), global positioning systems (GPS), and geographical information systems (GIS). PMID

  17. Landscape ecology and epidemiology of malaria associated with rubber plantations in Thailand: integrated approaches to malaria ecotoping.

    PubMed

    Kaewwaen, Wuthichai; Bhumiratana, Adisak

    2015-01-01

    The agricultural land use changes that are human-induced changes in agroforestry ecosystems and in physical environmental conditions contribute substantially to the potential risks for malaria transmission in receptive areas. Due to the pattern and extent of land use change, the risks or negatively ecosystemic outcomes are the results of the dynamics of malaria transmission, the susceptibility of human populations, and the geographical distribution of malaria vectors. This review focused basically on what are the potential effects of agricultural land use change as a result of the expansion of rubber plantations in Thailand and how significant the ecotopes of malaria-associated rubber plantations (MRP) are. More profoundly, this review synthesized the novel concepts and perspectives on applied landscape ecology and epidemiology of malaria, as well as approaches to determine the degree to which an MRP ecotope as fundamental landscape scale can establish malaria infection pocket(s). Malaria ecotoping encompasses the integrated approaches and tools applied to or used in modeling malaria transmission. The scalability of MRP ecotope depends upon its unique landscape structure as it is geographically associated with the infestation or reinfestation of Anopheles vectors, along with the attributes that are epidemiologically linked with the infections. The MRP ecotope can be depicted as the hotspot such that malaria transmission is modeled upon the MRP factors underlying human settlements and movement activities, health behaviors, land use/land cover change, malaria vector population dynamics, and agrienvironmental and climatic conditions. The systemic and uniform approaches to malaria ecotoping underpin the stratification of the potential risks for malaria transmission by making use of remotely sensed satellite imagery or landscape aerial photography using unmanned aerial vehicle (UAV), global positioning systems (GPS), and geographical information systems (GIS). PMID

  18. Targeting Plasmodium PI(4)K to eliminate malaria.

    PubMed

    McNamara, Case W; Lee, Marcus C S; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K S; Chatterjee, Arnab K; McCormack, Susan L; Manary, Micah J; Zeeman, Anne-Marie; Dechering, Koen J; Kumar, T R Santha; Henrich, Philipp P; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C; Kocken, Clemens H M; Glynne, Richard J; Bodenreider, Christophe; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A

    2013-12-12

    Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria. PMID:24284631

  19. Targeting Plasmodium PI(4)K to eliminate malaria

    NASA Astrophysics Data System (ADS)

    McNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.

    2013-12-01

    Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

  20. Malaria in pregnancy

    PubMed Central

    Soma-Pillay, P; Macdonald, A P

    2012-01-01

    Malaria is a complex parasitic disease affecting about 32 million pregnancies each year in sub-Saharan Africa. Pregnant women are especially susceptible to malarial infection and have the risk of developing severe disease and birth complications. The target of Millennium Development Goal 6 is to end malaria deaths by 2015. Maternal and perinatal morbidity and mortality due to malaria may be reduced by implementing preventive measures, early diagnosis of suspected cases, effective antimalarial therapy and treatment of complications.

  1. Malaria ecotypes and stratification.

    PubMed

    Schapira, Allan; Boutsika, Konstantina

    2012-01-01

    To deal with the variability of malaria, control programmes need to stratify their malaria problem into a number of smaller units. Such stratification may be based on the epidemiology of malaria or on its determinants such as ecology. An ecotype classification was developed by the World Health Organization (WHO) around 1990, and it is time to assess its usefulness for current malaria control as well as for malaria modelling on the basis of published research. Journal and grey literature was searched for articles on malaria or Anopheles combined with ecology or stratification. It was found that all malaria in the world today could be assigned to one or more of the following ecotypes: savanna, plains and valleys; forest and forest fringe; foothill; mountain fringe and northern and southern fringes; desert fringe; coastal and urban. However, some areas are in transitional or mixed zones; furthermore, the implications of any ecotype depend on the biogeographical region, sometimes subregion, and finally, the knowledge on physiography needs to be supplemented by local information on natural, anthropic and health system processes including malaria control. Ecotyping can therefore not be seen as a shortcut to determine control interventions, but rather as a framework to supplement available epidemiological and entomological data so as to assess malaria situations at the local level, think through the particular risks and opportunities and reinforce intersectoral action. With these caveats, it does however emerge that several ecotypic distinctions are well defined and have relatively constant implications for control within certain biogeographic regions. Forest environments in the Indo-malay and the Neotropics are, with a few exceptions, associated with much higher malaria risk than in adjacent areas; the vectors are difficult to control, and the anthropic factors also often converge to impose constraints. Urban malaria in Africa is associated with lower risk than savanna

  2. Robust inducible Cre recombinase activity in the human malaria parasite Plasmodium falciparum enables efficient gene deletion within a single asexual erythrocytic growth cycle.

    PubMed

    Collins, Christine R; Das, Sujaan; Wong, Eleanor H; Andenmatten, Nicole; Stallmach, Robert; Hackett, Fiona; Herman, Jean-Paul; Müller, Sylke; Meissner, Markus; Blackman, Michael J

    2013-05-01

    Asexual blood stages of the malaria parasite, which cause all the pathology associated with malaria, can readily be genetically modified by homologous recombination, enabling the functional study of parasite genes that are not essential in this part of the life cycle. However, no widely applicable method for conditional mutagenesis of essential asexual blood-stage malarial genes is available, hindering their functional analysis. We report the application of the DiCre conditional recombinase system to Plasmodium falciparum, the causative agent of the most dangerous form of malaria. We show that DiCre can be used to obtain rapid, highly regulated site-specific recombination in P. falciparum, capable of excising loxP-flanked sequences from a genomic locus with close to 100% efficiency within the time-span of a single erythrocytic growth cycle. DiCre-mediated deletion of the SERA5 3' UTR failed to reduce expression of the gene due to the existence of alternative cryptic polyadenylation sites within the modified locus. However, we successfully used the system to recycle the most widely used drug resistance marker for P. falciparum, human dihydrofolate reductase, in the process producing constitutively DiCre-expressing P. falciparum clones that have broad utility for the functional analysis of essential asexual blood-stage parasite genes. PMID:23489321

  3. Malaria outbreaks in China (1990–2013): a systematic review

    PubMed Central

    2014-01-01

    Background China has already achieved remarkable accomplishments in shrinking the malaria burden since the mid-20th Century. The country now plans to eliminate malaria by the year 2020. Looking at the dynamics of malaria outbreaks during the last decades might provide important information regarding the potential challenges of such an elimination strategy and might help to avoid mistakes of the past. Methods A systematic review of the published literature (English and Chinese) was conducted to identify malaria outbreaks during the period 1990 until 2013 in China. The main causes of outbreaks as described in these papers were categorized according to whether they were related to population migration, environmental factors, vector and host related factors, and operational problems of the health services. Results The review identified 36 malaria outbreaks over the 23-year study period, on which sufficient information was available. They mainly occurred in southern and central China involving 12 provinces/autonomous regions. More than half of all outbreaks (21/36, 58%) were attributed at least in part to population migration, with malaria importation to non- or low-endemic areas from high-endemic Chinese areas (13/15) or endemic countries (2/15) having been the most frequent reason (15/21, 71%). Other main causes were problems of the health services (15/36, 42%), in particular poor malaria case management (10/15, 67%), environmental factors (7/36, 19%), and vector and host related factors (5/36, 14%). Conclusions Beside a number of other challenges, addressing population movement causing malaria appears to be of particular importance to the national malaria programme. Strengthening of surveillance for malaria and early radical treatment of cases should thus be considered among the most important tools for preventing malaria outbreaks and for the final goal of malaria elimination in China. PMID:25012078

  4. Biodiversity Can Help Prevent Malaria Outbreaks in Tropical Forests

    PubMed Central

    Laporta, Gabriel Zorello; de Prado, Paulo Inácio Knegt Lopez; Kraenkel, Roberto André; Coutinho, Renato Mendes; Sallum, Maria Anice Mureb

    2013-01-01

    Background Plasmodium vivax is a widely distributed, neglected parasite that can cause malaria and death in tropical areas. It is associated with an estimated 80–300 million cases of malaria worldwide. Brazilian tropical rain forests encompass host- and vector-rich communities, in which two hypothetical mechanisms could play a role in the dynamics of malaria transmission. The first mechanism is the dilution effect caused by presence of wild warm-blooded animals, which can act as dead-end hosts to Plasmodium parasites. The second is diffuse mosquito vector competition, in which vector and non-vector mosquito species compete for blood feeding upon a defensive host. Considering that the World Health Organization Malaria Eradication Research Agenda calls for novel strategies to eliminate malaria transmission locally, we used mathematical modeling to assess those two mechanisms in a pristine tropical rain forest, where the primary vector is present but malaria is absent. Methodology/Principal Findings The Ross–Macdonald model and a biodiversity-oriented model were parameterized using newly collected data and data from the literature. The basic reproduction number () estimated employing Ross–Macdonald model indicated that malaria cases occur in the study location. However, no malaria cases have been reported since 1980. In contrast, the biodiversity-oriented model corroborated the absence of malaria transmission. In addition, the diffuse competition mechanism was negatively correlated with the risk of malaria transmission, which suggests a protective effect provided by the forest ecosystem. There is a non-linear, unimodal correlation between the mechanism of dead-end transmission of parasites and the risk of malaria transmission, suggesting a protective effect only under certain circumstances (e.g., a high abundance of wild warm-blooded animals). Conclusions/Significance To achieve biological conservation and to eliminate Plasmodium parasites in human populations

  5. Impact of Schistosoma mansoni on Malaria Transmission in Sub-Saharan Africa

    PubMed Central

    Ndeffo Mbah, Martial L.; Skrip, Laura; Greenhalgh, Scott; Hotez, Peter; Galvani, Alison P.

    2014-01-01

    Background Sub-Saharan Africa harbors the majority of the global burden of malaria and schistosomiasis infections. The co-endemicity of these two tropical diseases has prompted investigation into the mechanisms of coinfection, particularly the competing immunological responses associated with each disease. Epidemiological studies have shown that infection with Schistosoma mansoni is associated with a greater malaria incidence among school-age children. Methodology We developed a co-epidemic model of malaria and S. mansoni transmission dynamics which takes into account key epidemiological interaction between the two diseases in terms of elevated malaria incidence among individuals with S. mansoni high egg output. The model was parameterized for S. mansoni high-risk endemic communities, using epidemiological and clinical data of the interaction between S. mansoni and malaria among children in sub-Saharan Africa. We evaluated the potential impact of the S. mansoni–malaria interaction and mass treatment of schistosomiasis on malaria prevalence in co-endemic communities. Principal Findings Our results suggest that in the absence of mass drug administration of praziquantel, the interaction between S. mansoni and malaria may reduce the effectiveness of malaria treatment for curtailing malaria transmission, in S. mansoni high-risk endemic communities. However, when malaria treatment is used in combination with praziquantel, mass praziquantel administration may increase the effectiveness of malaria control intervention strategy for reducing malaria prevalence in malaria- S. mansoni co-endemic communities. Conclusions/Significance Schistosomiasis treatment and control programmes in regions where S. mansoni and malaria are highly prevalent may have indirect benefits on reducing malaria transmission as a result of disease interactions. In particular, mass praziquantel administration may not only have the direct benefit of reducing schistosomiasis infection, it may also

  6. An eco-hydrologic model of malaria outbreaks

    NASA Astrophysics Data System (ADS)

    Montosi, E.; Manzoni, S.; Porporato, A.; Montanari, A.

    2012-03-01

    Malaria is a geographically widespread infectious disease that is well known to be affected by climate variability at both seasonal and interannual timescales. In an effort to identify climatic factors that impact malaria dynamics, there has been considerable research focused on the development of appropriate disease models for malaria transmission and their consideration alongside climatic datasets. These analyses have focused largely on variation in temperature and rainfall as direct climatic drivers of malaria dynamics. Here, we further these efforts by considering additionally the role that soil water content may play in driving malaria incidence. Specifically, we hypothesize that hydro-climatic variability should be an important factor in controlling the availability of mosquito habitats, thereby governing mosquito growth rates. To test this hypothesis, we reduce a nonlinear eco-hydrologic model to a simple linear model through a series of consecutive assumptions and apply this model to malaria incidence data from three South African provinces. Despite the assumptions made in the reduction of the model, we show that soil water content can account for a significant portion of malaria's case variability beyond its seasonal patterns, whereas neither temperature nor rainfall alone can do so. Future work should therefore consider soil water content as a simple and computable variable for incorporation into climate-driven disease models of malaria and other vector-borne infectious diseases.

  7. Antibody responses to Plasmodium falciparum and Plasmodium vivax blood-stage and sporozoite antigens in the postpartum period

    PubMed Central

    McLean, Alistair R. D.; Boel, Machteld E.; McGready, Rose; Ataide, Ricardo; Drew, Damien; Tsuboi, Takafumi; Beeson, James G.; Nosten, François; Simpson, Julie A.; Fowkes, Freya J. I.

    2016-01-01

    During pregnancy a variety of immunological changes occur to accommodate the fetus. It is unknown whether these changes continue to affect humoral immunity postpartum or how quickly they resolve. IgG levels were measured to P. falciparum and P. vivax antigens in 201 postpartum and 201 controls over 12 weeks. Linear mixed-effects models assessed antibody maintenance over time and the effect of microscopically confirmed Plasmodium spp. infection on antibody levels, and whether this was different in postpartum women compared with control women. Postpartum women had reduced Plasmodium spp. antibody levels compared to controls at baseline. Over 12 weeks, mean antibody levels in postpartum women increased to levels observed in control women. Microscopically confirmed P. falciparum and P. vivax infections during follow-up were associated with an increase in species-specific antibodies with similar magnitudes of boosting observed in postpartum and control women. Antibodies specific for pregnancy-associated, VAR2CSA-expressing parasites did not rapidly decline postpartum and did not boost in response to infection in either postpartum or control women. After pregnancy, levels of malaria-specific antibodies were reduced, but recovered to levels seen in control women. There was no evidence of an impaired ability to mount a boosting response in postpartum women. PMID:27558000

  8. Antibody responses to Plasmodium falciparum and Plasmodium vivax blood-stage and sporozoite antigens in the postpartum period.

    PubMed

    McLean, Alistair R D; Boel, Machteld E; McGready, Rose; Ataide, Ricardo; Drew, Damien; Tsuboi, Takafumi; Beeson, James G; Nosten, François; Simpson, Julie A; Fowkes, Freya J I

    2016-01-01

    During pregnancy a variety of immunological changes occur to accommodate the fetus. It is unknown whether these changes continue to affect humoral immunity postpartum or how quickly they resolve. IgG levels were measured to P. falciparum and P. vivax antigens in 201 postpartum and 201 controls over 12 weeks. Linear mixed-effects models assessed antibody maintenance over time and the effect of microscopically confirmed Plasmodium spp. infection on antibody levels, and whether this was different in postpartum women compared with control women. Postpartum women had reduced Plasmodium spp. antibody levels compared to controls at baseline. Over 12 weeks, mean antibody levels in postpartum women increased to levels observed in control women. Microscopically confirmed P. falciparum and P. vivax infections during follow-up were associated with an increase in species-specific antibodies with similar magnitudes of boosting observed in postpartum and control women. Antibodies specific for pregnancy-associated, VAR2CSA-expressing parasites did not rapidly decline postpartum and did not boost in response to infection in either postpartum or control women. After pregnancy, levels of malaria-specific antibodies were reduced, but recovered to levels seen in control women. There was no evidence of an impaired ability to mount a boosting response in postpartum women. PMID:27558000

  9. Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population

    PubMed Central

    van Bruggen, Rebekah; Gualtieri, Christian; Iliescu, Alexandra; Louicharoen Cheepsunthorn, Chalisa; Mungkalasut, Punchalee; Trape, Jean-François; Modiano, David; Sodiomon Sirima, Bienvenu; Singhasivanon, Pratap; Lathrop, Mark; Sakuntabhai, Anavaj; Bureau, Jean-François; Gros, Philippe

    2015-01-01

    Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q) was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41) is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q) affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria. PMID:26658699

  10. Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production.

    PubMed

    Costa, Pedro A C; Leoratti, Fabiana M S; Figueiredo, Maria M; Tada, Mauro S; Pereira, Dhelio B; Junqueira, Caroline; Soares, Irene S; Barber, Daniel L; Gazzinelli, Ricardo T; Antonelli, Lis R V

    2015-12-15

    The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4(+) and CD8(+) T cells. Higher frequencies of CD4(+) express more than 1 regulatory molecule compared to CD8(+) T cells. Moreover, lower proportions of CD4(+) T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin-3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function. PMID:26019284

  11. [Malaria in Iraq].

    PubMed

    Shamo, F J

    2001-01-01

    Malaria control campaign started in Iraq in 1957. This made the country largely free of the disease. Since 1991, following the recent war, Iraq has been affected by serious epidemic of P. vivax malaria that started in 3 autonomous governorates and soon involved other parts of the country. There were 49,840 malaria cases in the country in 1995. The national malaria programme personnel did their best to contain and control the epidemic. Active and passive case detection and treatment were introduced. Free of charge drugs are provided at all levels in the endemic area. Vector control includes environmental management, distribution of Gambusia fish, larviciding, indoor residual spraying with pyrithroids. A total of 4134 malaria cases were recorded in the country in 1999. PMID:11548316

  12. Imaging liver-stage malaria parasites.

    PubMed

    Rankin, Kathleen E; Graewe, Stefanie; Heussler, Volker T; Stanway, Rebecca R

    2010-05-01

    Plasmodium parasites, the causative agents of malaria, first invade and develop within hepatocytes before infecting red blood cells and causing symptomatic disease. Because of the low infection rates in vitro and in vivo, the liver stage of Plasmodium infection is not very amenable to biochemical assays, but the large size of the parasite at this stage in comparison with Plasmodium blood stages makes it accessible to microscopic analysis. A variety of imaging techniques has been used to this aim, ranging from electron microscopy to widefield epifluorescence and laser scanning confocal microscopy. High-speed live video microscopy of fluorescent parasites in particular has radically changed our view on key events in Plasmodium liver-stage development. This includes the fate of motile sporozoites inoculated by Anopheles mosquitoes as well as the transport of merozoites within merosomes from the liver tissue into the blood vessel. It is safe to predict that in the near future the application of the latest microscopy techniques in Plasmodium research will bring important insights and allow us spectacular views of parasites during their development in the liver. PMID:20180802

  13. Epidemiologic aspects of the malaria transmission cycle in an area of very low incidence in Brazil

    PubMed Central

    Cerutti, Crispim; Boulos, Marcos; Coutinho, Arnídio F; Hatab, Maria do Carmo LD; Falqueto, Aloísio; Rezende, Helder R; Duarte, Ana Maria RC; Collins, William; Malafronte, Rosely S

    2007-01-01

    Background Extra-Amazonian autochthonous Plasmodium vivax infections have been reported in mountainous regions surrounded by the Atlantic Forest in Espírito Santo state, Brazil. Methods Sixty-five patients and 1,777 residents were surveyed between April 2001 and March 2004. Laboratory methods included thin and thick smears, multiplex-PCR, immunofluorescent assay (IFA) against P. vivax and Plasmodium malariae crude blood-stage antigens and enzyme-linked immunosorbent assay (ELISA) for antibodies against the P. vivax-complex (P. vivax and variants) and P. malariae/Plasmodium brasilianum circumsporozoite-protein (CSP) antigens. Results Average patient age was 35.1 years. Most (78.5%) were males; 64.6% lived in rural areas; 35.4% were farmers; and 12.3% students. There was no relevant history of travel. Ninety-five per cent of the patients were experiencing their first episode of malaria. Laboratory data from 51 patients were consistent with P. vivax infection, which was determined by thin smear. Of these samples, 48 were assayed by multiplex-PCR. Forty-five were positive for P. vivax, confirming the parasitological results, while P. malariae was detected in one sample and two gave negative results. Fifty percent of the 50 patients tested had IgG antibodies against the P. vivax-complex or P. malariae CSP as determined by ELISA. The percentages of residents with IgM and IgG antibodies detected by IFA for P. malariae, P. vivax and Plasmodium falciparum who did not complain of malaria symptoms at the time blood was collected were 30.1% and 56.5%, 6.2% and 37.7%, and 13.5% and 13%, respectively. The same sera that reacted to P. vivax also reacted to P. malariae. The following numbers of samples were positive in multiplex-PCR: 23 for P. vivax; 15 for P. malariae; 9 for P. falciparum and only one for P. falciparum and P. malariae. All thin and thick smears were negative. ELISA against CSP antigens was positive in 25.4%, 6.3%, 10.7% and 15.1% of the samples tested for

  14. Plasmodium falciparum XPD translocates in 5' to 3' direction, is expressed throughout the blood stages, and interacts with p44.

    PubMed

    Tajedin, Leila; Tarique, Mohammed; Tuteja, Renu

    2015-11-01

    XPD helicase, a TFIIH subunit, is essential for several processes including transcription, NER, cell cycle regulation, and apoptosis in eukaryotes. Another component of TFIIH, namely p44, is among the well-known interacting partners of XPD and is vital in regulating the helicase activities of latter. However, none of the above mentioned proteins have been functionally characterized in Plasmodium falciparum. Consequently, in this study, we performed detailed studies on XPD and its interacting partner, p44, from P. falciparum 3D7 strain. Accordingly, we expressed and purified recombinant PfXPD and its fragments and Pfp44 proteins and characterized the enzymatic activities of PfXPD and its fragments. The in vivo stage-specific expression and subcellular localizations of PfXPD and Pfp44 proteins were studied using the specific antibodies in the intraerythrocytic developmental stages of P. falciparum 3D7 strain. Our results suggest that PfXPD displays the characteristic ssDNA-dependent ATPase and 5'-3' DNA helicase activities. We also report the existence of two high molecular weight forms of p44 in P. falciparum 3D7 strain. Both PfXPD and Pfp44 colocalize in the nucleus and interact with each other, which suggest that they are most likely components of the same complex apparently, TFIIH. Furthermore, during trophozoite and schizont stages, both proteins exhibit a distinct cytoplasmic distribution pattern which implies that PfXPD and Pfp44 might also be involved in other functions. These studies will aid in understanding the basic biology of malaria parasite. PMID:25708921

  15. Neglected Plasmodium vivax malaria in northeastern States of India

    PubMed Central

    Sharma, Vinod P.; Dev, Vas; Phookan, Sobhan

    2015-01-01

    Background & objectives: The northeastern States of India are co-endemic for Plasmodium falciparum and P. vivax malaria. The transmission intensity is low-to-moderate resulting in intermediate to stable malaria. Malaria control prioritized P. falciparum being the predominant and life threatening infection (>70%). P. vivax malaria remained somewhat neglected. The present study provides a status report of P. vivax malaria in the northeastern States of India. Methods: Data on spatial distribution of P. vivax from seven northeastern States (Arunachal Pradesh, Assam, Manipur, Meghalaya, Mizoram, Nagaland and Tripura) were analysed retrospectively from 2008–2013. In addition, cross-sectional malarial surveys were conducted during 1991-2012 in malaria endemic pockets across the States of Assam, Meghalaya, Mizoram and Tripura to ascertain the prevalence of P. vivax in different age groups. Results: Vivax malaria was encountered in all northeastern States but there existed a clear division of two malaria ecotypes supporting ≤30 and >30 per cent of total malaria cases. High proportions of P. vivax cases (60–80%) were seen in Arunachal Pradesh and Nagaland in the north with alpine environment, 42-67 per cent in Manipur, whereas in Assam it varied from 23-31 per cent with subtropical and tropical climate. Meghalaya, Tripura and Mizoram had the lowest proportion of P. vivax cases. Malaria cases were recorded in all age groups but a higher proportion of P. vivax consistently occurred among <5 yr age group compared to P. falciparum (P<0.05). P. vivax cases were recorded throughout the year with peak coinciding with rainy season although transmission intensity and duration varied. Interpretation & conclusions: In northeast India, P. vivax is a neglected infection. Estimating the relapsing pattern and transmission dynamics of P. vivax in various ecological settings is an important pre-requisite for planning malaria elimination in the northeastern States. PMID:26139771

  16. Large-scale growth of the Plasmodium falciparum malaria parasite in a wave bioreactor.

    PubMed

    Dalton, John P; Demanga, Corine G; Reiling, Sarah J; Wunderlich, Juliane; Eng, Jenny W L; Rohrbach, Petra

    2012-01-01

    We describe methods for the large-scale in vitro culturing of synchronous and asynchronous blood-stage Plasmodium falciparum parasites in sterile disposable plastic bioreactors controlled by wave-induced motion (wave bioreactor). These cultures perform better than static flask cultures in terms of preserving parasite cell cycle synchronicity and reducing the number of multiple-infected erythrocytes. The straight-forward methods described here will facilitate the large scale production of malaria parasites for antigen and organelle isolation and characterisation, for the high throughput screening of compound libraries with whole cells or extracts, and the development of live- or whole-cell malaria vaccines under good manufacturing practice compliant standards. PMID:22326740

  17. Dynamics and role of antibodies to Plasmodium falciparum merozoite antigens in children living in two settings with differing malaria transmission intensity

    PubMed Central

    Kangoye, David Tiga; Mensah, Victorine Atanase; Murungi, Linda Muthoni; Nkumama, Irene; Nebie, Issa; Marsh, Kevin; Cisse, Badara; Bejon, Philip; Osier, Faith Hope Among’in; Sirima, Sodiomon Bienvenu; Yaro, Jean-Baptiste; Debe, Siaka; Traore, Safiatou; Ndaw, Aminata; Faye, Babacar; Soulama, Issiaka; Diarra, Amidou; Tiono, Alfred

    2016-01-01

    Background Young infants have reduced susceptibility to febrile malaria compared with older children, but the mechanism for this remains unclear. There are conflicting data on the role of passively acquired antibodies. Here, we examine antibody titres to merozoite surface antigens in the protection of children in their first two years of life in two settings with differing malaria transmission intensity and compare these titres to previously established protective thresholds. Methods Two cohorts of children aged four to six weeks were recruited in Banfora, Burkina and Keur Soce, Senegal and followed up for two years. Malaria infections were detected by light microscopic examination of blood smears collected at active and passive case detection visits. The titres of antibodies to the Plasmodium falciparum recombinant merozoite proteins (AMA1-3D7, MSP1-19, MSP2-Dd2, and MSP3-3D7) were measured by enzyme-linked immunosorbent assay at 1–6, 9, 12, 15 and 18 months of age and compared with the protective thresholds established in Kenyan children. Results Antibody titres were below the protective thresholds throughout the study period and we did not find any association with protection against febrile malaria. Antibodies to AMA1 and MSP1-19 appeared to be markers of exposure in the univariate analysis (and so associated with increasing risk) and adjusting for exposure reduced the strength and significance of this association. Conclusion The antibody levels we measured are unlikely to be responsible for the apparent protection against febrile malaria seen in young infants. Further work to identify protective antibody responses might include functional assays and a wider range of antigens. PMID:26541134

  18. Functional Analysis of the Leading Malaria Vaccine Candidate AMA-1 Reveals an Essential Role for the Cytoplasmic Domain in the Invasion Process

    PubMed Central

    Treeck, Moritz; Zacherl, Sonja; Herrmann, Susann; Cabrera, Ana; Kono, Maya; Struck, Nicole S.; Engelberg, Klemens; Haase, Silvia; Frischknecht, Friedrich; Miura, Kota; Spielmann, Tobias; Gilberger, Tim W.

    2009-01-01

    A key process in the lifecycle of the malaria parasite Plasmodium falciparum is the fast invasion of human erythrocytes. Entry into the host cell requires the apical membrane antigen 1 (AMA-1), a type I transmembrane protein located in the micronemes of the merozoite. Although AMA-1 is evolving into the leading blood-stage malaria vaccine candidate, its precise role in invasion is still unclear. We investigate AMA-1 function using live video microscopy in the absence and presence of an AMA-1 inhibitory peptide. This data reveals a crucial function of AMA-1 during the primary contact period upstream of the entry process at around the time of moving junction formation. We generate a Plasmodium falciparum cell line that expresses a functional GFP-tagged AMA-1. This allows the visualization of the dynamics of AMA-1 in live parasites. We functionally validate the ectopically expressed AMA-1 by establishing a complementation assay based on strain-specific inhibition. This method provides the basis for the functional analysis of essential genes that are refractory to any genetic manipulation. Using the complementation assay, we show that the cytoplasmic domain of AMA-1 is not required for correct trafficking and surface translocation but is essential for AMA-1 function. Although this function can be mimicked by the highly conserved cytoplasmic domains of P. vivax and P. berghei, the exchange with the heterologous domain of the microneme protein EBA-175 or the rhoptry protein Rh2b leads to a loss of function. We identify several residues in the cytoplasmic tail that are essential for AMA-1 function. We validate this data using additional transgenic parasite lines expressing AMA-1 mutants with TY1 epitopes. We show that the cytoplasmic domain of AMA-1 is phosphorylated. Mutational analysis suggests an important role for the phosphorylation in the invasion process, which might translate into novel therapeutic strategies. PMID:19283086

  19. Mechanisms of Stage-Transcending Protection Following Immunization of Mice with Late Liver Stage-Arresting Genetically Attenuated Malaria Parasites

    PubMed Central

    Sack, Brandon K.; Keitany, Gladys J.; Vaughan, Ashley M.; Miller, Jessica L.; Wang, Ruobing; Kappe, Stefan H. I.

    2015-01-01

    Malaria, caused by Plasmodium parasite infection, continues to be one of the leading causes of worldwide morbidity and mortality. Development of an effective vaccine has been encumbered by the complex life cycle of the parasite that has distinct pre-erythrocytic and erythrocytic stages of infection in the mammalian host. Historically, malaria vaccine development efforts have targeted each stage in isolation. An ideal vaccine, however, would target multiple life cycle stages with multiple arms of the immune system and be capable of eliminating initial infection in the liver, the subsequent blood stage infection, and would prevent further parasite transmission. We have previously shown that immunization of mice with Plasmodium yoelii genetically attenuated parasites (GAP) that arrest late in liver stage development elicits stage-transcending protection against both a sporozoite challenge and a direct blood stage challenge. Here, we show that this immunization strategy engenders both T- and B-cell responses that are essential for stage-transcending protection, but the relative importance of each is determined by the host genetic background. Furthermore, potent anti-blood stage antibodies elicited after GAP immunization rely heavily on FC-mediated functions including complement fixation and FC receptor binding. These protective antibodies recognize the merozoite surface but do not appear to recognize the immunodominant merozoite surface protein-1. The antigen(s) targeted by stage-transcending immunity are present in both the late liver stages and blood stage parasites. The data clearly show that GAP-engendered protective immune responses can target shared antigens of pre-erythrocytic and erythrocytic parasite life cycle stages. As such, this model constitutes a powerful tool to identify novel, protective and stage-transcending T and B cell targets for incorporation into a multi-stage subunit vaccine. PMID:25974076

  20. Neurological manifestations of malaria.

    PubMed

    Román, G C; Senanayake, N

    1992-03-01

    The involvement of the nervous system in malaria is reviewed in this paper. Cerebral malaria, the acute encephalopathy which complicates exclusively the infection by Plasmodium falciparum commonly affects children and adolescents in hyperendemic areas. Plugging of cerebral capillaries and venules by clumped, parasitized red cells causing sludging in the capillary circulation is one hypothesis to explain its pathogenesis. The other is a humoral hypothesis which proposes nonspecific, immune-mediated, inflammatory responses with release of vasoactive substances capable of producing endothelial damage and alterations of permeability. Cerebral malaria has a mortality rate up to 50%, and also a considerable longterm morbidity, particularly in children. Hypoglycemia, largely in patients treated with quinine, may complicate the cerebral symptomatology. Other central nervous manifestations of malaria include intracranial hemorrhage, cerebral arterial occlusion, and transient extrapyramidal and neuropsychiatric manifestations. A self-limiting, isolated cerebellar ataxia, presumably caused by immunological mechanisms, in patients recovering from falciparum malaria has been recognized in Sri Lanka. Malaria is a common cause of febrile seizures in the tropics, and it also contributes to the development of epilepsy in later life. Several reports of spinal cord and peripheral nerve involvement are also available. A transient muscle paralysis resembling periodic paralysis during febrile episodes of malaria has been described in some patients. The pathogenesis of these neurological manifestations remains unexplored, but offers excellent perspectives for research at a clinical as well as experimental level. PMID:1307475

  1. Malaria in Children

    PubMed Central

    Schumacher, Richard-Fabian; Spinelli, Elena

    2012-01-01

    This review is focused on childhood specific aspects of malaria, especially in resource-poor settings. We summarise the actual knowledge in the field of epidemiology, clinical presentation, diagnosis, management and prevention. These aspects are important as malaria is responsible for almost a quarter of all child death in sub-Saharan Africa. Malaria control is thus one key intervention to reduce childhood mortality, especially as malaria is also an important risk factor for other severe infections, namely bacteraemia. In children symptoms are more varied and often mimic other common childhood illness, particularly gastroenteritis, meningitis/encephalitis, or pneumonia. Fever is the key symptom, but the characteristic regular tertian and quartan patterns are rarely observed. There are no pathognomonic features for severe malaria in this age group. The well known clinical (fever, impaired consciousness, seizures, vomiting, respiratory distress) and laboratory (severe anaemia, thrombocytopenia, hypoglycaemia, metabolic acidosis, and hyperlactataemia) features of severe falciparum malaria in children, are equally typical for severe sepsis. Appropriate therapy (considering species, resistance patterns and individual patient factors) – possibly a drug combination of an artemisinin derivative with a long-acting antimalarial drug - reduces treatment duration to only three days and should be urgently started. While waiting for the results of ongoing vaccine trials, all effort should be made to better implement other malaria-control measures like the use of treated bed-nets, repellents and new chemoprophylaxis regimens. PMID:23205261

  2. [Malaria in Algerian Sahara].

    PubMed

    Hammadi, D; Boubidi, S C; Chaib, S E; Saber, A; Khechache, Y; Gasmi, M; Harrat, Z

    2009-08-01

    Thanks to the malaria eradication campaign launched in Algeria in 1968, the number of malaria cases fell down significantly from 95,424 cases in 1960 to 30 cases in 1978. At that time the northern part of the country was declared free of Plasmodium falciparum. Only few cases belonging to P. vivax persisted in residual foci in the middle part of the country. In the beginning of the eighties, the south of the country was marked by an increase of imported malaria cases. The resurgence of the disease in the oases coincided with the opening of the Trans-Saharan road and the booming trade with the neighbouring southern countries. Several authors insisted on the risk of introduction of malaria or its exotic potential vectors in Algeria via this new road. Now, the totality of malaria autochthonous cases in Algeria are located in the south of the country where 300 cases were declared during the period (1980-2007). The recent outbreak recorded in 2007 at the borders with Mall and the introduction of Anopheles gambiae into the Algerian territory show the vulnerability of this area to malaria which is probably emphasized by the local environmental changes. The authors assess the evolution of malaria in the Sahara region and draw up the distribution of the anopheles in this area. PMID:19739417

  3. Vaccination with Plasmodium knowlesi AMA1 formulated in the novel adjuvant co-vaccine HT™ protects against blood-stage challenge in rhesus macaques.

    PubMed

    Mahdi Abdel Hamid, Muzamil; Remarque, Edmond J; van Duivenvoorde, Leonie M; van der Werff, Nicole; Walraven, Vanessa; Faber, Bart W; Kocken, Clemens H M; Thomas, Alan W

    2011-01-01

    Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading blood stage vaccine candidate. Plasmodium knowlesi AMA1 (PkAMA1) was produced and purified using similar methodology as for clinical grade PfAMA1 yielding a pure, conformational intact protein. Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model. Six rhesus monkeys were vaccinated with PkAMA1 and a control group of 6 were vaccinated with PfAMA1. A total of 50 µg AMA1 was administered intramuscularly three times at 4 week intervals. One of six rhesus monkeys vaccinated with PkAMA1 was able to control parasitaemia, upon blood stage challenge with P. knowlesi H-strain. Four out of the remaining five showed a delay in parasite onset that correlated with functional antibody titres. In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period. Following a rest period, animals were boosted and challenged again. Four of the six rhesus monkeys vaccinated with PkAMA1 were able to control the parasitaemia, one had a delayed onset of parasitaemia and one animal was not protected, while all control animals required treatment. To confirm that the control of parasitaemia was AMA1-related, animals were allowed to recover, boosted and re-challenged with P. knowlesi Nuri strain. All control animals had to be treated with antimalarials by day 8, while five out of six PkAMA1 vaccinated animals were able to control parasitaemia. This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC(50) values correlated with estimated in vivo growth rates. PMID:21655233

  4. Analysis of human B-cell responses following ChAd63-MVA MSP1 and AMA1 immunization and controlled malaria infection

    PubMed Central

    Elias, Sean C; Choudhary, Prateek; de Cassan, Simone C; Biswas, Sumi; Collins, Katharine A; Halstead, Fenella D; Bliss, Carly M; Ewer, Katie J; Hodgson, Susanne H; Duncan, Christopher J A; Hill, Adrian V S; Draper, Simon J

    2014-01-01

    Acquisition of non-sterilizing natural immunity to Plasmodium falciparum malaria has been shown in low transmission areas following multiple exposures. However, conflicting data from endemic areas suggest that the parasite may interfere with the induction of effective B-cell responses. To date, the impact of blood-stage parasite exposure on antigen-specific B cells has not been reported following controlled human malaria infection (CHMI). Here we analysed human B-cell responses in a series of Phase I/IIa clinical trials, which include CHMI, using candidate virus-vectored vaccines encoding two blood-stage antigens: merozoite surface protein 1 (MSP1) and apical membrane antigen 1 (AMA1). Previously vaccinated volunteers show boosting of pre-existing antigen-specific memory B-cell (mBC) responses following CHMI. In contrast, unvaccinated malaria-naive control volunteers developed an mBC response against MSP1 but not AMA1. Serum IgG correlated with the mBC response after booster vaccination but this relationship was less well maintained following CHMI. A significant reduction in peripheral MSP1-specific mBC was observed at the point of diagnosis of blood-stage infection. This was coincident with a reduction in peripheral blood B-cell subsets expressing CXCR3 and elevated serum levels of interferon-γ and CXCL9, suggesting migration away from the periphery. These CHMI data confirm that mBC and antibody responses can be induced and boosted by blood-stage parasite exposure, in support of epidemiological studies on low-level parasite exposure. PMID:24303947

  5. Malaria: prevention in travellers

    PubMed Central

    Croft, Ashley

    2000-01-01

    Definition Malaria is caused by a protozoan infection of red blood cells with one of four species of the genus plasmodium: P falciparum, P vivax, P ovale, or P malariae.1 Clinically, malaria may present in different ways, but it is usually characterised by fever (which may be swinging), tachycardia, rigors, and sweating. Anaemia, hepatosplenomegaly, cerebral involvement, renal failure, and shock may occur. Incidence/prevalence Each year there are 300-500 million clinical cases of malaria. About 40% of the world's population is at risk of acquiring the disease.23 Each year 25-30 million people from non-tropical countries visit areas in which malaria is endemic,4 of whom between 10 000 and 30 000 contract malaria.5 Aetiology/risk factors Malaria is mainly a rural disease, requiring standing water nearby. It is transmitted by bites6 from infected female anopheline mosquitoes,7 mainly at dusk and during the night.18 In cities, mosquito bites are usually from female culicene mosquitoes, which are not vectors of malaria.9 Malaria is resurgent in most tropical countries and the risk to travellers is increasing.10 Prognosis Ninety per cent of travellers who contract malaria do not become ill until after they return home.5 “Imported malaria” is easily treated if diagnosed promptly, and it follows a serious course in only about 12% of people.1112 The most severe form of the disease is cerebral malaria, with a case fatality rate in adult travellers of 2-6%,3 mainly because of delays in diagnosis.5 Aims To reduce the risk of infection; to prevent illness and death. Outcomes Rates of malarial illness and death, and adverse effects of treatment. Proxy measures include number of mosquito bites and number of mosquitoes in indoor areas. We found limited evidence linking number of mosquito bites and risk of malaria.13 Methods Clinical Evidence search and appraisal in November 1999. We reviewed all identified systematic reviews and randomised controlled trials (RCTs

  6. Malaria and Vascular Endothelium

    PubMed Central

    de Alencar, Aristóteles Comte; de Lacerda, Marcus Vinícius Guimarães; Okoshi, Katashi; Okoshi, Marina Politi

    2014-01-01

    Involvement of the cardiovascular system in patients with infectious and parasitic diseases can result from both intrinsic mechanisms of the disease and drug intervention. Malaria is an example, considering that the endothelial injury by Plasmodium-infected erythrocytes can cause circulatory disorders. This is a literature review aimed at discussing the relationship between malaria and endothelial impairment, especially its effects on the cardiovascular system. We discuss the implications of endothelial aggression and the interdisciplinarity that should guide the malaria patient care, whose acute infection can contribute to precipitate or aggravate a preexisting heart disease. PMID:25014058

  7. Malaria and vascular endothelium.

    PubMed

    Alencar Filho, Aristóteles Comte de; Lacerda, Marcus Vinícius Guimarães de; Okoshi, Katashi; Okoshi, Marina Politi

    2014-08-01

    Involvement of the cardiovascular system in patients with infectious and parasitic diseases can result from both intrinsic mechanisms of the disease and drug intervention. Malaria is an example, considering that the endothelial injury by Plasmodium-infected erythrocytes can cause circulatory disorders. This is a literature review aimed at discussing the relationship between malaria and endothelial impairment, especially its effects on the cardiovascular system. We discuss the implications of endothelial aggression and the interdisciplinarity that should guide the malaria patient care, whose acute infection can contribute to precipitate or aggravate a preexisting heart disease. PMID:25014058

  8. Skill of ENSEMBLES seasonal re-forecasts for malaria prediction in West Africa

    NASA Astrophysics Data System (ADS)

    Jones, A. E.; Morse, A. P.

    2012-12-01

    This study examines the performance of malaria-relevant climate variables from the ENSEMBLES seasonal ensemble re-forecasts for sub-Saharan West Africa, using a dynamic malaria model to transform temperature and rainfall forecasts into simulated malaria incidence and verifying these forecasts against simulations obtained by driving the malaria model with General Circulation Model-derived reanalysis. Two subregions of forecast skill are identified: the highlands of Cameroon, where low temperatures limit simulated malaria during the forecast period and interannual variability in simulated malaria is closely linked to variability in temperature, and northern Nigeria/southern Niger, where simulated malaria variability is strongly associated with rainfall variability during the peak rain months.

  9. Optical remote sensing a potential tool for forecasting malaria in Orissa, India

    NASA Astrophysics Data System (ADS)

    Nizamuddin, Mohammad; Akhand, Kawsar; Roytman, Leonid; Kogan, Felix; Goldberg, Mitch

    2013-05-01

    Information on current and anticipated moisture and thermal condition from satellite data represents a source of affordable yet careful information for malaria forecasters to implement and control of epidemic. During the last decades Orissa state in India suffered from highest level of malaria incidence. This situation requires frequent monitoring of environmental conditions and dynamics of malaria occurrence. During 1985 to 2004 the NOAA AVHRR global vegetation index (GVI) dataset and its vegetation health (VH) have been studied and used as proxy for malaria fluctuation. This paper discusses applications of VH for early detecting and monitoring malaria incidence in Orissa. A significant relationship between satellite data and annual malaria incidences is found at least three months before the major malaria transmission period.

  10. Progress with viral vectored malaria vaccines: A multi-stage approach involving “unnatural immunity”

    PubMed Central

    Ewer, Katie J.; Sierra-Davidson, Kailan; Salman, Ahmed M.; Illingworth, Joseph J.; Draper, Simon J.; Biswas, Sumi; Hill, Adrian V.S.

    2015-01-01

    Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8+ T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, “unnatural immunity” comprising immune responses of very high magnitude will need to be induced. PMID:26476366

  11. Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity".

    PubMed

    Ewer, Katie J; Sierra-Davidson, Kailan; Salman, Ahmed M; Illingworth, Joseph J; Draper, Simon J; Biswas, Sumi; Hill, Adrian V S

    2015-12-22

    Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8(+) T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, "unnatural immunity" comprising immune responses of very high magnitude will need to be induced. PMID:26476366

  12. Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people

    PubMed Central

    Ménard, Didier; Barnadas, Céline; Bouchier, Christiane; Henry-Halldin, Cara; Gray, Laurie R.; Ratsimbasoa, Arsène; Thonier, Vincent; Carod, Jean-François; Domarle, Olivier; Colin, Yves; Bertrand, Olivier; Picot, Julien; King, Christopher L.; Grimberg, Brian T.; Mercereau-Puijalon, Odile; Zimmerman, Peter A.

    2010-01-01

    Malaria therapy, experimental, and epidemiological studies have shown that erythrocyte Duffy blood group-negative people, largely of African ancestry, are resistant to erythrocyte Plasmodium vivax infection. These findings established a paradigm that the Duffy antigen is required for P. vivax erythrocyte invasion. P. vivax is endemic in Madagascar, where admixture of Duffy-negative and Duffy-positive populations of diverse ethnic backgrounds has occurred over 2 millennia. There, we investigated susceptibility to P. vivax blood-stage infection and disease in association with Duffy blood group polymorphism. Duffy blood group genotyping identified 72% Duffy-negative individuals (FY*BES/*BES) in community surveys conducted at eight sentinel sites. Flow cytometry and adsorption–elution results confirmed the absence of Duffy antigen expression on Duffy-negative erythrocytes. P. vivax PCR positivity was observed in 8.8% (42/476) of asymptomatic Duffy-negative people. Clinical vivax malaria was identified in Duffy-negative subjects with nine P. vivax monoinfections and eight mixed Plasmodium species infections that included P. vivax (4.9 and 4.4% of 183 participants, respectively). Microscopy examination of blood smears confirmed blood-stage development of P. vivax, including gametocytes. Genotyping of polymorphic surface and microsatellite markers suggested that multiple P. vivax strains were infecting Duffy-negative people. In Madagascar, P. vivax has broken through its dependence on the Duffy antigen for establishing human blood-stage infection and disease. Further studies are necessary to identify the parasite and host molecules that enable this Duffy-independent P. vivax invasion of human erythrocytes. PMID:20231434

  13. A weather-driven model of malaria transmission

    PubMed Central

    Hoshen, Moshe B; Morse, Andrew P

    2004-01-01

    Background Climate is a major driving force behind malaria transmission and climate data are often used to account for the spatial, seasonal and interannual variation in malaria transmission. Methods This paper describes a mathematical-biological model of the parasite dynamics, comprising both the weather-dependent within-vector stages and the weather-independent within-host stages. Results Numerical evaluations of the model in both time and space show that it qualitatively reconstructs the prevalence of infection. Conclusion A process-based modelling structure has been developed that may be suitable for the simulation of malaria forecasts based on seasonal weather forecasts. PMID:15350206

  14. Immunopathology of malaria*

    PubMed Central

    Voller, Alister

    1974-01-01

    Antibodies with different spectra of reactivity are produced during malarial infections and marked changes in IgG and IgM levels occur. In addition malaria elicits serological changes that are usually associated with connective tissue disease. The excessive anaemia associated with malaria may, in part, be an autoimmune phenomenon. Transient nephritis accompanies many plasmodial infections but chronic malarial nephrotic syndrome is specifically associated with quartan malaria. Malarial infection leads to splenomegaly, the most extreme form of which is idiopathic tropical splenomegaly, which probably represents an aberrant immune response to the infection. Malaria can affect the humoral immune response to unrelated antigens and infectious agents. This may be relevant to the etiology of Burkitt's lymphoma. During pregnancy there is some loss of acquired immunity to P. falciparum and the placenta appears to be an immunologically privileged site for the multiplication of this parasite. PMID:4216408

  15. Malaria diseases and parasites.

    PubMed

    Ascenzi, A

    1999-09-01

    The milestones in the discovery of malaria parasites and their relationships with malaria diseases are presented and discussed with particular reference to the contribution of the Italian scientists. Laveran's discovery (1880) of the malaria parasite produced some schepticism among the Roman scientists who were under the influence of Tommasi-Crudeli, the discoverer of the supposed Bacillus malariae. However, Marchiafava and Celli confirmed soon Laveran's observations and, between 1883 and 1885, improved the description of the parasite adding important details. They described, then, the aestivo-autumnal tertian fever as a distinct disease from the 'primaverile' or benign tertian. This work influenced Golgi who went on to analyse the features that distinguish the benign tertian parasite from that of the quartan. The fact that in North Italy the aestivo-autumnal tertian fever was hardly ever found, whereas it was common in the Roman Campagna and the Pontin marshes, explains why it was Celli and Marchiafava and later Bignami and Bastianelli, and Marchiafava and Bignami--but not Golgi--who were committed to work on this pernicious form of malaria. By the early 1890s the Italian scientists came to define the three malaria parasites, presently known as Plasmodium vivax, P. malariae, and P. falciparum, and to associate them with precise anatomo-pathological and clinical features. By the middle 1890s the Italian school was prepared to contribute also to the discovery of the mosquito cycle in human malaria, clearly hypothesized by Bignami in 1896 and experimentally proved in 1898 by Bignami, Bastianelli and Grassi. PMID:10697831

  16. Malaria Diagnosis: A Brief Review

    PubMed Central

    Duangdee, Chatnapa; Wilairatana, Polrat; Krudsood, Srivicha

    2009-01-01

    Malaria is a major cause of death in tropical and sub-tropical countries, killing each year over 1 million people globally; 90% of fatalities occur in African children. Although effective ways to manage malaria now exist, the number of malaria cases is still increasing, due to several factors. In this emergency situation, prompt and effective diagnostic methods are essential for the management and control of malaria. Traditional methods for diagnosing malaria remain problematic; therefore, new technologies have been developed and introduced to overcome the limitations. This review details the currently available diagnostic methods for malaria. PMID:19488414

  17. Tetracyclines in malaria.

    PubMed

    Gaillard, Tiphaine; Madamet, Marylin; Pradines, Bruno

    2015-01-01

    Malaria, a parasite vector-borne disease, is one of the greatest health threats in tropical regions, despite the availability of malaria chemoprophylaxis. The emergence and rapid extension of Plasmodium falciparum resistance to various anti-malarial drugs has gradually limited the number of potential malaria therapeutics available to clinicians. In this context, doxycycline, a synthetically derived tetracycline, constitutes an interesting alternative for malaria treatment and prophylaxis. Doxycycline is a slow-acting blood schizontocidal agent that is highly effective at preventing malaria. In areas with chloroquine and multidrug-resistant P. falciparum parasites, doxycycline has already been successfully used in combination with quinine to treat malaria, and it has been proven to be effective and well-tolerated. Although not recommended for pregnant women and children younger than 8 years of age, severe adverse effects are rarely reported. In addition, resistance to doxycycline is rarely described. Prophylactic and clinical failures of doxycycline have been associated with both inadequate doses and poor patient compliance. The effects of tetracyclines on parasites are not completely understood. A better comprehension of the mechanisms underlying drug resistance would facilitate the identification of molecular markers of resistance to predict and survey the emergence of resistance. PMID:26555664

  18. UK malaria treatment guidelines.

    PubMed

    Lalloo, David G; Shingadia, Delane; Pasvol, Geoffrey; Chiodini, Peter L; Whitty, Christopher J; Beeching, Nicholas J; Hill, David R; Warrell, David A; Bannister, Barbara A

    2007-02-01

    Malaria is the tropical disease most commonly imported into the UK, with 1500-2000 cases reported each year, and 10-20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, atovaquone plus proguanil (Malarone) or co-artemether (Riamet

  19. The global pipeline of new medicines for the control and elimination of malaria

    PubMed Central

    2012-01-01

    Over the past decade, there has been a transformation in the portfolio of medicines to combat malaria. New fixed-dose artemisinin combination therapy is available, with four different types having received approval from Stringent Regulatory Authorities or the World Health Organization (WHO). However, there is still scope for improvement. The Malaria Eradication Research agenda identified several gaps in the current portfolio. Simpler regimens, such as a single-dose cure are needed, compared with the current three-day treatment. In addition, new medicines that prevent transmission and also relapse are needed, but with better safety profiles than current medicines. There is also a big opportunity for new medicines to prevent reinfection and to provide chemoprotection. This study reviews the global portfolio of new medicines in development against malaria, as of the summer of 2012. Cell-based phenotypic screening, and ‘fast followers’ of clinically validated classes, mean that there are now many new classes of molecules starting in clinical development, especially for the blood stages of malaria. There remain significant gaps for medicines blocking transmission, preventing relapse, and long-duration molecules for chemoprotection. The nascent pipeline of new medicines is significantly stronger than five years ago. However, there are still risks ahead in clinical development and sustainable funding of clinical studies is vital if this early promise is going to be delivered. PMID:22958514

  20. Assessing the Role of Climate Change in Malaria Transmission in Africa

    PubMed Central

    Ngarakana-Gwasira, E. T.; Bhunu, C. P.; Masocha, M.; Mashonjowa, E.

    2016-01-01

    The sensitivity of vector borne diseases like malaria to climate continues to raise considerable concern over the implications of climate change on future disease dynamics. The problem of malaria vectors shifting from their traditional locations to invade new zones is of important concern. A mathematical model incorporating rainfall and temperature is constructed to study the transmission dynamics of malaria. The reproduction number obtained is applied to gridded temperature and rainfall datasets for baseline climate and future climate with aid of GIS. As a result of climate change, malaria burden is likely to increase in the tropics, the highland regions, and East Africa and along the northern limit of falciparum malaria. Falciparum malaria will spread into the African highlands; however it is likely to die out at the southern limit of the disease. PMID:27066290

  1. Assessing the Role of Climate Change in Malaria Transmission in Africa.

    PubMed

    Ngarakana-Gwasira, E T; Bhunu, C P; Masocha, M; Mashonjowa, E

    2016-01-01

    The sensitivity of vector borne diseases like malaria to climate continues to raise considerable concern over the implications of climate change on future disease dynamics. The problem of malaria vectors shifting from their traditional locations to invade new zones is of important concern. A mathematical model incorporating rainfall and temperature is constructed to study the transmission dynamics of malaria. The reproduction number obtained is applied to gridded temperature and rainfall datasets for baseline climate and future climate with aid of GIS. As a result of climate change, malaria burden is likely to increase in the tropics, the highland regions, and East Africa and along the northern limit of falciparum malaria. Falciparum malaria will spread into the African highlands; however it is likely to die out at the southern limit of the disease. PMID:27066290

  2. [Malaria in the Americas].

    PubMed

    Carme, B; Venturin, C

    1999-01-01

    In 1996, malaria involving Plasmodium vivax, Plasmodium falciparum, and, to a lesser extent, Plasmodium malariae was endemic in 21 countries in the Americas. The Amazon river basin and bordering areas including the Guyanas were the most affected zones. Until the mid 1970s, endemic malaria appeared to be under control. However in the ensuing 15 year period, the situation deteriorated drastically. Although trends varied depending on location, aggregate indexes indicated a twofold increase with recrudescence in previously settled areas and emergence in newly populated zones. Since 1990, the situation has worsened further in some areas where increased incidences have been associated with a high levels of drug-resistant Plasmodium falciparum. However this species remains in minority except in the Guyanas where the highest annual incidences (100 to 500 cases per 1000) and the most drug-resistant Plasmodium have been reported. The causes underlying this deterioration are numerous and complex. In regions naturally prone to transmission of the disease, outbreaks have been intensified by unrestrained settlement. The resulting deforestation has created new breeding areas for Anopheles darlingi, the main vector of malaria in the Americas. Migration of poor populations to newly opened farming and mining areas has created highly exposed areas for malaria infection. Implementation of adequate medical care and prevention measures has been hindered by a lack of money and sociopolitical unrest. Climatic phenomenon related the El Nino have also been favorable to the return of malaria to the region. Except with regard to financial resources and political unrest, the same risk factors for malaria are present in French Guiana. PMID:10701211

  3. The treatment of malaria.

    PubMed

    White, N J

    1996-09-12

    Increasing drug resistance in Plasmodium falciparum and a resurgence of malaria in tropical areas have effected a change in treatment of malaria in the last two decades. Symptoms of malaria are fever, chills, headache, and malaise. The prognosis worsens as the parasite counts, counts of mature parasites, and counts of neutrophils containing pigment increase. Treatment depends on severity, age of patient, degree of background immunity, likely pattern of susceptibility to antimalarial drugs, and the cost and availability of drugs. Chloroquine should be used for P. vivax, P. malariae, and P. ovale. P. vivax has shown high resistance to chloroquine in Oceania, however. Primaquine may be needed to treat P. vivax and P. ovale to rid the body of hypnozoites that survive in the liver. Chloroquine can treat P. falciparum infections acquired in North Africa, Central America north of the Panama Canal, Haiti, or the Middle East but not in most of Africa and some parts of Asia and South America. In areas of low grade resistance to chloroquine, amodiaquine can be used to effectively treat falciparum malaria. A combination of sulfadoxine-pyrimethamine is responsive to falciparum infections with high grade resistance to chloroquine. Mefloquine, halofantrine, or quinine with tetracycline can be used to treat multidrug-resistant P. falciparum. Derivatives of artemisinin obtained from qinghao or sweet wormwood developed as pharmaceuticals in China are the most rapidly acting of all antimalarial drugs. Children tend to tolerate antimalarial drugs well. Children who weigh less than 15 kg should not be given mefloquine. Health workers should not prescribe primaquine to pregnant women or newborns due to the risk of hemolysis. Chloroquine, sulfadoxine-pyrimethamine, quinine, and quinidine can be safely given in therapeutic doses throughout pregnancy. Clinical manifestations of severe malaria are hypoglycemia, convulsions, severe anemia, acute renal failure, jaundice, pulmonary edema

  4. Malaria in the United Kingdom

    PubMed Central

    Bruce-Chwatt, L. J.; Southgate, B. A.; Draper, C. C.

    1974-01-01

    Over the past decade the United Kingdom had the second highest number of cases of imported malaria among European countries. There has been a substantial rise in recorded cases of malaria during the past three years though some of it may be due to improved notification. Fatal cases of malaria in visitors to Africa have averaged 6.5% of reported infections due to Plasmodium falciparum. Attacks of vivax malaria may occur several months after travellers return from a malarious country. PMID:4604717

  5. Malaria Ecology, Disease Burden and Global Climate Change

    NASA Astrophysics Data System (ADS)

    Mccord, G. C.

    2014-12-01

    Malaria has afflicted human society for over 2 million years, and remains one of the great killer diseases today. The disease is the fourth leading cause of death for children under five in low income countries (after neonatal disorders, diarrhea, and pneumonia) and is responsible for at least one in every five child deaths in sub-Saharan Africa. It kills up to 3 million people a year, though in recent years scale up of anti-malaria efforts in Africa may have brought deaths to below 1 million. Malaria is highly conditioned by ecology, because of which climate change is likely to change the local dynamics of the disease through changes in ambient temperature and precipitation. To assess the potential implications of climate change for the malaria burden, this paper employs a Malaria Ecology Index from the epidemiology literature, relates it to malaria incidence and mortality using global country-level data , and then draws implications for 2100 by extrapolating the index using several general circulation model (GCM) predictions of temperature and precipitation. The results highlight the climate change driven increase in the basic reproduction number of the disease and the resulting complications for further gains in elimination. For illustrative purposes, I report the change in malaria incidence and mortality if climate change were to happen immediately under current technology and public health efforts.

  6. The Cytoplasmic Prolyl-tRNA Synthetase of the Malaria Parasite is a Dual-Stage Target for Drug Development

    PubMed Central

    Herman, Jonathan D.; Pepper, Lauren R.; Cortese, Joseph F.; Estiu, Guillermina; Galinsky, Kevin; Zuzarte-Luis, Vanessa; Derbyshire, Emily R.; Ribacke, Ulf; Lukens, Amanda K.; Santos, Sofia A.; Patel, Vishal; Clish, Clary B.; Sullivan, William J.; Zhou, Huihao; Bopp, Selina E.; Schimmel, Paul; Lindquist, Susan; Clardy, Jon; Mota, Maria M.; Keller, Tracy L.; Whitman, Malcolm; Wiest, Olaf; Wirth, Dyann F.; Mazitschek, Ralph

    2015-01-01

    The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for the development of the next-generation of antimalarial drugs. Using an integrated chemogenomics approach that combined drug-resistance selection, whole genome sequencing and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivatives such as halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the P. berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is highly active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses, and represents a promising lead for the development of dual-stage next generation antimalarials. PMID:25995223

  7. Dynamics of insecticide resistance in malaria vectors in Benin: first evidence of the presence of L1014S kdr mutation in Anopheles gambiae from West Africa

    PubMed Central

    2011-01-01

    Background Insecticide resistance monitoring is essential to help national programmers to implement more effective and sustainable malaria control strategies in endemic countries. This study reported the spatial and seasonal variations of insecticide resistance in malaria vectors in Benin, West Africa. Methods Anopheles gambiae s.l populations were collected from October 2008 to June 2010 in four sites selected on the basis of different use of insecticides and environment. WHO susceptibility tests were carried out to detect resistance to DDT, fenitrothion, bendiocarb, permethrin and deltamethrin. The synergist piperonyl butoxide was used to assess the role of non-target site mechanisms in pyrethroid resistance. Anopheles gambiae mosquitoes were identified to species and to molecular M and S forms using PCR techniques. Molecular and biochemical assays were carried out to determine kdr and Ace.1R allelic frequencies and activity of the detoxification enzymes. Results Throughout the surveys very high levels of mortality to bendiocarb and fenitrothion were observed in An. gambiae s.l. populations. However, high frequencies of resistance to DDT and pyrethroids were seen in both M and S form of An. gambiae s.s. and Anopheles arabiensis. PBO increased the toxicity of permethrin and restored almost full susceptibility to deltamethrin. Anopheles gambiae s.l. mosquitoes from Cotonou and Malanville showed higher oxidase activity compared to the Kisumu susceptible strain in 2009, whereas the esterase activity was higher in the mosquitoes from Bohicon in both 2008 and 2009. A high frequency of 1014F kdr allele was initially showed in An. gambiae from Cotonou and Tori-Bossito whereas it increased in mosquitoes from Bohicon and Malanville during the second year. For the first time the L1014S kdr mutation was found in An. arabiensis in Benin. The ace.1R mutation was almost absent in An. gambiae s.l. Conclusion Pyrethroid and DDT resistance is widespread in malaria vector in Benin

  8. Modelling climate change and malaria transmission.

    PubMed

    Parham, Paul E; Michael, Edwin

    2010-01-01

    The impact of climate change on human health has received increasing attention in recent years, with potential impacts due to vector-borne diseases only now beginning to be understood. As the most severe vector-borne disease, with one million deaths globally in 2006, malaria is thought most likely to be affected by changes in climate variables due to the sensitivity of its transmission dynamics to environmental conditions. While considerable research has been carried out using statistical models to better assess the relationship between changes in environmental variables and malaria incidence, less progress has been made on developing process-based climate-driven mathematical models with greater explanatory power. Here, we develop a simple model of malaria transmission linked to climate which permits useful insights into the sensitivity of disease transmission to changes in rainfall and temperature variables. Both the impact of changes in the mean values of these key external variables and importantly temporal variation in these values are explored. We show that the development and analysis of such dynamic climate-driven transmission models will be crucial to understanding the rate at which P. falciparum and P. vivax may either infect, expand into or go extinct in populations as local environmental conditions change. Malaria becomes endemic in a population when the basic reproduction number R0 is greater than unity and we identify an optimum climate-driven transmission window for the disease, thus providing a useful indicator for determing how transmission risk may change as climate changes. Overall, our results indicate that considerable work is required to better understand ways in which global malaria incidence and distribution may alter with climate change. In particular, we show that the roles of seasonality, stochasticity and variability in environmental variables, as well as ultimately anthropogenic effects, require further study. The work presented here

  9. Polymorphisms in B Cell Co-Stimulatory Genes Are Associated with IgG Antibody Responses against Blood-Stage Proteins of Plasmodium vivax.

    PubMed

    Cassiano, Gustavo C; Furini, Adriana A C; Capobianco, Marcela P; Storti-Melo, Luciane M; Cunha, Maristela G; Kano, Flora S; Carvalho, Luzia H; Soares, Irene S; Santos, Sidney E; Póvoa, Marinete M; Machado, Ricardo L D

    2016-01-01

    The development of an effective immune response can help decrease mortality from malaria and its clinical symptoms. However, this mechanism is complex and has significant inter-individual variation, most likely owing to the genetic contribution of the human host. Therefore, this study aimed to investigate the influence of polymorphisms in genes involved in the costimulation of B-lymphocytes in the naturally acquired humoral immune response against proteins of the asexual stage of Plasmodium vivax. A total of 319 individuals living in an area of malaria transmission in the Brazilian Amazon were genotyped for four SNPs in the genes CD40, CD40L, BLYS and CD86. In addition, IgG antibodies against P. vivax apical membrane antigen 1 (PvAMA-1), Duffy binding protein (PvDBP) and merozoite surface protein 1 (PvMSP-119) were detected by ELISA. The SNP BLYS -871C>T was associated with the frequency of IgG responders to PvAMA-1 and PvMSP-119. The SNP CD40 -1C>T was associated with the IgG response against PvDBP, whereas IgG antibody titers against PvMSP-119 were influenced by the polymorphism CD86 +1057G>A. These data may help to elucidate the immunological aspects of vivax malaria and consequently assist in the design of malaria vaccines. PMID:26901523

  10. Roll back malaria update.

    PubMed

    1999-10-01

    This article presents the activities under WHO's Roll Back Malaria (RBM) program in Asia, particularly in Nepal, Indonesia, India, Bangladesh, Sri Lanka and the Philippines. In India, the RBM program will start in 5 districts with a major malaria problem. A national committee has been formed by researchers, which will be able to provide operational and strategic support and research expertise in relation to malaria. In Bangladesh, the RBM program was initiated in the sparsely populated hill tract areas of Banderban and Chittagong where access to health care is very poor. At the district level, effective partnerships with private practitioners, politicians, community leaders, school teachers, the press and district Ministry of Health officials are operating to plan for rolling back malaria. In Myanmar, Cambodia, Lao People's Democratic Republic, Yunnan province of China, Vietnam, and Thailand, the focus of the RBM program was to move health care closer to the malaria-infected communities. WHO¿s Global Health Leadership Fellowship Programme, supported by the UN Foundation and Rockefeller Foundation, enables potential leaders to experience the work of UN agencies and contribute to the work of the organization for 2 years. Three out of four persons appointed to the RBM program received prestigious awards: Dr. Paola Marchesini of Brazil; Dr. Tieman Diarra of Mali; and Dr. Bob Taylor of the UK. PMID:12295474

  11. Identifying Malaria Transmission Foci for Elimination Using Human Mobility Data.

    PubMed

    Ruktanonchai, Nick W; DeLeenheer, Patrick; Tatem, Andrew J; Alegana, Victor A; Caughlin, T Trevor; Zu Erbach-Schoenberg, Elisabeth; Lourenço, Christopher; Ruktanonchai, Corrine W; Smith, David L

    2016-04-01

    Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable. Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent. Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci. By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites. Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred. We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009. This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined. The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort. While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model. PMID:27043913

  12. Impact of climate change on global malaria distribution.

    PubMed

    Caminade, Cyril; Kovats, Sari; Rocklov, Joacim; Tompkins, Adrian M; Morse, Andrew P; Colón-González, Felipe J; Stenlund, Hans; Martens, Pim; Lloyd, Simon J

    2014-03-01

    Malaria is an important disease that has a global distribution and significant health burden. The spatial limits of its distribution and seasonal activity are sensitive to climate factors, as well as the local capacity to control the disease. Malaria is also one of the few health outcomes that has been modeled by more than one research group and can therefore facilitate the first model intercomparison for health impacts under a future with climate change. We used bias-corrected temperature and rainfall simulations from the Coupled Model Intercomparison Project Phase 5 climate models to compare the metrics of five statistical and dynamical malaria impact models for three future time periods (2030s, 2050s, and 2080s). We evaluated three malaria outcome metrics at global and regional levels: climate suitability, additional population at risk and additional person-months at risk across the model outputs. The malaria projections were based on five different global climate models, each run under four emission scenarios (Representative Concentration Pathways, RCPs) and a single population projection. We also investigated the modeling uncertainty associated with future projections of populations at risk for malaria owing to climate change. Our findings show an overall global net increase in climate suitability and a net increase in the population at risk, but with large uncertainties. The model outputs indicate a net increase in the annual person-months at risk when comparing from RCP2.6 to RCP8.5 from the 2050s to the 2080s. The malaria outcome metrics were highly sensitive to the choice of malaria impact model, especially over the epidemic fringes of the malaria distribution. PMID:24596427

  13. Identifying Malaria Transmission Foci for Elimination Using Human Mobility Data

    PubMed Central

    Ruktanonchai, Nick W.; DeLeenheer, Patrick; Tatem, Andrew J.; Alegana, Victor A.; Caughlin, T. Trevor; zu Erbach-Schoenberg, Elisabeth; Lourenço, Christopher; Ruktanonchai, Corrine W.; Smith, David L.

    2016-01-01

    Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable. Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent. Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci. By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites. Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred. We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009. This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined. The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort. While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model. PMID:27043913

  14. Impact of climate change on global malaria distribution

    PubMed Central

    Caminade, Cyril; Kovats, Sari; Rocklov, Joacim; Tompkins, Adrian M.; Morse, Andrew P.; Colón-González, Felipe J.; Stenlund, Hans; Martens, Pim; Lloyd, Simon J.

    2014-01-01

    Malaria is an important disease that has a global distribution and significant health burden. The spatial limits of its distribution and seasonal activity are sensitive to climate factors, as well as the local capacity to control the disease. Malaria is also one of the few health outcomes that has been modeled by more than one research group and can therefore facilitate the first model intercomparison for health impacts under a future with climate change. We used bias-corrected temperature and rainfall simulations from the Coupled Model Intercomparison Project Phase 5 climate models to compare the metrics of five statistical and dynamical malaria impact models for three future time periods (2030s, 2050s, and 2080s). We evaluated three malaria outcome metrics at global and regional levels: climate suitability, additional population at risk and additional person-months at risk across the model outputs. The malaria projections were based on five different global climate models, each run under four emission scenarios (Representative Concentration Pathways, RCPs) and a single population projection. We also investigated the modeling uncertainty associated with future projections of populations at risk for malaria owing to climate change. Our findings show an overall global net increase in climate suitability and a net increase in the population at risk, but with large uncertainties. The model outputs indicate a net increase in the annual person-months at risk when comparing from RCP2.6 to RCP8.5 from the 2050s to the 2080s. The malaria outcome metrics were highly sensitive to the choice of malaria impact model, especially over the epidemic fringes of the malaria distribution. PMID:24596427

  15. The TatD-like DNase of Plasmodium is a virulence factor and a potential malaria vaccine candidate

    PubMed Central

    Chang, Zhiguang; Jiang, Ning; Zhang, Yuanyuan; Lu, Huijun; Yin, Jigang; Wahlgren, Mats; Cheng, Xunjia; Cao, Yaming; Chen, Qijun

    2016-01-01

    Neutrophil extracellular traps (NETs), composed primarily of DNA and proteases, are released from activated neutrophils and contribute to the innate immune response by capturing pathogens. Plasmodium falciparum, the causative agent of severe malaria, thrives in its host by counteracting immune elimination. Here, we report the discovery of a novel virulence factor of P. falciparum, a TatD-like DNase (PfTatD) that is expressed primarily in the asexual blood stage and is likely utilized by the parasite to counteract NETs. PfTatD exhibits typical deoxyribonuclease activity, and its expression is higher in virulent parasites than in avirulent parasites. A P. berghei TatD-knockout parasite displays reduced pathogenicity in mice. Mice immunized with recombinant TatD exhibit increased immunity against lethal challenge. Our results suggest that the TatD-like DNase is an essential factor for the survival of malarial parasites in the host and is a potential malaria vaccine candidate. PMID:27151551

  16. The TatD-like DNase of Plasmodium is a virulence factor and a potential malaria vaccine candidate.

    PubMed

    Chang, Zhiguang; Jiang, Ning; Zhang, Yuanyuan; Lu, Huijun; Yin, Jigang; Wahlgren, Mats; Cheng, Xunjia; Cao, Yaming; Chen, Qijun

    2016-01-01

    Neutrophil extracellular traps (NETs), composed primarily of DNA and proteases, are released from activated neutrophils and contribute to the innate immune response by capturing pathogens. Plasmodium falciparum, the causative agent of severe malaria, thrives in its host by counteracting immune elimination. Here, we report the discovery of a novel virulence factor of P. falciparum, a TatD-like DNase (PfTatD) that is expressed primarily in the asexual blood stage and is likely utilized by the parasite to counteract NETs. PfTatD exhibits typical deoxyribonuclease activity, and its expression is higher in virulent parasites than in avirulent parasites. A P. berghei TatD-knockout parasite displays reduced pathogenicity in mice. Mice immunized with recombinant TatD exhibit increased immunity against lethal challenge. Our results suggest that the TatD-like DNase is an essential factor for the survival of malarial parasites in the host and is a potential malaria vaccine candidate. PMID:27151551

  17. Research toward Malaria Vaccines

    NASA Astrophysics Data System (ADS)

    Miller, Louis H.; Howard, Russell J.; Carter, Richard; Good, Michael F.; Nussenzweig, Victor; Nussenzweig, Ruth S.

    1986-12-01

    Malaria exacts a toll of disease to people in the Tropics that seems incomprehensible to those only familiar with medicine and human health in the developed world. The methods of molecular biology, immunology, and cell biology are now being used to develop an antimalarial vaccine. The Plasmodium parasites that cause malaria have many stages in their life cycle. Each stage is antigenically distinct and potentially could be interrupted by different vaccines. However, achieving complete protection by vaccination may require a better understanding of the complexities of B- and T-cell priming in natural infections and the development of an appropriate adjuvant for use in humans.

  18. Migration and Malaria in Europe

    PubMed Central

    Monge-Maillo, Begoña; López-Vélez, Rogelio

    2012-01-01

    The proportion of imported malaria cases due to immigrants in Europe has increased during the lasts decades, with higher rates associated with settled immigrants who travel to visit friends and relatives (VFRs) in their country of origin. Cases are mainly due to P. falciparum and Sub-Saharan Africa is the most common origin. Clinically, malaria in immigrants is characterised by a mild clinical presentation including asymptomatic or delayed malaria cases and low parasitic levels. These characteristics may be explained by a semi-immunity acquired after long periods of time exposed to stable malaria transmission. Malaria cases among immigrants, even asymptomatic patients with sub-microscopic parasitemia, could increase the risk of transmission and cause the reintroduction of malaria in certain areas that have adequate vectors and climate conditions. Moreover, imported malaria cases in immigrants can also play an important role in the non-vector transmission out of endemic areas, through blood transfusions, organ transplantation or congenital transmission or occupational exposures. Consequently, outside of endemic areas, malaria screening should be carried out among recently arrived immigrants coming from malaria endemic countries. The aim of screening is to reduce the risk of clinical malaria in the individual as well as to prevent autochthonous transmission of malaria in areas where it has been eradicated. PMID:22536477

  19. Osteoclasts Are Required for Hematopoietic Stem and Progenitor Cell Mobilization but Not for Stress Erythropoiesis in Plasmodium chabaudi adami Murine Malaria

    PubMed Central

    Roméro, Hugo; Warburton, Christopher; Sanchez-Dardon, Jaime; Scorza, Tatiana

    2016-01-01

    The anemia and inflammation concurrent with blood stage malaria trigger stress haematopoiesis and erythropoiesis. The activity of osteoclasts seems required for the mobilization of hematopoietic stem and progenitor cells (HSPC) from the bone marrow to the periphery. Knowing that BALB/c mice with acute Plasmodium chabaudi adami malaria have profound alterations in bone remodelling cells, we evaluated the extent to which osteoclasts influence their hematopoietic response to infection. For this, mice were treated with osteoclast inhibiting hormone calcitonin prior to parasite inoculation, and infection as well as hematological parameters was studied. In agreement with osteoclast-dependent HSPC mobilization, administration of calcitonin led to milder splenomegaly, reduced numbers of HSPC in the spleen, and their retention in the bone marrow. Although C-terminal telopeptide (CTX) levels, indicative of bone resorption, were lower in calcitonin-treated infected mice, they remained comparable in naive and control infected mice. Calcitonin-treated infected mice conveniently responded to anemia but generated less numbers of splenic macrophages and suffered from exacerbated infection; interestingly, calcitonin also decreased the number of macrophages generated in vitro. Globally, our results indicate that although osteoclast-dependent HSC mobilization from bone marrow to spleen is triggered in murine blood stage malaria, this activity is not essential for stress erythropoiesis. PMID:26903708

  20. The Plasmodium translocon of exported proteins component EXP2 is critical for establishing a patent malaria infection in mice.

    PubMed

    Kalanon, Ming; Bargieri, Daniel; Sturm, Angelika; Matthews, Kathryn; Ghosh, Sreejoyee; Goodman, Christopher D; Thiberge, Sabine; Mollard, Vanessa; McFadden, Geoffrey I; Ménard, Robert; de Koning-Ward, Tania F

    2016-03-01

    Export of most malaria proteins into the erythrocyte cytosol requires the Plasmodium translocon of exported proteins (PTEX) and a cleavable Plasmodium export element (PEXEL). In contrast, the contribution of PTEX in the liver stages and export of liver stage proteins is unknown. Here, using the FLP/FRT conditional mutatagenesis system, we generate transgenic Plasmodium berghei parasites deficient in EXP2, the putative pore-forming component of PTEX. Our data reveal that EXP2 is important for parasite growth in the liver and critical for parasite transition to the blood, with parasites impaired in their ability to generate a patent blood-stage infection. Surprisingly, whilst parasites expressing a functional PTEX machinery can efficiently export a PEXEL-bearing GFP reporter into the erythrocyte cytosol during a blood stage infection, this same reporter aggregates in large accumulations within the confines of the parasitophorous vacuole membrane during hepatocyte growth. Notably HSP101, the putative molecular motor of PTEX, could not be detected during the early liver stages of infection, which may explain why direct protein translocation of this soluble PEXEL-bearing reporter or indeed native PEXEL proteins into the hepatocyte cytosol has not been observed. This suggests that PTEX function may not be conserved between the blood and liver stages of malaria infection. PMID:26347246

  1. Tutorials for Africa - Malaria: MedlinePlus

    MedlinePlus

    Tutorials for Africa: Malaria In Uganda, the burden of malaria outranks that of all other diseases. This tutorial includes information about how malaria spreads, the importance of treatment and techniques for ...

  2. Malaria on the move: human population movement and malaria transmission.

    PubMed Central

    Martens, P.; Hall, L.

    2000-01-01

    Reports of malaria are increasing in many countries and in areas thought free of the disease. One of the factors contributing to the reemergence of malaria is human migration. People move for a number of reasons, including environmental deterioration, economic necessity, conflicts, and natural disasters. These factors are most likely to affect the poor, many of whom live in or near malarious areas. Identifying and understanding the influence of these population movements can improve prevention measures and malaria control programs. PMID:10756143

  3. Repetitive live sporozoites inoculation under arteether chemoprophylaxis confers protection against subsequent sporozoite challenge in rodent malaria model.

    PubMed

    Bhardwaj, Jyoti; Siddiqui, Arif Jamal; Goyal, Manish; Prakash, Kirtika; Soni, Awakash; Puri, Sunil K

    2016-06-01

    Inoculation with live sporozoites under prophylactic antimalarial cover (CPS-immunization) represents an alternate approach to develop sterile, reproducible, and long-term protection against malaria. Here, we have employed arteether (ART), a semi synthetic derivative of artemisinin to explore its potential as a chemoprophylaxis candidate in CPS approach and systematically compared the protective potential of arteether with mefloquine, azithromycin and primaquine. Blood stage patency and quantitative RT-PCR of liver stage parasite load were monitored as primary key end-points for protection against malaria challenge infection. For this purpose, sequential exposures of Plasmodium yoelii sporozoites under prophylactic treatment with arteether (ART), mefloquine (MFQ), azithromycin (AZ) or primaquine (PQ) was conducted in experimental Swiss mice. Our results show that during the first three sequential exposures (1st, 2nd and 3rd challenge) no marked difference in the blood stage patency was observed between control and CPS-ART group. However, delayed patency was recorded following 4th sporozoite challenge and mice enjoyed sterile protection after 5th sporozoite challenge. A similar response was observed in CPS-MFQ group, whereas earlier protection was recorded in CPS-AZ group i.e., after 4th sprozoite challenge. However, mice under PQ cover did not show any protection/delay in patency even after five sequential sporozoite inoculations, possibly due to inhibition of liver stage development. Furthermore, protection acquired by CPS-immunization is stage-specific as the protected mice remained susceptible to challenge with blood stage parasites. In short, the present study demonstrates that sporozoite administration under ART, MFQ or AZ treatment confers strong protection against subsequent sporozoite infection and the acquired response is dependent on the presence of liver stage parasites. PMID:26925772

  4. Sterile Protective Immunity to Malaria is Associated with a Panel of Novel P. falciparum Antigens*

    PubMed Central

    Trieu, Angela; Kayala, Matthew A.; Burk, Chad; Molina, Douglas M.; Freilich, Daniel A.; Richie, Thomas L.; Baldi, Pierre; Felgner, Philip L.; Doolan, Denise L.

    2011-01-01

    The development of an effective malaria vaccine remains a global public health priority. Less than 0.5% of the Plasmodium falciparum genome has been assessed as potential vaccine targets and candidate vaccines have been based almost exclusively on single antigens. It is possible that the failure to develop a malaria vaccine despite decades of effort might be attributed to this historic focus. To advance malaria vaccine development, we have fabricated protein microarrays representing 23% of the entire P. falciparum proteome and have probed these arrays with plasma from subjects with sterile protection or no protection after experimental immunization with radiation attenuated P. falciparum sporozoites. A panel of 19 pre-erythrocytic stage antigens was identified as strongly associated with sporozoite-induced protective immunity; 16 of these antigens were novel and 85% have been independently identified in sporozoite and/or liver stage proteomic or transcriptomic data sets. Reactivity to any individual antigen did not correlate with protection but there was a highly significant difference in the cumulative signal intensity between protected and not protected individuals. Functional annotation indicates that most of these signature proteins are involved in cell cycle/DNA processing and protein synthesis. In addition, 21 novel blood-stage specific antigens were identified. Our data provide the first evidence that sterile protective immunity against malaria is directed against a panel of novel P. falciparum antigens rather than one antigen in isolation. These results have important implications for vaccine development, suggesting that an efficacious malaria vaccine should be multivalent and targeted at a select panel of key antigens, many of which have not been previously characterized. PMID:21628511

  5. Identification of β-hematin inhibitors in the MMV Malaria Box.

    PubMed

    Fong, Kim Y; Sandlin, Rebecca D; Wright, David W

    2015-12-01

    The Malaria Box, assembled by the Medicines for Malaria Venture, is a set of 400 structurally diverse, commercially available compounds with demonstrated activity against blood-stage Plasmodium falciparum. The compounds are a representative subset of the 20,000 in vitro antimalarials identified from the high-throughput screening efforts of St. Jude Children's Research Hospital (TN, USA), Novartis and GlaxoSmithKline. In addition, a small set of active compounds from commercially available libraries was added to this group, but it has not previously been published. Elucidation of the biochemical pathways on which these compounds act is a major challenge; therefore, access to these compounds has been made available free of charge to the investigator community. Here, the Malaria Box compounds were tested for activity against the formation of β-hematin, a synthetic form of the heme detoxification biomineral, hemozoin. Further, the mechanism of action of these compounds within the malaria parasite was explored. Ten of the Malaria Box compounds demonstrated significant inhibition of β-hematin formation. In this assay, dose-response data revealed IC50 values ranging from 8.7 to 22.7 μM for these hits, each of which is more potent than chloroquine (a known inhibitor of hemozoin formation). The in vitro antimalarial activity of these ten hits was confirmed in cultures of the chloroquine sensitive D6 strain of the parasite resulting in IC50 values of 135-2165 nM, followed by testing in the multidrug resistant strain, C235. Cultures of P. falciparum (D6) were then examined for their heme distribution following treatment with nine of the commercially available confirmed compounds, seven of which disrupted the hemozoin pathway. PMID:26150923

  6. The impact of bed-net use on malaria prevalence

    PubMed Central

    Agusto, Folashade B.; Del Valle, Sara Y.; Blayneh, Kbenesh W.; Ngonghala, Calistus N.; Goncalves, Maria J.; Li, Nianpeng; Zhao, Ruijun; Gong, Hongfei

    2013-01-01

    Malaria infection continues to be a major problem in many parts of the world including the Americas, Asia, and Africa. Insecticide-treated bed-nets have shown to reduce malaria cases by 50%; however, improper handling and human behavior can diminish their effectiveness. We formulate and analyze a mathematical model that considers the transmission dynamics of malaria infection in mosquito and human populations and investigate the impact of bed-nets on its control. The effective reproduction number is derived and existence of backward bifurcation is presented. The backward bifurcation implies that the reduction of R below unity alone is not enough to eradicate malaria, except when the initial cases of infection in both populations are small. Our analysis demonstrate that bed-net usage has a positive impact in reducing the reproduction number R. The results show that if 75% of the population were to use bed-nets, malaria could be eliminated. We conclude that more data on the impact of human and mosquito behavior on malaria spread is needed to develop more realistic models and better predictions. PMID:23246718

  7. Projecting malaria hazard from climate change in eastern Africa using large ensembles to estimate uncertainty.

    PubMed

    Leedale, Joseph; Tompkins, Adrian M; Caminade, Cyril; Jones, Anne E; Nikulin, Grigory; Morse, Andrew P

    2016-01-01

    The effect of climate change on the spatiotemporal dynamics of malaria transmission is studied using an unprecedented ensemble of climate projections, employing three diverse bias correction and downscaling techniques, in order to partially account for uncertainty in climate- driven malaria projections. These large climate ensembles drive two dynamical and spatially explicit epidemiological malaria models to provide future hazard projections for the focus region of eastern Africa. While the two malaria models produce very distinct transmission patterns for the recent climate, their response to future climate change is similar in terms of sign and spatial distribution, with malaria transmission moving to higher altitudes in the East African Community (EAC) region, while transmission reduces in lowland, marginal transmission zones such as South Sudan. The climate model ensemble generally projects warmer and wetter conditions over EAC. The simulated malaria response appears to be driven by temperature rather than precipitation effects. This reduces the uncertainty due to the climate models, as precipitation trends in tropical regions are very diverse, projecting both drier and wetter conditions with the current state-of-the-art climate model ensemble. The magnitude of the projected changes differed considerably between the two dynamical malaria models, with one much more sensitive to climate change, highlighting that uncertainty in the malaria projections is also associated with the disease modelling approach. PMID:27063736

  8. Towards a Predictive Theory of Malaria: Connections to Spatio-temporal Variability of Climate and Hydrology

    NASA Astrophysics Data System (ADS)

    Endo, N.; Eltahir, E. A. B.

    2015-12-01

    Malaria transmission is closely linked to climatology, hydrology, environment, and the biology of local vectors. These factors interact with each other and non-linearly influence malaria transmission dynamics, making prediction and prevention challenging. Our work attempts to find a universality in the multi-dimensional system of malaria transmission and to develop a theory to predict emergence of malaria given a limited set of environmental and biological inputs.A credible malaria transmission dynamics model, HYDREMATS (Bomblies et al., 2008), was used under hypothetical settings to investigate the role of spatial and temporal distribution of vector breeding pools. HYDREMATS is a mechanistic model and capable of simulating the basic reproduction rate (Ro) without bold assumptions even under dynamic conditions. The spatial distribution of pools is mainly governed by hydrological factors; the impact of pool persistence and rainy season length on malaria transmission were investigated. Also analyzed was the impact of the temporal distribution of pools relative to human houses. We developed non-dimensional variables combining the hydrological and biological parameters. Simulated values of Ro from HYDREMATS are presented in a newly-introduced non-dimensional plane, which leads to a some-what universal theory describing the condition for sustainable malaria transmission. The findings were tested against observations both from the West Africa and the Ethiopian Highland, representing diverse hydroclimatological conditions. Predicated Ro values from the theory over the two regions are in good agreement with the observed malaria transmission data.

  9. Rapid diagnostic tests for malaria

    PubMed Central

    Daily, Jennifer; Hotte, Nora; Dolkart, Caitlin; Cunningham, Jane; Yadav, Prashant

    2015-01-01

    Abstract Maintaining quality, competitiveness and innovation in global health technology is a constant challenge for manufacturers, while affordability, access and equity are challenges for governments and international agencies. In this paper we discuss these issues with reference to rapid diagnostic tests for malaria. Strategies to control and eliminate malaria depend on early and accurate diagnosis. Rapid diagnostic tests for malaria require little training and equipment and can be performed by non-specialists in remote settings. Use of these tests has expanded significantly over the last few years, following recommendations to test all suspected malaria cases before treatment and the implementation of an evaluation programme to assess the performance of the malaria rapid diagnostic tests. Despite these gains, challenges exist that, if not addressed, could jeopardize the progress made to date. We discuss recent developments in rapid diagnostic tests for malaria, highlight some of the challenges and provide suggestions to address them. PMID:26668438

  10. Deletion of a Malaria Invasion Gene Reduces Death and Anemia, in Model Hosts

    PubMed Central

    Gómez, Noé D.; Safeukui, Innocent; Adelani, Aanuoluwa A.; Tewari, Rita; Reddy, Janardan K.; Rao, Sam; Holder, Anthony; Buffet, Pierre; Mohandas, Narla; Haldar, Kasturi

    2011-01-01

    Malaria parasites induce complex cellular and clinical phenotypes, including anemia, cerebral malaria and death in a wide range of mammalian hosts. Host genes and parasite ‘toxins’ have been implicated in malarial disease, but the contribution of parasite genes remains to be fully defined. Here we assess disease in BALB/c mice and Wistar rats infected by the rodent malaria parasite Plasmodium berghei with a gene knock out for merozoite surface protein (MSP) 7. MSP7 is not essential for infection but in P. falciparum, it enhances erythrocyte invasion by 20%. In vivo, as compared to wild type, the P. berghei Δmsp7 mutant is associated with an abrogation of death and a decrease from 3% to 2% in peak, circulating parasitemia. The Δmsp7 mutant is also associated with less anemia and modest increase in the size of follicles in the spleen. Together these data show that deletion of a single parasite invasion ligand modulates blood stage disease, as measured by death and anemia. This work is the first to assess the contribution of a gene present in all plasmodial species in severe disease. PMID:21980474

  11. N'Dribala (Cochlospermum planchonii) versus chloroquine for treatment of uncomplicated Plasmodium falciparum malaria.

    PubMed

    Benoit-Vical, F; Valentin, A; Da, B; Dakuyo, Z; Descamps, L; Mallié, M

    2003-11-01

    The aim of this work was to assess the efficacy of oral N'Dribala (tuberous roots decoction of Cochlospermum planchonii Hook) treatment versus chloroquine in non-severe malaria. The study included 85 patients with uncomplicated Plasmodium falciparum infection in Banfora, Burkina Faso. Forty-six patients that received N'Dribala beverage were compared to 21 patients treated with chloroquine. All patients were monitored with clinical examination and a parasitemia control by Giemsa-stained thick films. N'Dribala appeared safe and statistically as efficient as chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. At day 5 (D5), 57% of chloroquine-treated and 52% of N'Dribala-treated patients were cured with no detectable parasitemia (parasite density (Pd): 0) and more than 90% of whole patients were asymptomatic. N'Dribala is easily available in this country, cheap, without significant side effects and efficient with a clearly demonstrated activity on Plasmodium falciparum blood stages. This study enhances the traditional use of the Cochlospermum planchonii as alternative therapy for treatment of non-severe malaria. PMID:14522441

  12. Host-parasite interactions that guide red blood cell invasion by malaria parasites

    PubMed Central

    Paul, Aditya S.; Egan, Elizabeth S.; Duraisingh, Manoj T.

    2015-01-01

    Purpose of Review Malaria is caused by the infection and proliferation of parasites from the genus Plasmodium in red blood cells (RBCs). A free Plasmodium parasite, or merozoite, released from an infected RBC must invade another RBC host cell to sustain a blood-stage infection. Here, we review recent advances on RBC invasion by Plasmodium merozoites, focusing on specific molecular interactions between host and parasite. Recent findings Recent work highlights the central role of host-parasite interactions at virtually every stage of RBC invasion by merozoites. Biophysical experiments have for the first time measured the strength of merozoite-RBC attachment during invasion. For P. falciparum, there have been many key insights regarding the invasion ligand PfRh5 in particular, including its influence on host species tropism, a co-crystal structure with its RBC receptor basigin, and its suitability as a vaccine target. For P. vivax, researchers identified the origin and emergence of the parasite from Africa, demonstrating a natural link to the Duffy-negative RBC variant in African populations. For the simian parasite P. knowlesi, zoonotic invasion into human cells is linked to RBC age, which has implications for parasitemia during an infection and thus malaria. Summary New studies of the molecular and cellular mechanisms governing RBC invasion by Plasmodium parasites have shed light on various aspects of parasite biology and host cell tropism; and indicate opportunities for malaria control. PMID:25767956

  13. Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

    PubMed Central

    Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

    2015-01-01

    Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. PMID:25759576

  14. Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria

    PubMed Central

    Ruangweerayut, Ronnatrai; Looareesuwan, Sornchai; Hutchinson, David; Chauemung, Anurak; Banmairuroi, Vick; Na-Bangchang, Kesara

    2008-01-01

    Background This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. Methods A total of 70 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows: Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54). Results Both regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent Cmax: 3.74 vs 2.41 μg/ml; Cmax-ss: 2.80 vs 2.08 μg/ml; Cmax-min-ss: 2.03 vs 0.71 μg/ml; AUC: 23.31 vs 10.63 μg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, Cmin-ss was lower in this group (0.80 vs 1.37 μg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, Vz/F) and elimination half-life (t1/2z, t1/2e) were also significantly different between the two dosage regimens. In addition

  15. A dynamic model of some malaria-transmitting anopheline mosquitoes of the Afrotropical region. II. Validation of species distribution and seasonal variations

    PubMed Central

    2013-01-01

    Background The first part of this study aimed to develop a model for Anopheles gambiae s.l. with separate parametrization schemes for Anopheles gambiae s.s. and Anopheles arabiensis. The characterizations were constructed based on literature from the past decades. This part of the study is focusing on the model’s ability to separate the mean state of the two species of the An. gambiae complex in Africa. The model is also evaluated with respect to capturing the temporal variability of An. arabiensis in Ethiopia. Before conclusions and guidance based on models can be made, models need to be validated. Methods The model used in this paper is described in part one (Malaria Journal 2013, 12:28). For the validation of the model, a data base of 5,935 points on the presence of An. gambiae s.s. and An. arabiensis was constructed. An additional 992 points were collected on the presence An. gambiae s.l.. These data were used to assess if the model could recreate the spatial distribution of the two species. The dataset is made available in the public domain. This is followed by a case study from Madagascar where the model’s ability to recreate the relative fraction of each species is investigated. In the last section the model’s ability to reproduce the temporal variability of An. arabiensis in Ethiopia is tested. The model was compared with data from four papers, and one field survey covering two years. Results Overall, the model has a realistic representation of seasonal and year to year variability in mosquito densities in Ethiopia. The model is also able to describe the distribution of An. gambiae s.s. and An. arabiensis in sub-Saharan Africa. This implies this model can be used for seasonal and long term predictions of changes in the burden of malaria. Before models can be used to improving human health, or guide which interventions are to be applied where, there is a need to understand the system of interest. Validation is an important part of this process. It is

  16. Epidemic and Endemic Malaria Transmission Related to Fish Farming Ponds in the Amazon Frontier

    PubMed Central

    Barcellos, Christovam; Kitron, Uriel; Camara, Daniel Cardoso Portela; Pereira, Glaucio Rocha; Keppeler, Erlei Cassiano; da Silva-Nunes, Mônica

    2015-01-01

    Fish farming in the Amazon has been stimulated as a solution to increase economic development. However, poorly managed fish ponds have been sometimes associated with the presence of Anopheles spp. and consequently, with malaria transmission. In this study, we analyzed the spatial and temporal dynamics of malaria in the state of Acre (and more closely within a single county) to investigate the potential links between aquaculture and malaria transmission in this region. At the state level, we classified the 22 counties into three malaria endemicity patterns, based on the correlation between notification time series. Furthermore, the study period (2003–2013) was divided into two phases (epidemic and post-epidemic). Higher fish pond construction coincided both spatially and temporally with increased rate of malaria notification. Within one malaria endemic county, we investigated the relationship between the geolocation of malaria cases (2011–2012) and their distance to fish ponds. Entomological surveys carried out in these ponds provided measurements of anopheline abundance that were significantly associated with the abundance of malaria cases within 100 m of the ponds (P < 0.005; r = 0.39). These results taken together suggest that fish farming contributes to the maintenance of high transmission levels of malaria in this region. PMID:26361330

  17. Visualizing the uncertainty in the relationship between seasonal average climate and malaria risk

    PubMed Central

    MacLeod, D. A.; Morse, A. P.

    2014-01-01

    Around $1.6 billion per year is spent financing anti-malaria initiatives, and though malaria morbidity is falling, the impact of annual epidemics remains significant. Whilst malaria risk may increase with climate change, projections are highly uncertain and to sidestep this intractable uncertainty, adaptation efforts should improve societal ability to anticipate and mitigate individual events. Anticipation of climate-related events is made possible by seasonal climate forecasting, from which warnings of anomalous seasonal average temperature and rainfall, months in advance are possible. Seasonal climate hindcasts have been used to drive climate-based models for malaria, showing significant skill for observed malaria incidence. However, the relationship between seasonal average climate and malaria risk remains unquantified. Here we explore this relationship, using a dynamic weather-driven malaria model. We also quantify key uncertainty in the malaria model, by introducing variability in one of the first order uncertainties in model formulation. Results are visualized as location-specific impact surfaces: easily integrated with ensemble seasonal climate forecasts, and intuitively communicating quantified uncertainty. Methods are demonstrated for two epidemic regions, and are not limited to malaria modeling; the visualization method could be applied to any climate impact. PMID:25449318

  18. The epidemiology of malaria in adults in a rural area of southern Mozambique

    PubMed Central

    Mayor, Alfredo; Aponte, John J; Fogg, Carole; Saúte, Francisco; Greenwood, Brian; Dgedge, Martinho; Menendez, Clara; Alonso, Pedro L

    2007-01-01

    Background Epidemiological studies of malaria in adults who live in malaria endemic areas are scarce. More attention to the natural history of malaria affecting adults is needed to understand the dynamics of malaria infection and its interaction with the immune system. The present study was undertaken to investigate the clinical, parasitological and haematological status of adults exposed to malaria, and to characterize parasites in these individuals who progressively acquire protective immunity. Methods A cross-sectional survey of 249 adults was conducted in a malaria endemic area of Mozambique. Clinical, parasitological and haematological status of the study population was recorded. Sub-microscopic infections and multiplicity of infections were investigated using polymerase chain reaction (PCR) and restriction fragment length polymorphism of Plasmodium falciparum merozoite surface protein 2 (msp2). Results Prevalence of P. falciparum infection by microscopy (14%) and PCR (42%) decreased progressively during adulthood, in parallel with an increase in the prevalence of sub-microscopic infections. Anaemia was only related to parasitaemia as detected by PCR. Multiplicity of infection decreased with age and was higher in subjects with high P. falciparum densities, highlighting density-dependent constraints upon the PCR technique. Conclusion Adults of Manhiça progressively develop non-sterile, protective immunity against P. falciparum malaria. The method of parasite detection has a significant effect on the observed natural history of malaria infections. A more sensitive definition of malaria in adults should be formulated, considering symptoms such as diarrhoea, shivering and headache, combined with the presence of parasitaemia. PMID:17233881

  19. Visualizing the uncertainty in the relationship between seasonal average climate and malaria risk.

    PubMed

    MacLeod, D A; Morse, A P

    2014-01-01

    Around $1.6 billion per year is spent financing anti-malaria initiatives, and though malaria morbidity is falling, the impact of annual epidemics remains significant. Whilst malaria risk may increase with climate change, projections are highly uncertain and to sidestep this intractable uncertainty, adaptation efforts should improve societal ability to anticipate and mitigate individual events. Anticipation of climate-related events is made possible by seasonal climate forecasting, from which warnings of anomalous seasonal average temperature and rainfall, months in advance are possible. Seasonal climate hindcasts have been used to drive climate-based models for malaria, showing significant skill for observed malaria incidence. However, the relationship between seasonal average climate and malaria risk remains unquantified. Here we explore this relationship, using a dynamic weather-driven malaria model. We also quantify key uncertainty in the malaria model, by introducing variability in one of the first order uncertainties in model formulation. Results are visualized as location-specific impact surfaces: easily integrated with ensemble seasonal climate forecasts, and intuitively communicating quantified uncertainty. Methods are demonstrated for two epidemic regions, and are not limited to malaria modeling; the visualization method could be applied to any climate impact. PMID:25449318

  20. Epidemic and Endemic Malaria Transmission Related to Fish Farming Ponds in the Amazon Frontier.

    PubMed

    Reis, Izabel Cristina Dos; Honório, Nildimar Alves; Barros, Fábio Saito Monteiro de; Barcellos, Christovam; Kitron, Uriel; Camara, Daniel Cardoso Portela; Pereira, Glaucio Rocha; Keppeler, Erlei Cassiano; da Silva-Nunes, Mônica; Codeço, Cláudia Torres

    2015-01-01

    Fish farming in the Amazon has been stimulated as a solution to increase economic development. However, poorly managed fish ponds have been sometimes associated with the presence of Anopheles spp. and consequently, with malaria transmission. In this study, we analyzed the spatial and temporal dynamics of malaria in the state of Acre (and more closely within a single county) to investigate the potential links between aquaculture and malaria transmission in this region. At the state level, we classified the 22 counties into three malaria endemicity patterns, based on the correlation between notification time series. Furthermore, the study period (2003-2013) was divided into two phases (epidemic and post-epidemic). Higher fish pond construction coincided both spatially and temporally with increased rate of malaria notification. Within one malaria endemic county, we investigated the relationship between the geolocation of malaria cases (2011-2012) and their distance to fish ponds. Entomological surveys carried out in these ponds provided measurements of anopheline abundance that were significantly associated with the abundance of malaria cases within 100 m of the ponds (P < 0.005; r = 0.39). These results taken together suggest that fish farming contributes to the maintenance of high transmission levels of malaria in this region. PMID:26361330

  1. Visualizing the uncertainty in the relationship between seasonal average climate and malaria risk

    NASA Astrophysics Data System (ADS)

    MacLeod, D. A.; Morse, A. P.

    2014-12-01

    Around $1.6 billion per year is spent financing anti-malaria initiatives, and though malaria morbidity is falling, the impact of annual epidemics remains significant. Whilst malaria risk may increase with climate change, projections are highly uncertain and to sidestep this intractable uncertainty, adaptation efforts should improve societal ability to anticipate and mitigate individual events. Anticipation of climate-related events is made possible by seasonal climate forecasting, from which warnings of anomalous seasonal average temperature and rainfall, months in advance are possible. Seasonal climate hindcasts have been used to drive climate-based models for malaria, showing significant skill for observed malaria incidence. However, the relationship between seasonal average climate and malaria risk remains unquantified. Here we explore this relationship, using a dynamic weather-driven malaria model. We also quantify key uncertainty in the malaria model, by introducing variability in one of the first order uncertainties in model formulation. Results are visualized as location-specific impact surfaces: easily integrated with ensemble seasonal climate forecasts, and intuitively communicating quantified uncertainty. Methods are demonstrated for two epidemic regions, and are not limited to malaria modeling; the visualization method could be applied to any climate impact.

  2. Malaria elimination: surveillance and response

    PubMed Central

    Bridges, Daniel J; Winters, Anna M; Hamer, Davidson H

    2012-01-01

    In the last decade, substantial progress has been made in reducing malaria-associated morbidity and mortality across the globe. Nevertheless, sustained malaria control is essential to continue this downward trend. In some countries, where aggressive malaria control has reduced malaria to a low burden level, elimination, either nationally or subnationally, is now the aim. As countries or areas with a low malaria burden move towards elimination, there is a transition away from programs of universal coverage towards a strategy of localized detection and response to individual malaria cases. To do so and succeed, it is imperative that a strong surveillance and response system is supported, that community cadres are trained to provide appropriate diagnostics and treatment, and that field diagnostics are further developed such that their sensitivity allows for the detection and subsequent treatment of malaria reservoirs in low prevalence environments. To be certain, there are big challenges on the road to elimination, notably the development of drug and insecticide resistance. Nevertheless, countries like Zambia are making great strides towards implementing systems that support malaria elimination in target areas. Continued development of new diagnostics and antimalarial therapies is needed to support progress in malaria control and elimination. PMID:23265423

  3. Concurrent meningitis and vivax malaria

    PubMed Central

    Santra, Tuhin; Datta, Sumana; Agrawal, Neha; Bar, Mita; Kar, Arnab; Adhikary, Apu; Ranjan, Kunal

    2015-01-01

    Malaria is an endemic infectious disease in India. It is often associated with other infective conditions but concomitant infection of malaria and meningitis are uncommon. We present a case of meningitis with vivax malaria infection in a 24-year-old lady. This case emphasizes the importance of high index of clinical suspicion to detect other infective conditions like meningitis when fever does not improve even after anti-malarial treatment in a patient of malaria before switching therapy suspecting drug resistance, which is quite common in this part of world. PMID:26985423

  4. Establishment of a murine model of cerebral malaria in KunMing mice infected with Plasmodium berghei ANKA.

    PubMed

    Ding, Yan; Xu, Wenyue; Zhou, Taoli; Liu, Taiping; Zheng, Hong; Fu, Yong

    2016-10-01

    Malaria remains one of the most devastating diseases. Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection resulting in high mortality and morbidity worldwide. Analysis of precise mechanisms of CM in humans is difficult for ethical reasons and animal models of CM have been employed to study malaria pathogenesis. Here, we describe a new experimental cerebral malaria (ECM) model with Plasmodium berghei ANKA infection in KunMing (KM) mice. KM mice developed ECM after blood-stage or sporozoites infection, and the development of ECM in KM mice has a dose-dependent relationship with sporozoites inoculums. Histopathological findings revealed important features associated with ECM, including accumulation of mononuclear cells and red blood cells in brain microvascular, and brain parenchymal haemorrhages. Blood-brain barrier (BBB) examination showed that BBB disruption was present in infected KM mice when displaying clinical signs of CM. In vivo bioluminescent imaging experiment indicated that parasitized red blood cells accumulated in most vital organs including heart, lung, spleen, kidney, liver and brain. The levels of inflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, interleukin (IL)-17, IL-12, IL-6 and IL-10 were all remarkably increased in KM mice infected with P. berghei ANKA. This study indicates that P. berghei ANKA infection in KM mice can be used as ECM model to extend further research on genetic, pharmacological and vaccine studies of CM. PMID:27574013

  5. Malaria control in Tanzania

    SciTech Connect

    Yhdego, M.; Majura, P. )

    1988-01-01

    A review of the malaria control programs and the problem encountered in the United Republic of Tanzania since 1945 to the year 1986 is discussed. Buguruni, one of the squatter areas in the city of Dar es Salaam, is chosen as a case study in order to evaluate the economic advantage of engineering methods for the control of malaria infection. Although the initial capital cost of engineering methods may be high, the cost effectiveness requires a much lower financial burden of only about Tshs. 3 million compared with the conventional methods of larviciding and insecticiding which requires more than Tshs. 10 million. Finally, recommendations for the adoption of engineering methods are made concerning the upgrading of existing roads and footpaths in general with particular emphasis on drainage of large pools of water which serve as breeding sites for mosquitoes.

  6. The Dynamics of Natural Plasmodium falciparum Infections

    PubMed Central

    Felger, Ingrid; Maire, Martin; Bretscher, Michael T.; Falk, Nicole; Tiaden, André; Sama, Wilson; Beck, Hans-Peter; Owusu-Agyei, Seth; Smith, Thomas A.

    2012-01-01

    Background Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood. Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super-infection and imperfect detectability of parasites. Consequently, information on effects of host immune status or age on infection dynamics is fragmentary. Methods An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals. High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR. Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites. Results Allowing for imperfect detection substantially increased estimates of FOI and duration. Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children. Persistence of individual parasite clones was characteristic of all age-groups. Duration peaked in 5–9 year old children (average duration 319 days, 95% confidence interval 318;320). Conclusions The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections. This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections. PMID:23029082

  7. Oxidative Stress in Malaria

    PubMed Central

    Percário, Sandro; Moreira, Danilo R.; Gomes, Bruno A. Q.; Ferreira, Michelli E. S.; Gonçalves, Ana Carolina M.; Laurindo, Paula S. O. C.; Vilhena, Thyago C.; Dolabela, Maria F.; Green, Michael D.

    2012-01-01

    Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise. In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy. PMID:23208374

  8. Artemether for severe malaria

    PubMed Central

    Esu, Ekpereonne; Effa, Emmanuel E; Opie, Oko N; Uwaoma, Amirahobu; Meremikwu, Martin M

    2014-01-01

    Background In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation, many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. This review evaluates intramuscular artemether compared with both quinine and artesunate. Objectives To assess the efficacy and safety of intramuscular artemether versus any other parenteral medication in treating severe malaria in adults and children. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS, ISI Web of Science, conference proceedings and reference lists of articles. We also searched the WHO clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 9 April 2014. Selection criteria Randomized controlled trials (RCTs) comparing intramuscular artemether with intravenous or intramuscular antimalarial for treating severe malaria. Data collection and analysis The primary outcome was all-cause death.Two authors independently assessed trial eligibility, risk of bias and extracted data. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), and presented both measures with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses and assessed the quality of the evidence using the GRADE approach. Main results We included 18 RCTs, enrolling 2662 adults and children with severe malaria, carried out in Africa (11) and in Asia (7). Artemether versus quinine For children in Africa, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.96, 95% CI 0.76 to 1.20; 12 trials, 1447 participants, moderate quality evidence). Coma recovery may be about five hours shorter with

  9. Folate metabolism in malaria

    PubMed Central

    Ferone, Robert

    1977-01-01

    It is known that malaria parasites are inhibited by sulfonamides and antifolate compounds, require 4-aminobenzoic acid for growth, and respond only partly to intact folic and folinic acids. Biochemical data obtained during the last decade on the synthesis of nucleic acid precursors and on folate enzymes in malaria support the hypothesis that malaria parasites are similar to microorganisms that synthesize folate cofactors de novo. Sulfa drugs inhibit plasmodial dihydropteroate synthase (EC 2.5.1.15). Pyrimethamine and many other antifolate compounds bind to tetrahydrofolate dehydrogenase (EC 1.5.1.3) of the parasite more tightly than to the host enzyme. However, the metabolic consequences of the depletion of folate cofactors as a result of drug inhibition are not yet known. Other areas to be studied are the origin of the pteridine moiety of folates, the addition of glutamate(s) in folate cofactor biosynthesis, the means by which intact, exogenous folates affect malarial growth, and demonstration of the enzymes and reactions involving N5-methyl tetrahydrofolate. PMID:338184

  10. Roll Back Malaria.

    PubMed

    Nabarro, D

    1999-09-01

    Roll Back Malaria is an initiative intended to halve the suffering caused by this disease by 2010. The initiative is being developed as a social movement. Action is directed by national authorities backed by a global partnership which consists of development agencies, banks, private sector groups and researchers. The World Health Organization, the World Bank, UNICEF and UNDP founded the partnership in October 1998. The WHO has established a new Cabinet Project, and a WHO-wide strategy and workplan, to support the partnership. High quality, practical, consistent and relevant technical advice is made available through networks of experts based in research, academic, and disease control institutions, particularly those in endemic countries. The initiative also supports research and development of new products and tools to control malaria. Implementation of Roll Back Malaria began with a series of in-country consultations in 1998, followed by sub-regional consensus building and inception meetings. The current period is one of momentum building at country level during which national authorities are developing their own strategies with the global partners. It is anticipated that, during the year 2000, RBM movements will become active in at least 30 countries. PMID:10697910

  11. Profiling the host response to malaria vaccination and malaria challenge.

    PubMed

    Dunachie, Susanna; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research. PMID:26256528

  12. Profiling the host response to malaria vaccination and malaria challenge

    PubMed Central

    Dunachie, Susanna; Hill, Adrian V.S.; Fletcher, Helen A.

    2015-01-01

    A vaccine for malaria is urgently required. The RTS,S vaccine represents major progress, but is only partially effective. Development of the next generation of highly effective vaccines requires elucidation of the protective immune response. Immunity to malaria is known to be complex, and pattern-based approaches such as global gene expression profiling are ideal for understanding response to vaccination and protection against disease. The availability of experimental sporozoite challenge in humans to test candidate malaria vaccines offers a precious opportunity unavailable for other current targets of vaccine research such as HIV, tuberculosis and Ebola. However, a limited number of transcriptional profiling studies in the context of malaria vaccine research have been published to date. This review outlines the background, existing studies, limits and opportunities for gene expression studies to accelerate malaria vaccine research. PMID:26256528

  13. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships

    PubMed Central

    Walker, Karen M; Okitsu, Shinji; Porter, David W; Duncan, Christopher; Amacker, Mario; Pluschke, Gerd; Cavanagh, David R; Hill, Adrian V S; Todryk, Stephen M

    2015-01-01

    This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11–12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119, correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. PMID:25471322

  14. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships.

    PubMed

    Walker, Karen M; Okitsu, Shinji; Porter, David W; Duncan, Christopher; Amacker, Mario; Pluschke, Gerd; Cavanagh, David R; Hill, Adrian V S; Todryk, Stephen M

    2015-05-01

    This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119 , correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. PMID:25471322

  15. Malaria vector species in Colombia: a review.

    PubMed

    Montoya-Lerma, James; Solarte, Yezid A; Giraldo-Calderón, Gloria Isabel; Quiñones, Martha L; Ruiz-López, Freddy; Wilkerson, Richard C; González, Ranulfo

    2011-08-01

    Here we present a comprehensive review of the literature on the vectorial importance of the major Anopheles malaria vectors in Colombia. We provide basic information on the geographical distribution, altitudinal range, immature habitats, adult behaviour, feeding preferences and anthropophily, endophily and infectivity rates. We additionally review information on the life cycle, longevity and population fluctuation of Colombian Anopheles species. Emphasis was placed on the primary vectors that have been epidemiologically incriminated in malaria transmission: Anopheles darlingi, Anopheles albimanus and Anopheles nuneztovari. The role of a selection of local, regional or secondary vectors (e.g., Anopheles pseudopunctipennis and Anopheles neivai) is also discussed. We highlight the importance of combining biological, morphological and molecular data for the correct taxonomical determination of a given species, particularly for members of the species complexes. We likewise emphasise the importance of studying the bionomics of primary and secondary vectors along with an examination of the local conditions affecting the transmission of malaria. The presence and spread of the major vectors and the emergence of secondary species capable of transmitting human Plasmodia are of great interest. When selecting control measures, the anopheline diversity in the region must be considered. Variation in macroclimate conditions over a species' geographical range must be well understood and targeted to plan effective control measures based on the population dynamics of the local Anopheles species. PMID:21881778

  16. Predicting optimal transmission investment in malaria parasites.

    PubMed

    Greischar, Megan A; Mideo, Nicole; Read, Andrew F; Bjørnstad, Ottar N

    2016-07-01

    In vertebrate hosts, malaria parasites face a tradeoff between replicating and the production of transmission stages that can be passed onto mosquitoes. This tradeoff is analogous to growth-reproduction tradeoffs in multicellular organisms. We use a mathematical model tailored to the life cycle and dynamics of malaria parasites to identify allocation strategies that maximize cumulative transmission potential to mosquitoes. We show that plastic strategies can substantially outperform fixed allocation because parasites can achieve greater fitness by investing in proliferation early and delaying the production of transmission stages. Parasites should further benefit from restraining transmission investment later in infection, because such a strategy can help maintain parasite numbers in the face of resource depletion. Early allocation decisions are predicted to have the greatest impact on parasite fitness. If the immune response saturates as parasite numbers increase, parasites should benefit from even longer delays prior to transmission investment. The presence of a competing strain selects for consistently lower levels of transmission investment and dramatically increased exploitation of the red blood cell resource. While we provide a detailed analysis of tradeoffs pertaining to malaria life history, our approach for identifying optimal plastic allocation strategies may be broadly applicable. PMID:27271841

  17. Malaria vector species in Colombia - A review

    PubMed Central

    Montoya-Lerma, James; Solarte, Yezid A; Giraldo-Calderón, Gloria Isabel; Quiñones, Martha L; Ruiz-López, Freddy; Wilkerson, Richard C; González, Ranulfo

    2016-01-01

    Here we present a comprehensive review of the literature on the vectorial importance of the major Anopheles malaria vectors in Colombia. We provide basic information on the geographical distribution, altitudinal range, immature habitats, adult behaviour, feeding preferences and anthropophily, endophily and infectivity rates. We additionally review information on the life cycle, longevity and population fluctuation of Colombian Anopheles species. Emphasis was placed on the primary vectors that have been epidemiologically incriminated in malaria transmission: Anopheles darlingi, Anopheles albimanus and Anopheles nuneztovari. The role of a selection of local, regional or secondary vectors (e.g., Anopheles pseudopunctipennis and Anopheles neivai) is also discussed. We highlight the importance of combining biological, morphological and molecular data for the correct taxonomical determination of a given species, particularly for members of the species complexes. We likewise emphasise the importance of studying the bionomics of primary and secondary vectors along with an examination of the local conditions affecting the transmission of malaria. The presence and spread of the major vectors and the emergence of secondary species capable of transmitting human Plasmodia are of great interest. When selecting control measures, the anopheline diversity in the region must be considered. Variation in macroclimate conditions over a species’ geographical range must be well understood and targeted to plan effective control measures based on the population dynamics of the local Anopheles species. PMID:21881778

  18. Immunogenicity and protection from malaria infection in BK-SE36 vaccinated volunteers in Uganda is not influenced by HLA-DRB1 alleles.

    PubMed

    Tougan, Takahiro; Ito, Kazuya; Palacpac, Nirianne Marie Q; Egwang, Thomas G; Horii, Toshihiro

    2016-10-01

    SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Designated as BK-SE36, the SE36 antigen was formulated with aluminum hydroxyl gel (AHG) and produced under Good Manufacturing Practice (GMP) constraints. In a Phase Ib clinical trial and follow-up study in Uganda, the risk for malaria symptoms was reduced by 72% compared with the control group. Although promising, the number of responders to the vaccine in 6-20years-olds was approximately 30% with the majority in the younger cohort. This is in contrast to the phase Ia clinical trial where response to the vaccine was 100% in Japanese malaria naive adults. A consideration that can be of importance is the involvement of host genetic factors that may influence the ability to mount an effective immune response to vaccination as well as susceptibility to malaria infection. We, therefore, analyzed allelic polymorphism of human leukocyte antigen (HLA)-DRB1 alleles using sequence-based typing (SBT). In this study, DRB1 alleles did not influence antibody response to BK-SE36 and the vaccinees susceptibility to clinical malaria. PMID:27343834

  19. Quantification of Plasmodium falciparum malaria from complex infections in the Peruvian Amazon using quantitative PCR of the merozoite surface protein 1, block 2 (PfMSP1-B2): in vitro dynamics reveal density-dependent interactions.

    PubMed

    Zervos, Thomas M; Hernandez, Jean N; Sutton, Patrick L; Branch, Oralee H

    2012-05-01

    The majority of Plasmodium falciparum field isolates are defined as complex infections because they contain multiple genetically distinct clones. Studying interactions between clones in complex infections in vivo and in vitro could elucidate important phenomena in malaria infection, transmission and treatment. Using quantitative PCR (qPCR) of the P. falciparum merozoite surface protein 1, block 2 (PfMSP1-B2), we provide a sensitive and efficient genotyping method. This is important for epidemiological studies because it makes it possible to study genotype-specific growth dynamics. We compared 3 PfMSP1-B2 genotyping methods by analysing 79 field isolates from the Peruvian Amazon. In vivo observations from other studies using these techniques led to the hypothesis that clones within complex infections interact. By co-culturing clones with different PfMSP1-B2 genotypes, and measuring parasitaemia using qPCR, we found that suppression of clonal expansion was a factor of the collective density of all clones present in a culture. PfMSP1-B2 qPCR enabled us to find in vitro evidence for parasite-parasite interactions and could facilitate future investigations of growth trends in naturally occurring complex infections. PMID:22339946

  20. Malaria diagnostics in clinical trials.

    PubMed

    Murphy, Sean C; Shott, Joseph P; Parikh, Sunil; Etter, Paige; Prescott, William R; Stewart, V Ann

    2013-11-01

    Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests. PMID:24062484

  1. Newer approaches to malaria control

    PubMed Central

    Damodaran, SE; Pradhan, Prita; Pradhan, Suresh Chandra

    2011-01-01

    Malaria is the third leading cause of death due to infectious diseases affecting around 243 million people, causing 863,000 deaths each year, and is a major public health problem. Most of the malarial deaths occur in children below 5 years and is a major contributor of under-five mortality. As a result of environmental and climatic changes, there is a change in vector population and distribution, leading to resurgence of malaria at numerous foci. Resistance to antimalarials is a major challenge to malaria control and there are new drug developments, new approaches to treatment strategies, combination therapy to overcome resistance and progress in vaccine development. Now, artemisinin-based combination therapy is the first-line therapy as the malarial parasite has developed resistance to other antimalarials. Reports of artemisinin resistance are appearing and identification of new drug targets gains utmost importance. As there is a shift from malaria control to malaria eradication, more research is focused on malaria vaccine development. A malaria vaccine, RTS,S, is in phase III of development and may become the first successful one. Due to resistance to insecticides and lack of environmental sanitation, the conventional methods of vector control are turning out to be futile. To overcome this, novel strategies like sterile insect technique and transgenic mosquitoes are pursued for effective vector control. As a result of the global organizations stepping up their efforts with continued research, eradication of malaria can turn out to be a reality. PMID:23508211

  2. Malaria Diagnostics in Clinical Trials

    PubMed Central

    Murphy, Sean C.; Shott, Joseph P.; Parikh, Sunil; Etter, Paige; Prescott, William R.; Stewart, V. Ann

    2013-01-01

    Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests. PMID:24062484

  3. Mathematical models of malaria - a review

    PubMed Central

    2011-01-01

    Mathematical models have been used to provide an explicit framework for understanding malaria transmission dynamics in human population for over 100 years. With the disease still thriving and threatening to be a major source of death and disability due to changed environmental and socio-economic conditions, it is necessary to make a critical assessment of the existing models, and study their evolution and efficacy in describing the host-parasite biology. In this article, starting from the basic Ross model, the key mathematical models and their underlying features, based on their specific contributions in the understanding of spread and transmission of malaria have been discussed. The first aim of this article is to develop, starting from the basic models, a hierarchical structure of a range of deterministic models of different levels of complexity. The second objective is to elaborate, using some of the representative mathematical models, the evolution of modelling strategies to describe malaria incidence by including the critical features of host-vector-parasite interactions. Emphasis is more on the evolution of the deterministic differential equation based epidemiological compartment models with a brief discussion on data based statistical models. In this comprehensive survey, the approach has been to summarize the modelling activity in this area so that it helps reach a wider range of researchers working on epidemiology, transmission, and other aspects of malaria. This may facilitate the mathematicians to further develop suitable models in this direction relevant to the present scenario, and help the biologists and public health personnel to adopt better understanding of the modelling strategies to control the disease PMID:21777413

  4. Using rainfall estimates to predict malaria transmission

    NASA Astrophysics Data System (ADS)

    Tretkoff, Ernie

    2011-05-01

    Malaria kills nearly a million people each year, mostly in rural Africa. The disease is spread by mosquitoes, which thrive in wet areas, so malaria transmission is closely linked to rainfall. Rainfall estimates could therefore be used to help predict potential malaria transmission. However, rain gauge networks are sparse in many of the rural areas that are hit hardest by malaria.

  5. Progress with new malaria vaccines.

    PubMed Central

    Webster, Daniel; Hill, Adrian V. S.

    2003-01-01

    Malaria is a parasitic disease of major global health significance that causes an estimated 2.7 million deaths each year. In this review we describe the burden of malaria and discuss the complicated life cycle of Plasmodium falciparum, the parasite responsible for most of the deaths from the disease, before reviewing the evidence that suggests that a malaria vaccine is an attainable goal. Significant advances have recently been made in vaccine science, and we review new vaccine technologies and the evaluation of candidate malaria vaccines in human and animal studies worldwide. Finally, we discuss the prospects for a malaria vaccine and the need for iterative vaccine development as well as potential hurdles to be overcome. PMID:14997243

  6. N-terminal processing of proteins exported by malaria parasites

    PubMed Central

    Chang, Henry H.; Falick, Arnold M.; Carlton, Peter M.; Sedat, John W.; DeRisi, Joseph L.; Marletta, Michael A.

    2010-01-01

    Malaria parasites utilize a short N-terminal amino acid motif termed the Plasmodium export element (PEXEL) to export an array of proteins to the host erythrocyte during blood stage infection. Using immunoaffinity chromatography and mass spectrometry, insight into this signal-mediated trafficking mechanism was gained by discovering that the PEXEL motif is cleaved and N-acetylated. PfHRPII and PfEMP2 are two soluble proteins exported by Plasmodium falciparum that were demonstrated to undergo PEXEL cleavage and N-acetylation, thus indicating that this N-terminal processing may be general to many exported soluble proteins. It was established that PEXEL processing occurs upstream of the brefeldin A-sensitive trafficking step in the P. falciparum secretory pathway, therefore cleavage and N-acetylation of the PEXEL motif occurs in the endoplasmic reticulum (ER) of the parasite. Furthermore, it was shown that the recognition of the processed N-terminus of exported proteins within the parasitophorous vacuole may be crucial for protein transport to the host erythrocyte. It appears that the PEXEL may be defined as a novel ER peptidase cleavage site and a classical N-acetyltransferase substrate sequence. PMID:18534695

  7. Potential for malaria seasonal forecasting in Africa

    NASA Astrophysics Data System (ADS)

    Tompkins, Adrian; Di Giuseppe, Francesca; Colon-Gonzalez, Felipe; Namanya, Didas; Friday, Agabe

    2014-05-01

    As monthly and seasonal dynamical prediction systems have improved their skill in the tropics over recent years, there is now the potential to use these forecasts to drive dynamical malaria modelling systems to provide early warnings in epidemic and meso-endemic regions. We outline a new pilot operational system that has been developed at ECMWF and ICTP. It uses a precipitation bias correction methodology to seamlessly join the monthly ensemble prediction system (EPS) and seasonal (system 4) forecast systems of ECMWF together. The resulting temperature and rainfall forecasts for Africa are then used to drive the recently developed ICTP malaria model known as VECTRI. The resulting coupled system of ECMWF climate forecasts and VECTRI thus produces predictions of malaria prevalence rates and transmission intensity across Africa. The forecasts are filtered to highlight the regions and months in which the system has particular value due to high year to year variability. In addition to epidemic areas, these also include meso and hyper-endemic regions which undergo considerable variability in the onset months. We demonstrate the limits of the forecast skill as a function of lead-time, showing that for many areas the dynamical system can add one to two months additional warning time to a system based on environmental monitoring. We then evaluate the past forecasts against district level case data in Uganda and show that when interventions can be discounted, the system can show significant skill at predicting interannual variability in transmission intensity up to 3 or 4 months ahead at the district scale. The prospects for a operational implementation will be briefly discussed.

  8. Temporal and spatial distribution of malaria within an agricultural settlement of the Brazilian Amazon.

    PubMed

    de Barros, Fábio Saito Monteiro; Honório, Nildimar Alves; Arruda, Mércia Eliane

    2011-06-01

    Malaria has reemerged in tropical regions with rapid population growth and deforestation. The dynamics of malaria transmission in agricultural settlements of the Amazon have been poorly defined. We studied the spatial distribution of malaria incidence in Roraima, Brazil, using multi regression analysis on 12 parameters that described social, housing, and behavioral variables. Malaria cases were associated with the proximity of Anopheles darlingi breeding sites, the main vector in these areas. During the dry season, transmission was enhanced near a temporary river. Cases occurred throughout the year near fish-farming dams. Epidemiological models derived from urban or riverine malaria are probably inadequate for describing disease transmission in agricultural settlements, where cases are clustered near breeding sites, while the majority of the population remains unaffected. Identification of these areas, associated with residual insecticide spraying or surveillance, may considerably decrease the costs of control efforts. PMID:21635654

  9. The geography of malaria genetics in the Democratic Republic of Congo: A complex and fragmented landscape

    PubMed Central

    Carrel, Margaret; Patel, Jaymin; Taylor, Steve M.; Janko, Mark; Mwandagalirwa, Melchior Kashamuka; Tshefu, Antoinette K.; Escalante, Ananias A.; McCollum, Andrea; Alam, Md Tauqeer; Udhayakumar, Venkatachalam; Meshnick, Steven; Emch, Michael

    2014-01-01

    Understanding how malaria parasites move between populations is important, particularly given the potential for malaria to be reintroduced into areas where it was previously eliminated. We examine the distribution of malaria genetics across seven sites within the Democratic Republic of Congo (DRC) and two nearby countries, Ghana and Kenya, in order to understand how the relatedness of malaria parasites varies across space, and whether there are barriers to the flow of malaria parasites within the DRC or across borders. Parasite DNA was retrieved from dried blood spots from 7 Demographic and Health Survey sample clusters in the DRC. Malaria genetic characteristics of parasites from Ghana and Kenya were also obtained. For each of 9 geographic sites (7 DRC, 1 Ghana and 1 Kenya), a pair-wise RST statistic was calculated, indicating the genetic distance between malaria parasites found in those locations. Mapping genetics across the spatial extent of the study area indicates a complex genetic landscape, where relatedness between two proximal sites may be relatively high (RST > 0.64) or low (RST < 0.05), and where distal sites also exhibit both high and low genetic similarity. Mantel’s tests suggest that malaria genetics differ as geographic distances increase. Principal Coordinate Analysis suggests that genetically related samples are not co-located. Barrier analysis reveals no significant barriers to gene flow between locations. Malaria genetics in the DRC have a complex and fragmented landscape. Limited exchange of genes across space is reflected in greater genetic distance between malaria parasites isolated at greater geographic distances. There is, however, evidence for close genetic ties between distally located sample locations, indicating that movement of malaria parasites and flow of genes is being driven by factors other than distance decay. This research demonstrates the contributions that spatial disease ecology and landscape genetics can make to

  10. UK malaria treatment guidelines 2016.

    PubMed

    Lalloo, David G; Shingadia, Delane; Bell, David J; Beeching, Nicholas J; Whitty, Christopher J M; Chiodini, Peter L

    2016-06-01

    1.Malaria is the tropical disease most commonly imported into the UK, with 1300-1800 cases reported each year, and 2-11 deaths. 2. Approximately three quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. 3. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other species of plasmodium: Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. 4. Mixed infections with more than one species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. 5. There are no typical clinical features of malaria; even fever is not invariably present. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints. 6. A diagnosis of malaria must always be sought in a feverish or sick child or adult who has visited malaria-endemic areas. Specific country information on malaria can be found at http://travelhealthpro.org.uk/. P. falciparum infection rarely presents more than six months after exposure but presentation of other species can occur more than a year after exposure. 7. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until more than one blood specimen has been examined. Other travel related infections, especially viral haemorrhagic fevers, should also be considered. 8. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites. P. falciparum and P. vivax (depending upon the product) malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens. RDTs for other Plasmodium species are not as reliable. 9

  11. Occlusion of Small Vessels by Malaria-Infected Red Blood Cells

    NASA Astrophysics Data System (ADS)

    Lei, Huan; Fedosov, Dmitry; Caswell, Bruce; Karniadakis, George

    2010-11-01

    We use dissipative particle dynamics (DPD) method to study malaria-infected red blood cells (i-RBC). We have developed a multi-scale model to describe both static and dynamic properties of RBCs. With this model, we study the adhesive interaction between RBCs as well as the interaction between the Plasmodium falciparum (Pf)-parasitized cells and a vessel wall coated with purified ICAM-1. In this talk, we will discuss the effect of the Pf-parasitized malaria cell on the flow resistance of the blood flow at different parasetimia levels. The blood flow in malaria disease shows high flow resistance as compared with the healthy case due to both the stiffening of the i-RBCs (up to ten times) as well as the adhesion dynamics. For certain sizes of of small vessels, the malaria-infected cells can even lead to occlusion of the blood flow, in agreement with recent experiments.

  12. Clinical pharmacology and malaria.

    PubMed

    Breckenridge, A M; Winstanley, P A

    1997-10-01

    The role of clinical pharmacology in improving the prevention and treatment of malaria is reviewed. A series of general and specific issues is discussed, concentrating on risk-benefit and cost-effectiveness. The techniques of clinical pharmacokinetics play an important role in the optimal use of drugs and this is illustrated by studies on quinine and proguanil. In discussing amodiaquine toxicity, the role of the pharmacologist and the chemist in designing out drug toxicity lends hope for producing a new generation of antimalarial drugs. PMID:9625927

  13. Bioorganometallic Chemistry and Malaria

    NASA Astrophysics Data System (ADS)

    Biot, Christophe; Dive, Daniel

    This chapter summarizes recent developments in the design, synthesis, and structure-activity relationship studies of organometallic antimalarials. It begins with a general introduction to malaria and the biology of the parasite Plasmodium falciparum, with a focus on the heme detoxification system. Then, a number of metal complexes from the literature are reported for their antiplasmodial activity. The second half of the chapter deals with the serendipitous discovery of ferroquine, its mechanism(s) of action, and the failure to induce a resistance. Last, but not least, we suggest that the bioorganometallic approach offers the potential for the design of novel therapeutic agents.

  14. Serological testing in malaria*

    PubMed Central

    1974-01-01

    The main purpose of this paper is to evaluate, in a critical manner, various serological tests with general emphasis on their value in the epidemiological assessment of malaria. Several tests have been employed in the past. However, the present memorandum will deal only with the methods that have been widely used recently—i.e., indirect immunofluorescence (IFA), passive haemagglutination (IHA), and gel-diffusion. The three immunoglobulins most commonly involved in these tests are IgG, IgM, and—to a lesser extent—IgA. PMID:4218506

  15. Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis

    SciTech Connect

    Baldwin, Michael; Russo, Crystal; Li, Xuerong; Chishti, Athar H.

    2014-08-08

    Highlights: • PfSPP is an ER resident protease. • PfSPP is expressed both as a monomer and dimer. • The signal peptide of HSP101 is the first known substrate of PfSPP. • Reduced PfSPP activity may significantly affect ER homeostasis. - Abstract: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.

  16. A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

    PubMed Central

    Carraz, Maëlle; Jossang, Akino; Franetich, Jean-François; Siau, Anthony; Ciceron, Liliane; Hannoun, Laurent; Sauerwein, Robert; Frappier, François; Rasoanaivo, Philippe; Snounou, Georges; Mazier, Dominique

    2006-01-01

    Background The global spread of multidrug–resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. Methods and Findings Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 μM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 μM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 μM, TI 46, and IC50 42.4 μM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. Conclusions A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal

  17. Modelling challenges in context: lessons from malaria, HIV, and tuberculosis

    PubMed Central

    Childs, Lauren M.; Abuelezam, Nadia N.; Dye, Christopher; Gupta, Sunetra; Murray, Megan B.; Williams, Brian G.; Buckee, Caroline O.

    2015-01-01

    Malaria, HIV, and tuberculosis (TB) collectively account for several million deaths each year, with all three ranking among the top ten killers in low-income countries. Despite being caused by very different organisms, malaria, HIV, and TB present a suite of challenges for mathematical modellers that are particularly pronounced in these infections, but represent general problems in infectious disease modelling, and highlight many of the challenges described throughout this issue. Here, we describe some of the unifying challenges that arise in modelling malaria, HIV, and TB, including variation in dynamics within the host, diversity in the pathogen, and heterogeneity in human contact networks and behaviour. Through the lens of these three pathogens, we provide specific examples of the other challenges in this issue and discuss their implications for informing public health efforts. PMID:25843394

  18. Modelling challenges in context: lessons from malaria, HIV, and tuberculosis.

    PubMed

    Childs, Lauren M; Abuelezam, Nadia N; Dye, Christopher; Gupta, Sunetra; Murray, Megan B; Williams, Brian G; Buckee, Caroline O

    2015-03-01

    Malaria, HIV, and tuberculosis (TB) collectively account for several million deaths each year, with all three ranking among the top ten killers in low-income countries. Despite being caused by very different organisms, malaria, HIV, and TB present a suite of challenges for mathematical modellers that are particularly pronounced in these infections, but represent general problems in infectious disease modelling, and highlight many of the challenges described throughout this issue. Here, we describe some of the unifying challenges that arise in modelling malaria, HIV, and TB, including variation in dynamics within the host, diversity in the pathogen, and heterogeneity in human contact networks and behaviour. Through the lens of these three pathogens, we provide specific examples of the other challenges in this issue and discuss their implications for informing public health efforts. PMID:25843394

  19. Malaria epidemiology and control in Southern Africa.

    PubMed

    Mharakurwa, Sungano; Thuma, Philip E; Norris, Douglas E; Mulenga, Modest; Chalwe, Victor; Chipeta, James; Munyati, Shungu; Mutambu, Susan; Mason, Peter R

    2012-03-01

    The burden of malaria has decreased dramatically within the past several years in parts of sub-Saharan Africa, following the scale-up of interventions supported by the Roll Back Malaria Partnership, the President's Malaria Initiative and other partners. It is important to appreciate that the reductions in malaria have not been uniform between and within countries, with some areas experiencing resurgence instead. Furthermore, while interventions have greatly reduced the burden of malaria in many countries, it is also recognized that the malaria decline pre-dated widespread intervention efforts, at least in some cases where data are available. This raises more questions as what other factors may have been contributing to the reduction in malaria transmission and to what extent. The International Center of Excellence for Malaria Research (ICEMR) in Southern Africa aims to better understand the underlying malaria epidemiology, vector ecology and parasite genomics using three contrasting settings of malaria transmission in Zambia and Zimbabwe: an area of successful malaria control, an area of resurgent malaria and an area where interventions have not been effective. The Southern Africa ICEMR will capitalize on the opportunity to investigate the complexities of malaria transmission while adapting to intervention and establish the evidence-base to guide effective and sustainable malaria intervention strategies. Key approaches to attain this goal for the region will include close collaboration with national malaria control programs and contribution to capacity building at the individual, institutional and national levels. PMID:21756864

  20. Insecticide-Treated Net Campaign and Malaria Transmission in Western Kenya: 2003–2015

    PubMed Central

    Zhou, Guofa; Lee, Ming-Chieh; Githeko, Andrew K.; Atieli, Harrysone E.; Yan, Guiyun

    2016-01-01

    Insecticide-treated nets (ITNs) are among the three major intervention measures that have reduced malaria transmission in the past decade. However, increased insecticide resistance in vectors, together with outdoor transmission, has limited the efficacy of the ITN scaling-up efforts. Observations on longitudinal changes in ITN coverage and its impact on malaria transmission allow policy makers to make informed adjustments to control strategies. We analyzed field surveys on ITN ownership, malaria parasite prevalence, and malaria vector population dynamics in seven sentinel sites in western Kenya from 2003 to 2015. We found that ITN ownership has increased from an average of 18% in 2003 to 85% in 2015. Malaria parasite prevalence in school children decreased by about 70% from 2003 to 2008 (the first mass distribution of free ITNs was in 2006) but has resurged by >50% since then. At the community level, use of ITNs reduced infections by 23% in 2008 and 43% in 2010, although the reduction was down to 25% in 2011. The indoor-resting density of the predominant vector, Anopheles gambiae, has been suppressed since 2007; however, Anopheles funestus populations have resurged and have increased 20-fold in some places since 2007. In conclusion, there is limited room for further increase in ITN coverage in western Kenya. The rebounding in malaria transmission highlights the urgent need of new or improved malaria control interventions so as to further reduce malaria transmission. PMID:27574601

  1. Insecticide-Treated Net Campaign and Malaria Transmission in Western Kenya: 2003-2015.

    PubMed

    Zhou, Guofa; Lee, Ming-Chieh; Githeko, Andrew K; Atieli, Harrysone E; Yan, Guiyun

    2016-01-01

    Insecticide-treated nets (ITNs) are among the three major intervention measures that have reduced malaria transmission in the past decade. However, increased insecticide resistance in vectors, together with outdoor transmission, has limited the efficacy of the ITN scaling-up efforts. Observations on longitudinal changes in ITN coverage and its impact on malaria transmission allow policy makers to make informed adjustments to control strategies. We analyzed field surveys on ITN ownership, malaria parasite prevalence, and malaria vector population dynamics in seven sentinel sites in western Kenya from 2003 to 2015. We found that ITN ownership has increased from an average of 18% in 2003 to 85% in 2015. Malaria parasite prevalence in school children decreased by about 70% from 2003 to 2008 (the first mass distribution of free ITNs was in 2006) but has resurged by >50% since then. At the community level, use of ITNs reduced infections by 23% in 2008 and 43% in 2010, although the reduction was down to 25% in 2011. The indoor-resting density of the predominant vector, Anopheles gambiae, has been suppressed since 2007; however, Anopheles funestus populations have resurged and have increased 20-fold in some places since 2007. In conclusion, there is limited room for further increase in ITN coverage in western Kenya. The rebounding in malaria transmission highlights the urgent need of new or improved malaria control interventions so as to further reduce malaria transmission. PMID:27574601

  2. Demonstration of successful malaria forecasts for Botswana using an operational seasonal climate model

    NASA Astrophysics Data System (ADS)

    MacLeod, Dave A.; Jones, Anne; Di Giuseppe, Francesca; Caminade, Cyril; Morse, Andrew P.

    2015-04-01

    The severity and timing of seasonal malaria epidemics is strongly linked with temperature and rainfall. Advance warning of meteorological conditions from seasonal climate models can therefore potentially anticipate unusually strong epidemic events, building resilience and adapting to possible changes in the frequency of such events. Here we present validation of a process-based, dynamic malaria model driven by hindcasts from a state-of-the-art seasonal climate model from the European Centre for Medium-Range Weather Forecasts. We validate the climate and malaria models against observed meteorological and incidence data for Botswana over the period 1982-2006 the longest record of observed incidence data which has been used to validate a modeling system of this kind. We consider the impact of climate model biases, the relationship between climate and epidemiological predictability and the potential for skillful malaria forecasts. Forecast skill is demonstrated for upper tercile malaria incidence for the Botswana malaria season (January-May), using forecasts issued at the start of November; the forecast system anticipates six out of the seven upper tercile malaria seasons in the observational period. The length of the validation time series gives confidence in the conclusion that it is possible to make reliable forecasts of seasonal malaria risk, forming a key part of a health early warning system for Botswana and contributing to efforts to adapt to climate change.

  3. Complement Activation in Placental Malaria

    PubMed Central

    McDonald, Chloe R.; Tran, Vanessa; Kain, Kevin C.

    2015-01-01

    Sixty percent of all pregnancies worldwide occur in malaria endemic regions. Pregnant women are at greater risk of malaria infection than their non-pregnant counterparts and have a higher risk of adverse birth outcomes including low birth weight resulting from intrauterine growth restriction and/or preterm birth. The complement system plays an essential role in placental and fetal development as well as the host innate immune response to malaria infection. Excessive or dysregulated complement activation has been associated with the pathobiology of severe malaria and with poor pregnancy outcomes, dependent and independent of infection. Here we review the role of complement in malaria and pregnancy and discuss its part in mediating altered placental angiogenesis, malaria-induced adverse birth outcomes, and disruptions to the in utero environment with possible consequences on fetal neurodevelopment. A detailed understanding of the mechanisms underlying adverse birth outcomes, and the impact of maternal malaria infection on fetal neurodevelopment, may lead to biomarkers to identify at-risk pregnancies and novel therapeutic interventions to prevent these complications. PMID:26733992

  4. Forcing Versus Feedback: Epidemic Malaria and Monsoon Rains in Northwest India

    PubMed Central

    Ionides, Edward L.; Bouma, Menno; Dhiman, Ramesh C.; Yadav, Rajpal S.; Pascual, Mercedes

    2010-01-01

    Malaria epidemics in regions with seasonal windows of transmission can vary greatly in size from year to year. A central question has been whether these interannual cycles are driven by climate, are instead generated by the intrinsic dynamics of the disease, or result from the resonance of these two mechanisms. This corresponds to the more general inverse problem of identifying the respective roles of external forcings vs. internal feedbacks from time series for nonlinear and noisy systems. We propose here a quantitative approach to formally compare rival hypotheses on climate vs. disease dynamics, or external forcings vs. internal feedbacks, that combines dynamical models with recently developed, computational inference methods. The interannual patterns of epidemic malaria are investigated here for desert regions of northwest India, with extensive epidemiological records for Plasmodium falciparum malaria for the past two decades. We formulate a dynamical model of malaria transmission that explicitly incorporates rainfall, and we rely on recent advances on parameter estimation for nonlinear and stochastic dynamical systems based on sequential Monte Carlo methods. Results show a significant effect of rainfall in the inter-annual variability of epidemic malaria that involves a threshold in the disease response. The model exhibits high prediction skill for yearly cases in the malaria transmission season following the monsoonal rains. Consideration of a more complex model with clinical immunity demonstrates the robustness of the findings and suggests a role of infected individuals that lack clinical symptoms as a reservoir for transmission. Our results indicate that the nonlinear dynamics of the disease itself play a role at the seasonal, but not the interannual, time scales. They illustrate the feasibility of forecasting malaria epidemics in desert and semi-arid regions of India based on climate variability. This approach should be applicable to malaria in other

  5. Plasmodium vivax Merozoite Surface Protein-3 (PvMSP3): Expression of an 11 Member Multigene Family in Blood-Stage Parasites

    PubMed Central

    Jiang, Jianlin; Barnwell, John W.; Meyer, Esmeralda V. S.; Galinski, Mary R.

    2013-01-01

    Background Three members of the Plasmodium vivax merozoite surface protein-3 (PvMSP3) family (PvMSP3-α, PvMSP3-β and PvMSP3-γ) were initially characterized and later shown to be part of a larger highly diverse family, encoded by a cluster of genes arranged head-to-tail in chromosome 10. PvMSP3-α and PvMSP3-β have become genetic markers in epidemiological studies, and are being evaluated as vaccine candidates. This research investigates the gene and protein expression of the entire family and pertinent implications. Methodology/Principal Findings A 60 kb multigene locus from chromosome 10 in P. vivax (Salvador 1 strain) was studied to classify the number of pvmsp3 genes present, and compare their transcription, translation and protein localization patterns during blood-stage development. Eleven pvmsp3 paralogs encode an N-terminal NLRNG signature motif, a central domain containing repeated variable heptad sequences, and conserved hydrophilic C-terminal features. One additional ORF in the locus lacks these features and was excluded as a member of the family. Transcripts representing all eleven pvmsp3 genes were detected in trophozoite- and schizont-stage RNA. Quantitative immunoblots using schizont-stage extracts and antibodies specific for each PvMSP3 protein demonstrated that all but PvMSP3.11 could be detected. Homologs were also detected by immunoblot in the closely related simian species, P. cynomolgi and P. knowlesi. Immunofluorescence assays confirmed that eight of the PvMSP3s are present in mature schizonts. Uniquely, PvMSP3.7 was expressed exclusively at the apical end of merozoites. Conclusion/Significance Specific proteins were detected representing the expression of 10 out of 11 genes confirmed as members of the pvmsp3 family. Eight PvMSP3s were visualized surrounding merozoites. In contrast, PvMSP3.7 was detected at the apical end of the merozoites. Pvmsp3.11 transcripts were present, though no corresponding protein was detected. PvMSP3 functions

  6. Ungulate malaria parasites.

    PubMed

    Templeton, Thomas J; Asada, Masahito; Jiratanh, Montakan; Ishikawa, Sohta A; Tiawsirisup, Sonthaya; Sivakumar, Thillaiampalam; Namangala, Boniface; Takeda, Mika; Mohkaew, Kingdao; Ngamjituea, Supawan; Inoue, Noboru; Sugimoto, Chihiro; Inagaki, Yuji; Suzuki, Yasuhiko; Yokoyama, Naoaki; Kaewthamasorn, Morakot; Kaneko, Osamu

    2016-01-01

    Haemosporida parasites of even-toed ungulates are diverse and globally distributed, but since their discovery in 1913 their characterization has relied exclusively on microscopy-based descriptions. In order to bring molecular approaches to bear on the identity and evolutionary relationships of ungulate malaria parasites, we conducted Plasmodium cytb-specific nested PCR surveys using blood from water buffalo in Vietnam and Thailand, and goats in Zambia. We found that Plasmodium is readily detectable from water buffalo in these countries, indicating that buffalo Plasmodium is distributed in a wider region than India, which is the only area in which buffalo Plasmodium has been reported. Two types (I and II) of Plasmodium sequences were identified from water buffalo and a third type (III) was isolated from goat. Morphology of the parasite was confirmed in Giemsa-reagent stained blood smears for the Type I sample. Complete mitochondrial DNA sequences were isolated and used to infer a phylogeny in which ungulate malaria parasites form a monophyletic clade within the Haemosporida, and branch prior to the clade containing bird, lizard and other mammalian Plasmodium. Thus it is likely that host switching of Plasmodium from birds to mammals occurred multiple times, with a switch to ungulates independently from other mammalian Plasmodium. PMID:26996979

  7. Healthy malaria control.

    PubMed

    Mathen, K

    1998-01-01

    According to an article in the May 27, 1998, issue of the Times of India, Dr. Menno Jan Bouma, an epidemiologist from the London School of Hygiene and Tropical Medicine, has suggested spraying India's cows, goats, and buffaloes with insecticide in a bid to combat malaria. This strategy, however, fails to fully consider what is currently known about insect behavior, insecticides' modes of action, and the interaction between the two in the environment. A population of insects can ultimately develop resistance and adapt to the repeated onslaught of insecticides. Furthermore, each type of insecticide which could potentially be used has its own set of problems with regard to the environment, the products into which they break down, and how they affect wildlife and humans. The once commonplace spraying of livestock in the West led to Mad Cow Disease, Chicken Flu, and other problems. India's meat and dairy products will definitely be contaminated should the country's livestock be sprayed with insecticides. In the long-term interest of humankind, efforts must be made to contain, not eradicate, mosquitoes and malaria. PMID:12348880

  8. Ungulate malaria parasites

    PubMed Central

    Templeton, Thomas J.; Asada, Masahito; Jiratanh, Montakan; Ishikawa, Sohta A.; Tiawsirisup, Sonthaya; Sivakumar, Thillaiampalam; Namangala, Boniface; Takeda, Mika; Mohkaew, Kingdao; Ngamjituea, Supawan; Inoue, Noboru; Sugimoto, Chihiro; Inagaki, Yuji; Suzuki, Yasuhiko; Yokoyama, Naoaki; Kaewthamasorn, Morakot; Kaneko, Osamu

    2016-01-01

    Haemosporida parasites of even-toed ungulates are diverse and globally distributed, but since their discovery in 1913 their characterization has relied exclusively on microscopy-based descriptions. In order to bring molecular approaches to bear on the identity and evolutionary relationships of ungulate malaria parasites, we conducted Plasmodium cytb-specific nested PCR surveys using blood from water buffalo in Vietnam and Thailand, and goats in Zambia. We found that Plasmodium is readily detectable from water buffalo in these countries, indicating that buffalo Plasmodium is distributed in a wider region than India, which is the only area in which buffalo Plasmodium has been reported. Two types (I and II) of Plasmodium sequences were identified from water buffalo and a third type (III) was isolated from goat. Morphology of the parasite was confirmed in Giemsa-reagent stained blood smears for the Type I sample. Complete mitochondrial DNA sequences were isolated and used to infer a phylogeny in which ungulate malaria parasites form a monophyletic clade within the Haemosporida, and branch prior to the clade containing bird, lizard and other mammalian Plasmodium. Thus it is likely that host switching of Plasmodium from birds to mammals occurred multiple times, with a switch to ungulates independently from other mammalian Plasmodium. PMID:26996979

  9. Shape of Key Malaria Protein Could Help Improve Vaccine Efficacy

    MedlinePlus

    ... Malaria > Research Malaria Understanding Research NIAID Role Basic Biology Prevention and Control Strategies Strategic Partnerships and Research ... the malaria parasite. Related Links Global Research​ Vector Biology International Centers of Excellence for Malaria Research (ICEMR) ...

  10. Malaria in Kenya's Western Highlands

    PubMed Central

    Hay, Simon I.; Omumbo, Judy A.; Snow, Robert W.

    2005-01-01

    Records from tea estates in the Kericho district in Kenya show that malaria reemerged in the 1980s. Renewed epidemic activity coincided with the emergence of chloroquine-resistant Plasmodium falciparum malaria and may have been triggered by the failure of antimalarial drugs. Meteorologic changes, population movements, degradation of health services, and changes in Anopheles vector populations are possible contributing factors. The highland malaria epidemics of the 1940s were stopped largely by sporontocidal drugs, and combination chemotherapy has recently limited transmission. Antimalarial drugs can limit the pool of gametocytes available to infect mosquitoes during the brief transmission season. PMID:16229773

  11. Atypical neurological manifestations of malaria

    PubMed Central

    Singla, Neeraj; Gupta, Monica; Singh, Ram; Kumar, Ashwani

    2014-01-01

    Malaria is known as a great mimic. It can manifest subtly or abruptly, typically or atypically. This aspect of the disease can frequently mislead physicians. We present two patients of malaria with atypical neurological manifestations. The first patient of Plasmodium falciparum malaria presented with fever and altered sensorium; MRI of the brain suggested cerebral venous thrombosis. The second patient of Plasmodium vivax presented with fever, double vision and right eye lateral rectus palsy due to unilateral sixth cranial nerve involvement. Both patients were managed with antimalarials and supportive medical management, and had uneventful recoveries. PMID:25150266

  12. [Prospects for malaria elimination in Azerbaijan].

    PubMed

    Kondrashin, A V; Baranova, A M; Mammedov, S; Gasimov, É; Morozova, L F; Stepanova, E V

    2011-01-01

    Epidemiological analysis of the malaria in the Republic of Azerbaijan has revealed that: 1. In the past year, malaria problem has considerably improved in reducing morbidity and the number of active foci of malaria in the republic. 2. All active foci of malaria have been in its endemic area. 3. Despite the presence of favorable climatic preconditions for malaria in a large part of the republic, socioeconomic preconditions are considerably decreased, causing the malariogenic potential to substantially reduce. 4. All sets a favorable stage for possible interruption of local malaria transmission on the whole territory of the republic provided that financial support for the national malaria elimination program will be increased from the country's government and other sources in conjunction with the implementation of revised malaria control strategy and with the use of current methods for the detection, diagnosis, treatment, and prevention of malaria. PMID:21476253

  13. The stage-specific in vitro efficacy of a malaria antigen cocktail provides valuable insights into the development of effective multi-stage vaccines.

    PubMed

    Spiegel, Holger; Boes, Alexander; Kastilan, Robin; Kapelski, Stephanie; Edgue, Güven; Beiss, Veronique; Chubodova, Ivana; Scheuermayer, Matthias; Pradel, Gabriele; Schillberg, Stefan; Reimann, Andreas; Fischer, Rainer

    2015-10-01

    Multicomponent vaccines targeting different stages of Plasmodium falciparum represent a promising, holistic concept towards better malaria vaccines. Additionally, an effective vaccine candidate should demonstrate cross-strain specificity because many antigens are polymorphic, which can reduce vaccine efficacy. A cocktail of recombinant fusion proteins (VAMAX-Mix) featuring three diversity-covering variants of the blood-stage antigen PfAMA1, each combined with the conserved sexual-stage antigen Pfs25 and one of the pre-erythrocytic-stage antigens PfCSP_TSR or PfCelTOS, or the additional blood-stage antigen PfMSP1_19, was produced in Pichia pastoris and used to immunize rabbits. The immune sera and purified IgG were used to perform various assays determining antigen specific titers and in vitro efficacy against different parasite stages and strains. In functional in vitro assays we observed robust inhibition of blood-stage (up to 90%), and sexual-stage parasites (up to 100%) and biased inhibition of pre-erythrocytic parasites (0-40%). Cross-strain blood-stage efficacy was observed in erythrocyte invasion assays using four different P. falciparum strains. The quantification of antigen-specific IgGs allowed the determination of specific IC50 values. The significant difference in antigen-specific IC50 requirements, the direct correlation between antigen-specific IgG and the relative quantitative representation of antigens within the cocktail, provide valuable implementations for future multi-stage, multi-component vaccine designs. PMID:25913888

  14. Transcription Profiling of Malaria-Naïve and Semi-immune Colombian Volunteers in a Plasmodium vivax Sporozoite Challenge

    PubMed Central

    Rojas-Peña, Monica L.; Vallejo, Andres; Herrera, Sócrates; Gibson, Greg; Arévalo-Herrera, Myriam

    2015-01-01

    Background Continued exposure to malaria-causing parasites in endemic regions of malaria induces significant levels of acquired immunity in adult individuals. A better understanding of the transcriptional basis for this acquired immunological response may provide insight into how the immune system can be boosted during vaccination, and into why infected individuals differ in symptomology. Methodology/Principal Findings Peripheral blood gene expression profiles of 9 semi-immune volunteers from a Plasmodium vivax malaria prevalent region (Buenaventura, Colombia) were compared to those of 7 naïve individuals from a region with no reported transmission of malaria (Cali, Colombia) after a controlled infection mosquito bite challenge with P. vivax. A Fluidigm nanoscale quantitative RT-PCR array was used to survey altered expression of 96 blood informative transcripts at 7 timepoints after controlled infection, and RNASeq was used to contrast pre-infection and early parasitemia timepoints. There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity. This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis. Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali. Conclusion/Significance Gene expression profiling of whole blood reveals the type and duration of the immune response to P. vivax infection, and highlights a subset of genes that may mediate adaptive immunity. PMID:26244760

  15. Socio-demographic factors influencing knowledge, attitude and practice (KAP) regarding malaria in Bangladesh

    PubMed Central

    2012-01-01

    Background A clear understanding of the social and behavioral risk factors, and knowledge gaps, related to exposure to malaria are essential when developing guidelines and recommendations for more effective disease prevention in many malaria endemic areas of the world including Bangladesh and elsewhere in the South East Asia. To-date, the level of knowledge that human populations, residing in moderate to high malaria risk zones, have with respect to the basic pathogen transmission dynamics, risk factors for malaria or disease preventative strategies, has not been assessed in Bangladesh. The purpose of this study was to address this gap by conducting surveys of the knowledge, attitudes and practices (KAP) of people, from variable socio-demographic backgrounds, residing in selected rural malaria endemic areas in Bangladesh. Methods The KAP survey was conducted in portions of six different malaria endemic districts in Bangladesh from July to October 2011. The survey consisted of interviewing residence of these malaria endemic districts using a structured questionnaire and interviewers also completed observational checklists at each household where people were interviewed. The study area was further divided into two zones (1 and 2) based on differences in the physical geography and level of malaria endemicity in the two zones. Data from the questionnaires and observational checklists were analysised using Statistical Package for Social Sciences 16.0 (SPSS, Inc., Chicago, IL, USA). Results A total of 468 individuals from individual households were interviewed, and most respondents were female. Monthly incomes varied within and among the zones. It was found that 46.4% and 41% of respondents’ family had malaria within the past one year in zones 1 and 2, respectively. Nearly 86% of the respondents did not know the exact cause of malaria or the role of Anopheles mosquitoes in the pathogen’s transmission. Knowledge on malaria transmission and symptoms of the respondents

  16. Investigating malaria risk in the northern region of Nigeria using satellite imagery

    NASA Astrophysics Data System (ADS)

    Emetere, M. E.; Nikouravan, Bijan; Olawole, O. F.

    2015-08-01

    The dynamics of infectious diseases are dependent on salient environment and climate factors which are directly proportional to its transmission. Malaria is a common disease of typical tropics of the West African sub-region. The influences of malaria transmission via meteorological and environmental parameters were examined. Remotely sensed parameters i.e. skin temperature, sensible heat flux, latent heat flux and total precipitation were obtained from the NASA-MERRA. The results show that the meteorological and environmental parameters of northern Nigeria favour the long malaria dominance.

  17. Malaria Prophylaxis: A Comprehensive Review

    PubMed Central

    Castelli, Francesco; Odolini, Silvia; Autino, Beatrice; Foca, Emanuele; Russo, Rosario

    2010-01-01

    The flow of international travellers to and from malaria-endemic areas, especially Africa, has increased in recent years. Apart from the very high morbidity and mortality burden imposed on malaria-endemic areas, imported malaria is the main cause of fever possibly causing severe disease and death in travellers coming from tropical and subtropical areas, particularly Sub-Saharan Africa. The importance of behavioural preventive measures (bed nets, repellents, etc.), adequate chemoprophylaxis and, in selected circumstances, stand-by emergency treatment may not be overemphasized. However, no prophylactic regimen may offer complete protection. Expert advice is needed to tailor prophylactic advice according to traveller (age, baseline clinical conditions, etc.) and travel (destination, season, etc.) characteristics in order to reduce malaria risk.

  18. Malaria selectively targets pregnancy receptors.

    PubMed

    Chishti, Athar H

    2015-01-01

    In this issue of Blood, Rieger et al show that malaria parasite infiltration in the human placenta requires a specific geometry and affinity of host receptors to facilitate strong adhesion. PMID:25573970

  19. Malaria ecology and climate change

    NASA Astrophysics Data System (ADS)

    McCord, G. C.

    2016-05-01

    Understanding the costs that climate change will exact on society is crucial to devising an appropriate policy response. One of the channels through while climate change will affect human society is through vector-borne diseases whose epidemiology is conditioned by ambient ecology. This paper introduces the literature on malaria, its cost on society, and the consequences of climate change to the physics community in hopes of inspiring synergistic research in the area of climate change and health. It then demonstrates the use of one ecological indicator of malaria suitability to provide an order-of-magnitude assessment of how climate change might affect the malaria burden. The average of Global Circulation Model end-of-century predictions implies a 47% average increase in the basic reproduction number of the disease in today's malarious areas, significantly complicating malaria elimination efforts.

  20. The March Toward Malaria Vaccines.

    PubMed

    Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L; Duffy, Patrick E

    2015-12-01

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  1. The march toward malaria vaccines.

    PubMed

    Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L; Duffy, Patrick E

    2015-11-27

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  2. Using infective mosquitoes to challenge monkeys with Plasmodium knowlesi in malaria vaccine studies

    PubMed Central

    2014-01-01

    Background When rhesus monkeys (Macaca mulatta) are used to test malaria vaccines, animals are often challenged by the intravenous injection of sporozoites. However, natural exposure to malaria comes via mosquito bite, and antibodies can neutralize sporozoites as they traverse the skin. Thus, intravenous injection may not fairly assess humoral immunity from anti-sporozoite malaria vaccines. To better assess malaria vaccines in rhesus, a method to challenge large numbers of monkeys by mosquito bite was developed. Methods Several species and strains of mosquitoes were tested for their ability to produce Plasmodium knowlesi sporozoites. Donor monkey parasitaemia effects on oocyst and sporozoite numbers and mosquito mortality were documented. Methylparaben added to mosquito feed was tested to improve mosquito survival. To determine the number of bites needed to infect a monkey, animals were exposed to various numbers of P. knowlesi-infected mosquitoes. Finally, P. knowlesi-infected mosquitoes were used to challenge 17 monkeys in a malaria vaccine trial, and the effect of number of infectious bites on monkey parasitaemia was documented. Results Anopheles dirus, Anopheles crascens, and Anopheles dirus X (a cross between the two species) produced large numbers of P. knowlesi sporozoites. Mosquito survival to day 14, when sporozoites fill the salivary glands, averaged only 32% when donor monkeys had a parasitaemia above 2%. However, when donor monkey parasitaemia was below 2%, mosquitoes survived twice as well and contained ample sporozoites in their salivary glands. Adding methylparaben to sugar solutions did not improve survival of infected mosquitoes. Plasmodium knowlesi was very infectious, with all monkeys developing blood stage infections if one or more infected mosquitoes successfully fed. There was also a dose-response, with monkeys that received higher numbers of infected mosquito bites developing malaria sooner. Conclusions Anopheles dirus, An. crascens and a

  3. Strategic roles for behaviour change communication in a changing malaria landscape

    PubMed Central

    2014-01-01

    Strong evidence suggests that quality strategic behaviour change communication (BCC) can improve malaria prevention and treatment behaviours. As progress is made towards malaria elimination, BCC becomes an even more important tool. BCC can be used 1) to reach populations who remain at risk as transmission dynamics change (e.g. mobile populations), 2) to facilitate identification of people with asymptomatic infections and their compliance with treatment, 3) to inform communities of the optimal timing of malaria control interventions, and 4) to explain changing diagnostic concerns (e.g. increasing false negatives as parasite density and multiplicity of infections fall) and treatment guidelines. The purpose of this commentary is to highlight the benefits and value for money that BCC brings to all aspects of malaria control, and to discuss areas of operations research needed as transmission dynamics change. PMID:24383426

  4. Strategic roles for behaviour change communication in a changing malaria landscape.

    PubMed

    Koenker, Hannah; Keating, Joseph; Alilio, Martin; Acosta, Angela; Lynch, Matthew; Nafo-Traore, Fatoumata

    2014-01-01

    Strong evidence suggests that quality strategic behaviour change communication (BCC) can improve malaria prevention and treatment behaviours. As progress is made towards malaria elimination, BCC becomes an even more important tool. BCC can be used 1) to reach populations who remain at risk as transmission dynamics change (e.g. mobile populations), 2) to facilitate identification of people with asymptomatic infections and their compliance with treatment, 3) to inform communities of the optimal timing of malaria control interventions, and 4) to explain changing diagnostic concerns (e.g. increasing false negatives as parasite density and multiplicity of infections fall) and treatment guidelines. The purpose of this commentary is to highlight the benefits and value for money that BCC brings to all aspects of malaria control, and to discuss areas of operations research needed as transmission dynamics change. PMID:24383426

  5. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia

    PubMed Central

    Maude, Richard J; Pontavornpinyo, Wirichada; Saralamba, Sompob; Aguas, Ricardo; Yeung, Shunmay; Dondorp, Arjen M; Day, Nicholas PJ; White, Nicholas J; White, Lisa J

    2009-01-01

    Background Artemisinin combination therapy (ACT) is now the recommended first-line treatment for falciparum malaria throughout the world. Initiatives to eliminate malaria are critically dependent on its efficacy. There is recent worrying evidence that artemisinin resistance has arisen on the Thai-Cambodian border. Urgent containment interventions are planned and about to be executed. Mathematical modeling approaches to intervention design are now integrated into the field of malaria epidemiology and control. The use of such an approach to investigate the likely effectiveness of different containment measures with the ultimate aim of eliminating artemisinin-resistant malaria is described. Methods A population dynamic mathematical modeling framework was developed to explore the relative effectiveness of a variety of containment interventions in eliminating artemisinin-resistant malaria in western Cambodia. Results The most effective intervention to eliminate artemisinin-resistant malaria was a switch of treatment from artemisinin monotherapy to ACT (mean time to elimination 3.42 years (95% CI 3.32–3.60 years). However, with this approach it is predicted that elimination of artemisinin-resistant malaria using ACT can be achieved only by elimination of all malaria. This is because the various forms of ACT are more effective against infections with artemisinin-sensitive parasites, leaving the more resistant infections as an increasing proportion of the dwindling parasite population. Conclusion Containment of artemisinin-resistant malaria can be achieved by elimination of malaria from western Cambodia using ACT. The "last man standing" is the most resistant and thus this strategy must be sustained until elimination is truly achieved. PMID:19228438

  6. Protection against malaria by immunization with non-attenuated sporozoites under single-dose piperaquine-tetraphosphate chemoprophylaxis.

    PubMed

    Pfeil, Johannes; Sepp, Katharina Jutta; Heiss, Kirsten; Meister, Michael; Mueller, Ann-Kristin; Borrmann, Steffen

    2014-10-14

    Experimental whole-parasite immunization through concurrent administration of infectious Plasmodium sporozoites with drugs that prevent pathogenic blood-stage infection represents the current benchmark in malaria vaccine development. Key questions concerning translation remain, including the requirement for single-dose drug regimens that can reliably prevent breakthrough infections. We assessed the feasibility and efficacy of immunization with single-dose piperaquine chemoprophylaxis and concurrent sporozoite administration (PPQ-CPS) in the murine P. berghei ANKA/C57BL/6 infection model. We demonstrate that PPQ-CPS is protective with an efficacy comparable to previous findings using whole-parasite immunization under chloroquine chemoprophylaxis. PPQ-CPS immunization resulted in an expansion of intrahepatic and intrasplenic effector memory CD8(+) T cells. In summary, PPQ-CPS appears to be a safe and efficacious immunization regimen in the rodent malaria model and may thus become an important improvement regarding the translation of whole-parasite immunization toward a human malaria vaccine. PMID:25203450

  7. Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans

    PubMed Central

    Sundriyal, Sandeep; Caron, Joachim; Chen, Patty; Witkowski, Benoit; Menard, Didier; Suwanarusk, Rossarin; Renia, Laurent; Nosten, Francois; Jiménez-Díaz, María Belén; Angulo-Barturen, Iñigo; Martínez, María Santos; Ferrer, Santiago; Sanz, Laura M.; Gamo, Francisco-Javier; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael J.; Sinden, Robert E.; Fuchter, Matthew J.

    2014-01-01

    Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC50s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria. PMID:25421480

  8. Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.

    PubMed

    Malmquist, Nicholas A; Sundriyal, Sandeep; Caron, Joachim; Chen, Patty; Witkowski, Benoit; Menard, Didier; Suwanarusk, Rossarin; Renia, Laurent; Nosten, Francois; Jiménez-Díaz, María Belén; Angulo-Barturen, Iñigo; Santos Martínez, María; Ferrer, Santiago; Sanz, Laura M; Gamo, Francisco-Javier; Wittlin, Sergio; Duffy, Sandra; Avery, Vicky M; Ruecker, Andrea; Delves, Michael J; Sinden, Robert E; Fuchter, Matthew J; Scherf, Artur

    2015-02-01

    Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC50s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria. PMID:25421480

  9. Malaria and anemia.

    PubMed

    Ekvall, Håkan

    2003-03-01

    Anemia due to infection is a major health problem in endemic areas for young children and pregnant women. The anemia is caused by excess removal of nonparasitized erythrocytes in addition to immune destruction of parasitized red cells, and impaired compensation for this loss by bone marrow dysfunction. The pathogenesis is complex, and a predominant mechanism has not been identified. Certain parasite and host characteristics may modify the anemia. Concomitant infections and nutritional deficiencies also contribute to anemia and may interact with the malarial infection. Few preventive strategies exist, and the management of severe malarial anemia with blood transfusion carries a risk of HIV transmission. The current increase in malaria-specific childhood mortality in sub-Saharan Africa attributed to drug-resistant infection is likely partly related to an increase in severe anemia. This review summarizes recent findings on the pathogenesis and epidemiology of malarial anemia. PMID:12579035

  10. [Malaria and intestinal protozoa].

    PubMed

    Rojo-Marcos, Gerardo; Cuadros-González, Juan

    2016-03-01

    Malaria is life threatening and requires urgent diagnosis and treatment. Incidence and mortality are being reduced in endemic areas. Clinical features are unspecific so in imported cases it is vital the history of staying in a malarious area. The first line treatments for Plasmodium falciparum are artemisinin combination therapies, chloroquine in most non-falciparum and intravenous artesunate if any severity criteria. Human infections with intestinal protozoa are distributed worldwide with a high global morbid-mortality. They cause diarrhea and sometimes invasive disease, although most are asymptomatic. In our environment populations at higher risk are children, including adopted abroad, immune-suppressed, travelers, immigrants, people in contact with animals or who engage in oral-anal sex. Diagnostic microscopic examination has low sensitivity improving with antigen detection or molecular methods. Antiparasitic resistances are emerging lately. PMID:26832999

  11. Sickle Cell Anaemia and Malaria

    PubMed Central

    Luzzatto, Lucio

    2012-01-01

    Sickle cell anaemia is a major chapter within haemolytic anaemias; at the same time, its epidemiology is a remarkable signature of the past and present world distribution of Plasmodium falciparum malaria. In this brief review, in keeping with the theme of this journal, we focus on the close and complex relationship betweeen this blood disease and this infectious disease. On one hand, heterozygotes for the sickle gene (AS) are relatively protected against the danger of dying of malaria, as now firmly established through a number of clinical field studies from different parts of Africa. In addition, experimental work is consistent with a plausibile mechanism: namely, that in AS heterozygotes P falciparum-infected red cells sickle preferentially and are then removed by macrophages. On the other hand, patients who are homozygous for the sickle gene and therefore suffer from sickle cell anaemia (SCA) are highly susceptible to the lethal effects of malaria. The simplest explanation of this fact is that malaria makes the anaemia of SCA more severe; in addition, in SCA there is often hyposplenism, which reduces clearance of parasites. From the point of view of public health it is important that in malaria-endemic countries patients with SCA, and particularly children, be protected from malaria by appropriate prophylaxis. PMID:23170194

  12. Treatment of severe malaria.

    PubMed Central

    Warrell, D A

    1989-01-01

    In the treatment of severe Plasmodium falciparum infection antimalarial drugs should, ideally, be given by controlled rate intravenous infusion until the patient is able to swallow tablets. In cases where infection has been acquired in a chloroquine resistant area, and where it has broken through chloroquine prophylaxis or where the geographical origin or species are uncertain, quinine is the treatment of choice. When access to parenteral quinine is likely to be delayed, parenteral quinidine is an effective alternative. A loading dose of quinine is recommended in order to achieve therapeutic plasma concentrations as quickly as possible. In the case of chloroquine sensitive P. falciparum infection, chloroquine, which can be given safely by slow intravenous infusion, may be more rapidly effective and has fewer toxic effects than quinine. There is limited experience with parenteral administration of pyrimethamine sulphonamide combinations such as Fansidar, and resistance to these drugs has developed in South East Asia and elsewhere. Mefloquine and halofantrine cannot be given parenterally. Qinghaosu derivatives are not readily available and have not been adequately tested outside China. Supportive treatment includes the prevention or early detection and treatment of complications, strict attention to fluid balance, provision of adequate nursing for unconscious patients and avoidance of harmful ancillary treatments. Anaemia is inevitable and out of proportion to detectable parasitaemia. Hypotension and shock ('algid malaria') are often attributable to secondary gram-negative septicaemia requiring appropriate antimicrobial therapy and haemodynamic resuscitation. Many patients with severe falciparum malaria are hypovolaemic on admission to hospital and require cautious fluid replacement. Failure to rehydrate these patients may lead to circulatory collapse, lactic acidosis, renal failure and severe hyponatraemia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2693726

  13. The TLR2 is activated by sporozoites and suppresses intrahepatic rodent malaria parasite development

    PubMed Central

    Zheng, Hong; Tan, Zhangping; Zhou, TaoLi; Zhu, Feng; Ding, Yan; Liu, Taiping; Wu, Yuzhang; Xu, Wenyue

    2015-01-01

    TLRs (Toll-like receptors) play an important role in the initiation of innate immune responses against invading microorganisms. Although several TLRs have been reported to be involved in the innate immune response against the blood-stage of malaria parasites, the role of TLRs in the development of the pre-erythrocytic stage is still largely unknown. Here, we found that sporozoite and its lysate could significantly activate the TLR2, and induce macrophages to release proinflammatory cytokines, including IL-6, MCP-1 and TNF-α, in a TLR2-dependent manner. Further studies showed that sporozoite and its lysate could be recognized by either TLR2 homodimers or TLR2/1 and TLR2/6 heterodimers, implicating the complexity of TLR2 agonist in sporozoite. Interestingly, the TLR2 signaling can significantly suppress the development of the pre-erythrocytic stage of Plasmodium yoelii, as both liver parasite load and subsequent parasitemia were significantly elevated in both TLR2- and MyD88-deficient mice. Additionally, the observed higher level of parasite burden in TLR2−/− mice was found to be closely associated with a reduction in proinflammatory cytokines in the liver. Therefore, we provide the first evidence that sporozoites can activate the TLR2 signaling, which in turn significantly inhibits the intrahepatic parasites. This may provide us with novel clues to design preventive anti-malaria therapies. PMID:26667391

  14. Translational repression of the cpw-wpc gene family in the malaria parasite Plasmodium.

    PubMed

    Rao, Pavitra N; Santos, Jorge M; Pain, Arnab; Templeton, Thomas J; Mair, Gunnar R

    2016-10-01

    The technical challenges of working with the sexual stages of the malaria parasite Plasmodium have hindered the characterization of sexual stage antigens in the quest for a successful malaria transmission-blocking vaccine. One such predicted and largely uncharacterized group of sexual stage candidate antigens is the CPW-WPC family of proteins. CPW-WPC proteins are named for a characteristic domain that contains two conserved motifs, CPxxW and WPC. Conserved across Apicomplexa, this family is also present earlier in the Alveolata in the free-living, non-parasitophorous, photosynthetic chromerids, Chromera and Vitrella. In Plasmodium falciparum and Plasmodium berghei blood stage parasites, the transcripts of all nine cpw-wpc genes have been detected in gametocytes. RNA immunoprecipitation followed by reverse transcriptase-PCR reveals all P. berghei cpw-wpc transcripts to be bound by the translational repressors DOZI and CITH, and thus are likely under translational control prior to transmission from the rodent host to the mosquito vector in P. berghei. The GFP tagging of two endogenous P. berghei genes confirmed translational silencing in the gametocyte and translation in ookinetes. By establishing a luciferase transgene assay, we show that the 3' untranslated region of PF3D7_1331400 controls protein expression of this reporter in P. falciparum gametocytes. Our analyses suggest that cpw-wpc genes are translationally silenced in gametocytes across Plasmodium spp. and activated during ookinete formation and thus may have a role in transmission to the mosquito. PMID:27312996

  15. Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein

    PubMed Central

    Sahu, Tejram; Malkov, Vlad; Morrison, Robert; Pei, Ying; Juompan, Laure; Milman, Neta; Zarling, Stasya; Anderson, Charles; Wong-Madden, Sharon; Wendler, Jason; Ishizuka, Andrew; MacMillen, Zachary W.; Garcia, Valentino; Kappe, Stefan H. I.; Krzych, Urszula; Duffy, Patrick E.

    2016-01-01

    Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP. PMID:27434123

  16. The Plasmodium PHIST and RESA-Like Protein Families of Human and Rodent Malaria Parasites.

    PubMed

    Moreira, Cristina K; Naissant, Bernina; Coppi, Alida; Bennett, Brandy L; Aime, Elena; Franke-Fayard, Blandine; Janse, Chris J; Coppens, Isabelle; Sinnis, Photini; Templeton, Thomas J

    2016-01-01

    The phist gene family has members identified across the Plasmodium genus, defined by the presence of a domain of roughly 150 amino acids having conserved aromatic residues and an all alpha-helical structure. The family is highly amplified in P. falciparum, with 65 predicted genes in the genome of the 3D7 isolate. In contrast, in the rodent malaria parasite P. berghei 3 genes are identified, one of which is an apparent pseudogene. Transcripts of the P. berghei phist genes are predominant in schizonts, whereas in P. falciparum transcript profiles span different asexual blood stages and gametocytes. We pursued targeted disruption of P. berghei phist genes in order to characterize a simplistic model for the expanded phist gene repertoire in P. falciparum. Unsuccessful attempts to disrupt P. berghei PBANKA_114540 suggest that this phist gene is essential, while knockout of phist PBANKA_122900 shows an apparent normal progression and non-essential function throughout the life cycle. Epitope-tagging of P. falciparum and P. berghei phist genes confirmed protein export to the erythrocyte cytoplasm and localization with a punctate pattern. Three P. berghei PEXEL/HT-positive exported proteins exhibit at least partial co-localization, in support of a common vesicular compartment in the cytoplasm of erythrocytes infected with rodent malaria parasites. PMID:27022937

  17. Development and Application of a Simple Plaque Assay for the Human Malaria Parasite Plasmodium falciparum

    PubMed Central

    Thomas, James A.; Collins, Christine R.; Das, Sujaan; Hackett, Fiona; Graindorge, Arnault; Bell, Donald; Deu, Edgar; Blackman, Michael J.

    2016-01-01

    Malaria is caused by an obligate intracellular protozoan parasite that replicates within and destroys erythrocytes. Asexual blood stages of the causative agent of the most virulent form of human malaria, Plasmodium falciparum, can be cultivated indefinitely in vitro in human erythrocytes, facilitating experimental analysis of parasite cell biology, biochemistry and genetics. However, efforts to improve understanding of the basic biology of this important pathogen and to develop urgently required new antimalarial drugs and vaccines, suffer from a paucity of basic research tools. This includes a simple means of quantifying the effects of drugs, antibodies and gene modifications on parasite fitness and replication rates. Here we describe the development and validation of an extremely simple, robust plaque assay that can be used to visualise parasite replication and resulting host erythrocyte destruction at the level of clonal parasite populations. We demonstrate applications of the plaque assay by using it for the phenotypic characterisation of two P. falciparum conditional mutants displaying reduced fitness in vitro. PMID:27332706

  18. High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission

    PubMed Central

    Plouffe, David M.; Wree, Melanie; Du, Alan Y.; Meister, Stephan; Li, Fengwu; Patra, Kailash; Lubar, Aristea; Okitsu, Shinji L.; Flannery, Erika L.; Kato, Nobutaka; Tanaseichuk, Olga; Comer, Eamon; Zhou, Bin; Kuhen, Kelli; Zhou, Yingyao; Leroy, Didier; Schreiber, Stuart L.; Scherer, Christina A.; Vinetz, Joseph; Winzeler, Elizabeth A.

    2016-01-01

    Summary Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chemical libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small molecules with transmission-blocking capacity. SaLSSA analysis of 13,983 unique compounds uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4-aminoquinolines, as well as compounds active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compounds with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiological differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs. PMID:26749441

  19. The Plasmodium PHIST and RESA-Like Protein Families of Human and Rodent Malaria Parasites

    PubMed Central

    Moreira, Cristina K.; Naissant, Bernina; Coppi, Alida; Bennett, Brandy L.; Aime, Elena; Franke-Fayard, Blandine; Janse, Chris J.; Coppens, Isabelle; Sinnis, Photini; Templeton, Thomas J.

    2016-01-01

    The phist gene family has members identified across the Plasmodium genus, defined by the presence of a domain of roughly 150 amino acids having conserved aromatic residues and an all alpha-helical structure. The family is highly amplified in P. falciparum, with 65 predicted genes in the genome of the 3D7 isolate. In contrast, in the rodent malaria parasite P. berghei 3 genes are identified, one of which is an apparent pseudogene. Transcripts of the P. berghei phist genes are predominant in schizonts, whereas in P. falciparum transcript profiles span different asexual blood stages and gametocytes. We pursued targeted disruption of P. berghei phist genes in order to characterize a simplistic model for the expanded phist gene repertoire in P. falciparum. Unsuccessful attempts to disrupt P. berghei PBANKA_114540 suggest that this phist gene is essential, while knockout of phist PBANKA_122900 shows an apparent normal progression and non-essential function throughout the life cycle. Epitope-tagging of P. falciparum and P. berghei phist genes confirmed protein export to the erythrocyte cytoplasm and localization with a punctate pattern. Three P. berghei PEXEL/HT-positive exported proteins exhibit at least partial co-localization, in support of a common vesicular compartment in the cytoplasm of erythrocytes infected with rodent malaria parasites. PMID:27022937

  20. Cyclic GMP Balance Is Critical for Malaria Parasite Transmission from the Mosquito to the Mammalian Host

    PubMed Central

    Lakshmanan, Viswanathan; Fishbaugher, Matthew E.; Morrison, Bob; Baldwin, Michael; Macarulay, Michael; Vaughan, Ashley M.; Mikolajczak, Sebastian A.

    2015-01-01

    ABSTRACT Transmission of malaria occurs during Anopheles mosquito vector blood meals, when Plasmodium sporozoites that have invaded the mosquito salivary glands are delivered to the mammalian host. Sporozoites display a unique form of motility that is essential for their movement across cellular host barriers and invasion of hepatocytes. While the molecular machinery powering motility and invasion is increasingly well defined, the signaling events that control these essential parasite activities have not been clearly delineated. Here, we identify a phosphodiesterase (PDEγ) in Plasmodium, a regulator of signaling through cyclic nucleotide second messengers. Reverse transcriptase PCR (RT-PCR) analysis and epitope tagging of endogenous PDEγ detected its expression in blood stages and sporozoites of Plasmodium yoelii. Deletion of PDEγ (pdeγ−) rendered sporozoites nonmotile, and they failed to invade the mosquito salivary glands. Consequently, PDEγ deletion completely blocked parasite transmission by mosquito bite. Strikingly, pdeγ− sporozoites showed dramatically elevated levels of cyclic GMP (cGMP), indicating that a perturbation in cyclic nucleotide balance is involved in the observed phenotypic defects. Transcriptome sequencing (RNA-Seq) analysis of pdeγ− sporozoites revealed reduced transcript abundance of genes that encode key components of the motility and invasion apparatus. Our data reveal a crucial role for PDEγ in maintaining the cyclic nucleotide balance in the malaria parasite sporozoite stage, which in turn is essential for parasite transmission from mosquito to mammal. PMID:25784701

  1. In vivo photoacoustic flow cytometry for early malaria diagnosis.

    PubMed

    Cai, Chengzhong; Carey, Kai A; Nedosekin, Dmitry A; Menyaev, Yulian A; Sarimollaoglu, Mustafa; Galanzha, Ekaterina I; Stumhofer, Jason S; Zharov, Vladimir P

    2016-06-01

    In vivo photoacoustic (PA) flow cytometry (PAFC) has already demonstrated a great potential for the diagnosis of deadly diseases through ultrasensitive detection of rare disease-associated circulating markers in whole blood volume. Here, we demonstrate the first application of this powerful technique for early diagnosis of malaria through label-free detection of malaria parasite-produced hemozoin in infected red blood cells (iRBCs) as high-contrast PA agent. The existing malaria tests using blood smears can detect the disease at 0.001-0.1% of parasitemia. On the contrary, linear PAFC showed a potential for noninvasive malaria diagnosis at an extremely low level of parasitemia of 0.0000001%, which is ∼10(3) times better than the existing tests. Multicolor time-of-flight PAFC with high-pulse repetition rate lasers at wavelengths of 532, 671, and 820 nm demonstrated rapid spectral and spatial identification and quantitative enumeration of individual iRBCs. Integration of PAFC with fluorescence flow cytometry (FFC) provided real-time simultaneous detection of single iRBCs and parasites expressing green fluorescence proteins, respectively. A combination of linear and nonlinear nanobubble-based multicolor PAFC showed capability to real-time control therapy efficiency by counting of iRBCs before, during, and after treatment. Our results suggest that high-sensitivity, high-resolution ultrafast PAFC-FFC platform represents a powerful research tool to provide the insight on malaria progression through dynamic study of parasite-cell interactions directly in bloodstream, whereas portable hand-worn PAFC device could be broadly used in humans for early malaria diagnosis. © 2016 International Society for Advancement of Cytometry. PMID:27078044

  2. Re-Emerging Malaria Vectors in Rural Sahel (nouna, Burkina Faso): the Paluclim Project

    NASA Astrophysics Data System (ADS)

    Vignolles, Cécile; Sauerborn, Rainer; Dambach, Peter; Viel, Christian; Soubeyroux, Jean-Michel; Sié, Ali; Rogier, Christophe; Tourre, Yves M.

    2016-06-01

    The Paluclim project applied the tele-epidemiology approach, linking climate, environment and public health (CNES, 2008), to rural malaria in Nouna (Burkina Faso). It was to analyze the climate impact on vectorial risks, and its consequences on entomological risks forecast. The objectives were to: 1) produce entomological risks maps in the Nouna region, 2) produce dynamic maps on larvae sites and their productivity, 3) study the climate impact on malaria risks, and 4) evaluate the feasibility of strategic larviciding approach.

  3. Analysis of Trend of Malaria Prevalence in the Ten Asian Countries from 2006 to 2011: A Longitudinal Study

    PubMed Central

    Roy, Shongkour; Khatun, Tanjina

    2015-01-01

    Background. To control the malaria mortality, the global and national communities have worked together and produced impressive results in the world. Some of the Asian counties' malaria mortality rate is more compared to countries with high health facilities around the world. This paper's main aim is to describe trend of malaria cases and mortality in 10 Asian countries using the World Health Organization data. Methods. Malaria mortality data was collected systematically from WHO and UN database for the period 2006–2011. We estimated malaria mortality by age and countries. We also explored the dynamic relationships among malaria death rate, total populations, and geographical region using a map. During 2006–2011, the average malaria death per 10,000 population of all ages was 0.239 (95% CI 0.104 to 0.373), of children aged less than 5 year 1.143 (0.598 to 1.687), and of age greater than 5 years 0.089 (0.043 to 0.137) in Asian countries. Malaria prevalence per 10,000 populations steadily decreased from 486.7 in 2006 to 298.9 in 2011. Conclusion. The findings show that malaria mortality is higher for children aged less than 5 years compared with with adults selected in Asian countries except Sri Lanka. PMID:26693382

  4. [Current malaria situation in Turkey].

    PubMed

    Gockchinar, T; Kalipsi, S

    2001-01-01

    Geographically, Turkey is situated in an area where malaria is very risky. The climatic conditions in the region are suitable for the malaria vector to proliferate. Due to agricultural infrastructural changes, GAP and other similar projects, insufficient environmental conditions, urbanization, national and international population moves, are a key to manage malaria control activities. It is estimated that malaria will be a potential danger for Turkey in the forthcoming years. The disease is located largely in south-eastern Anatolia. The Diyarbakir, Batman, Sanliurfa, Siirt, and Mardin districts are the most affected areas. In western districts, like Aydin and Manisa, an increase in the number of indigenous cases can be observed from time to time. This is due to workers moving from malaria districts to western parts to final work. Since these workers cannot be controlled, the population living in these regions get infected from indigenous cases. There were 84,345 malaria cases in 1994 and 82,096 in 1995, they decreased to 60,884 in 1996 and numbered 35,456 in 1997. They accounted for 36,842 and 20,963 in 1998 and 1999, respectively. In Turkey there are almost all cases of P. vivax malaria. There are also P. vivax and P. falciparum malaria cases coming from other countries: There were 321 P. vivax cases, including 2 P. falciparum ones, arriving to Turkey from Iraq in 1995. The P. vivax malaria cases accounted for 229 in 1996, and 67, cases P. vivax including 12 P. falciparum cases, in 1997, and 4 P. vivax cases in 1998 that came from that country. One P. vivax case entered Turkey from Georgia in 1998. The cause of higher incidence of P. vivax cases in 1995, it decreasing in 1999, is the lack of border controls over workers coming to Turkey. The other internationally imported cases are from Syria, Sudan, Pakistan, Afghanistan, Nigeria, India, Azerbaijan, Malaysia, Ghana, Indonesia, Yemen. Our examinations have shown that none of these internationally imported cases

  5. [Current malaria situation in Turkmenistan].

    PubMed

    Amangel'diev, K A

    2001-01-01

    Malaria is one of the main health problems facing most developing countries having a hot climate. It is a problem in Turkmenistan. The country is situated in Central Asia, north of the Kopetdag mountains, between the Caspian Sea to the west and the Amu-Darya river to the east. Turkmenistan stretches for a distance of 1,100 km from west to east and 650 km from north to south. It borders Kazakhstan in the north, Uzbekistan in the east and north-east, Iran in the south, and Afghanistan in the south-east. Seven malaria vector species are found in Turkmenistan, the main ones being Anopheles superpictus, An. pulcherrimus, and An. martinius. The potentially endemic area consists of the floodplains of the Tejen and Murgab rivers, with a long chain of reservoirs built along them. In 1980 most cases of imported malaria were recorded in military personnel who had returned from service in Afghanistan. In the past years, only tertian (Plasmodium vivax) malaria has been recorded and there have been no death from malaria over that period. In the Serkhetabad (Gushgi) district there are currently 5 active foci of malaria infection, with a population of 22,000 people. In 1999, forty nine cases of P. vivax malaria were recorded in Turkmenistan. Of them, 36 cases, including 4 children under 14 years were diagnosed for the first time while 13 were relapses. There were 88 fewer cases than those in the previous year (by a factor of 2.8). There were 17 more cases of imported malaria than those in 1998 (by a factor of 1.7), most of which occurred in the foci of malaria infection (Serkhetabad, Tagtabazar, and Kerki districts), in the city of Ashkhabat and in Lebap, Dashkhovuz and Akhal Regions. The emergence of indigenous malaria in the border areas was due to the importation of the disease at intervals by infected mosquitoes flying in from neighbouring countries (e.g. Afghanistan), the lack of drugs to treat the first cases and the lack of alternative insecticides. Most patients suffer

  6. Malaria in Brazil: an overview

    PubMed Central

    2010-01-01

    Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in

  7. Choosing a Drug to Prevent Malaria

    MedlinePlus

    ... a CDC Malaria Branch clinician. malaria@cdc.gov File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  8. Malaria Vaccine Shows Promise in Small Study

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_158765.html Malaria Vaccine Shows Promise in Small Study It protected more ... May 10, 2016 (HealthDay News) -- An experimental malaria vaccine protects a majority of adults against the mosquito- ...

  9. Mapping residual transmission for malaria elimination.

    PubMed

    Reiner, Robert C; Le Menach, Arnaud; Kunene, Simon; Ntshalintshali, Nyasatu; Hsiang, Michelle S; Perkins, T Alex; Greenhouse, Bryan; Tatem, Andrew J; Cohen, Justin M; Smith, David L

    2015-01-01

    Eliminating malaria from a defined region involves draining the endemic parasite reservoir and minimizing local malaria transmission around imported malaria infections . In the last phases of malaria elimination, as universal interventions reap diminishing marginal returns, national resources must become increasingly devoted to identifying where residual transmission is occurring. The needs for accurate measures of progress and practical advice about how to allocate scarce resources require new analytical methods to quantify fine-grained heterogeneity in malaria risk. Using routine national surveillance data from Swaziland (a sub-Saharan country on the verge of elimination), we estimated individual reproductive numbers. Fine-grained maps of reproductive numbers and local malaria importation rates were combined to show 'malariogenic potential', a first for malaria elimination. As countries approach elimination, these individual-based measures of transmission risk provide meaningful metrics for planning programmatic responses and prioritizing areas where interventions will contribute most to malaria elimination. PMID:26714110

  10. Malaria Vaccine Shows Promise in Small Study

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_158765.html Malaria Vaccine Shows Promise in Small Study It protected more ... May 10, 2016 (HealthDay News) -- An experimental malaria vaccine protects a majority of adults against the mosquito- ...

  11. Malaria infection and human evolution.

    PubMed

    Sabbatani, Sergio; Manfredi, Roberto; Fiorino, Sirio

    2010-03-01

    During the evolution of the genus Homo, with regard to the species habilis, erectus and sapiens, malaria has played a key biological role in influencing human development. The plasmodia causing malaria have evolved in two ways, in biological and phylogenetic terms: Plasmodium vivax, Plasmodium malariae and Plasmodium ovale appear to have either coevolved with human mankind, or encountered human species during the most ancient phases of Homo evolution; on the other hand, Plasmodium falciparum has been transmitted to humans by monkeys in a more recent period, probably between the end of the Mesolithic and the beginning of the Neolithic age. The authors show both direct and indirect biomolecular evidence of malarial infection, detected in buried subjects, dating to ancient times and brought to light in the course of archaeological excavations in major Mediterranean sites. In this review of the literature the authors present scientific evidence confirming the role of malaria in affecting the evolution of populations in Mediterranean countries. The people living in several different Mediterranean regions, the cradle of western civilization, have been progressively influenced by malaria in the course of the spread of this endemic disease in recent millennia. In addition, populations affected by endemic malaria progressively developed cultural, dietary and behavioural adaptation mechanisms, which contributed to diminish the risk of disease. These habits were probably not fully conscious. Nevertheless it may be thought that both these customs and biological modifications, caused by malarial plasmodia, favoured the emergence of groups of people with greater resistance to malaria. All these factors have diminished the unfavourable demographic impact of the disease, also positively influencing the general development and growth of civilization. PMID:20424529

  12. The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission

    PubMed Central

    Santos, Jorge M.; Kehrer, Jessica; Franke-Fayard, Blandine; Frischknecht, Friedrich; Janse, Chris J.; Mair, Gunnar R.

    2015-01-01

    The post-translational addition of C-16 long chain fatty acids to protein cysteine residues is catalysed by palmitoyl-S-acyl-transferases (PAT) and affects the affinity of a modified protein for membranes and therefore its subcellular localisation. In apicomplexan parasites this reversible protein modification regulates numerous biological processes and specifically affects cell motility, and invasion of host cells by Plasmodium falciparum merozoites and Toxoplasma gondii tachyzoites. Using inhibitor studies we show here that palmitoylation is key to transformation of zygotes into ookinetes during initial mosquito infection with P. berghei. We identify DHHC2 as a unique PAT mediating ookinete formation and morphogenesis. Essential for life cycle progression in asexual blood stage parasites and thus refractory to gene deletion analyses, we used promoter swap (ps) methodology to maintain dhhc2 expression in asexual blood stages but down regulate expression in sexual stage parasites and during post-fertilization development of the zygote. The ps mutant showed normal gamete formation, fertilisation and DNA replication to tetraploid cells, but was characterised by a complete block in post-fertilisation development and ookinete formation. Our report highlights the crucial nature of the DHHC2 palmitoyl-S-acyltransferase for transmission of the malaria parasite to the mosquito vector through its essential role for ookinete morphogenesis. PMID:26526684

  13. The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission.

    PubMed

    Santos, Jorge M; Kehrer, Jessica; Franke-Fayard, Blandine; Frischknecht, Friedrich; Janse, Chris J; Mair, Gunnar R

    2015-01-01

    The post-translational addition of C-16 long chain fatty acids to protein cysteine residues is catalysed by palmitoyl-S-acyl-transferases (PAT) and affects the affinity of a modified protein for membranes and therefore its subcellular localisation. In apicomplexan parasites this reversible protein modification regulates numerous biological processes and specifically affects cell motility, and invasion of host cells by Plasmodium falciparum merozoites and Toxoplasma gondii tachyzoites. Using inhibitor studies we show here that palmitoylation is key to transformation of zygotes into ookinetes during initial mosquito infection with P. berghei. We identify DHHC2 as a unique PAT mediating ookinete formation and morphogenesis. Essential for life cycle progression in asexual blood stage parasites and thus refractory to gene deletion analyses, we used promoter swap (ps) methodology to maintain dhhc2 expression in asexual blood stages but down regulate expression in sexual stage parasites and during post-fertilization development of the zygote. The ps mutant showed normal gamete formation, fertilisation and DNA replication to tetraploid cells, but was characterised by a complete block in post-fertilisation development and ookinete formation. Our report highlights the crucial nature of the DHHC2 palmitoyl-S-acyltransferase for transmission of the malaria parasite to the mosquito vector through its essential role for ookinete morphogenesis. PMID:26526684

  14. Amino acid efflux by asexual blood-stage Plasmodium falciparum and its utility in interrogating the kinetics of hemoglobin endocytosis and catabolism in vivo.

    PubMed

    Dalal, Seema; Klemba, Michael

    2015-06-01

    The endocytosis and catabolism of large quantities of host cell hemoglobin is a hallmark of the intraerythrocytic asexual stage of the human malaria parasite Plasmodium falciparum. It is known that the parasite's production of amino acids from hemoglobin far exceeds its metabolic needs. Here, we show that P. falciparum effluxes large quantities of certain non-polar (Ala, Leu, Val, Pro, Phe, Gly) and polar (Ser, Thr, His) amino acids to the external medium. That these amino acids originate from hemoglobin catabolism is indicated by the strong correlation between individual amino acid efflux rates and their abundances in hemoglobin, and the ability of the food vacuole falcipain inhibitor E-64d to greatly suppress efflux rates. We then developed a rapid, sensitive and precise method for quantifying flux through the hemoglobin endocytic-catabolic pathway that is based on leucine efflux. Optimization of the method involved the generation of a novel amino acid-restricted RPMI formulation as well as the validation of D-norvaline as an internal standard. The utility of this method was demonstrated by characterizing the effects of the phosphatidylinositol-3-kinase inhibitors wortmannin and dihydroartemisinin on the kinetics of Leu efflux. Both compounds rapidly inhibited Leu efflux, which is consistent with a role for phosphtidylinositol-3-phosphate production in the delivery of hemoglobin to the food vacuole; however, wortmannin inhibition was transient, which was likely due to the instability of this compound in culture medium. The simplicity, convenience and non-invasive nature of the Leu efflux assay described here makes it ideal for characterizing the in vivo kinetics of hemoglobin endocytosis and catabolism, for inhibitor target validation studies, and for medium-throughput screens to identify novel inhibitors of cytostomal endocytosis. PMID:26215764

  15. Amino acid efflux by asexual blood-stage Plasmodium falciparum and its utility in interrogating the kinetics of hemoglobin endocytosis and catabolism in vivo

    PubMed Central

    Dalal, Seema; Klemba, Michael

    2015-01-01

    The endocytosis and catabolism of large quantities of host cell hemoglobin is a hallmark of the intraerythrocytic asexual stage of the human malaria parasite Plasmodium falciparum. It is known that the parasite’s production of amino acids from hemoglobin far exceeds its metabolic needs. Here, we show that P. falciparum effluxes large quantities of certain non-polar (Ala, Leu, Val, Pro, Phe, Gly) and polar (Ser, Thr, His) amino acids to the external medium. That these amino acids originate from hemoglobin catabolism is indicated by the strong correlation between individual amino acid efflux rates and their abundances in hemoglobin, and the ability of the food vacuole falcipain inhibitor E-64d to greatly suppress efflux rates. We then developed a rapid, sensitive and precise method for quantifying flux through the hemoglobin endocytic-catabolic pathway that is based on leucine efflux. Optimization of the method involved the generation of a novel amino acid-restricted RPMI formulation as well as the validation of D-norvaline as an internal standard. The utility of this method was demonstrated by characterizing the effects of the phosphatidylinositol-3-kinase inhibitors wortmannin and dihydroartemisinin on the kinetics of Leu efflux. Both compounds rapidly inhibited Leu efflux, which is consistent with a role for phosphtidylinositol-3-phosphate production in the delivery of hemoglobin to the food vacuole; however, wortmannin inhibition was transient, which was likely due to the instability of this compound in culture medium. The simplicity, convenience and non-invasive nature of the Leu efflux assay described here makes it ideal for characterizing the in vivo kinetics of hemoglobin endocytosis and catabolism, for inhibitor target validation studies, and for medium-throughput screens to identify novel inhibitors of cytostomal endocytosis. PMID:26215764

  16. Malaria research and eradication in the USSR

    PubMed Central

    Bruce-Chwatt, Leonard J.

    1959-01-01

    Relatively little is known outside the USSR about the past history of malaria in that country, the contribution of its scientists to malaria research, the recent progress of Soviet malariology, or the achievements of the Soviet Union in the eradication of malaria. These achievements are of particular interest because the general strategy of malaria eradication in the USSR has many technical, administrative, and economic and social features not seen elsewhere. PMID:13805136

  17. An Integrated Atmospheric and Hydrological Based Malaria Epidemic Alert System

    NASA Astrophysics Data System (ADS)

    Asefi Najafabady, S.; Li, J.; Nair, U. S.; Welch, R. M.; Srivastava, A.; Nagpal, B. N.; Saxena, R.; Benedict, M. E.

    2005-05-01

    Malaria is a growing global threat, with increasing morbidity and mortality. In India there have been >40 epidemics in the last five years, in part due to abnormal meteorological conditions as well as the buildup of an immunologically naïve population. In most parts of India, periodic epidemics of malaria occur every five to seven years. Malaria epidemics are serious national/regional health emergencies, occurring with little or no warning where the public health system is unprepared to respond to the emerging problem. However, epidemic conditions develop over several weeks, theoretically allowing time for preventative action. The study area for the proposed research is located in Mewat, south of Delhi. It is estimated that 90% of the malaria burden is influenced by environmental factors, so that successful malaria intervention approaches must be adapted to local environmental conditions. Of particular importance are air and water temperature, relative humidity, soil moisture, and precipitation. Extreme climatic conditions prevail in Mewat, with uneven topography, 450mm average annual rainfall in 25 to 35 days, high temperature variability in different seasons, low relative humidity. Automated surface measurements are obtained for temperature, relative humidity, water temperature, precipitation and soil moisture. The Regional Atmospheric Modeling System (RAMS) is used to predict these variables over the spatial domain which are used in dynamic hydrological models to yield the parameters important to malaria transmission, including surface wetness, mean water table depth, percent surface saturation and total surface runoff. The locations of saturated surface regions associated with mosquito breeding sites near populated regions, along with water temperature, and then are used to determine larvae development and mosquito abundance. ASTER, LANDSAT and MODIS imagery are used to retrieve soil moisture, vegetation indices and land cover types. Pan-sharpened 1m spatial

  18. Plant-Mediated Effects on Mosquito Capacity to Transmit Human Malaria

    PubMed Central

    Hien, Domonbabele F. d. S.; Roche, Benjamin; Diabaté, Abdoulaye; Yerbanga, Rakiswende S.; Cohuet, Anna; Yameogo, Bienvenue K.; Gouagna, Louis-Clément; Hopkins, Richard J.; Ouedraogo, Georges A.; Simard, Frédéric; Ignell, Rickard; Lefevre, Thierry

    2016-01-01

    The ecological context in which mosquitoes and malaria parasites interact has received little attention, compared to the genetic and molecular aspects of malaria transmission. Plant nectar and fruits are important for the nutritional ecology of malaria vectors, but how the natural diversity of plant-derived sugar sources affects mosquito competence for malaria parasites is unclear. To test this, we infected Anopheles coluzzi, an important African malaria vector, with sympatric field isolates of Plasmodium falciparum, using direct membrane feeding assays. Through a series of experiments, we then examined the effects of sugar meals from Thevetia neriifolia and Barleria lupilina cuttings that included flowers, and fruit from Lannea microcarpa and Mangifera indica on parasite and mosquito traits that are key for determining the intensity of malaria transmission. We found that the source of plant sugar meal differentially affected infection prevalence and intensity, the development duration of the parasites, as well as the survival and fecundity of the vector. These effects are likely the result of complex interactions between toxic secondary metabolites and the nutritional quality of the plant sugar source, as well as of host resource availability and parasite growth. Using an epidemiological model, we show that plant sugar source can be a significant driver of malaria transmission dynamics, with some plant species exhibiting either transmission-reducing or -enhancing activities. PMID:27490374

  19. Climate change and highland malaria: fresh air for a hot debate.

    PubMed

    Chaves, Luis Fernando; Koenraadt, Constantianus J M

    2010-03-01

    In recent decades, malaria has become established in zones at the margin of its previous distribution, especially in the highlands of East Africa. Studies in this region have sparked a heated debate over the importance of climate change in the territorial expansion of malaria, where positions range from its neglect to the reification of correlations as causes. Here, we review studies supporting and rebutting the role of climatic change as a driving force for highland invasion by malaria. We assessed the conclusions from both sides of the argument and found that evidence for the role of climate in these dynamics is robust. However, we also argue that over-emphasizing the importance of climate is misleading for setting a research agenda, even one which attempts to understand climate change impacts on emerging malaria patterns. We review alternative drivers for the emergence of this disease and highlight the problems still calling for research if the multidimensional nature of malaria is to be adequately tackled. We also contextualize highland malaria as an ongoing evolutionary process. Finally, we present Schmalhausen's law, which explains the lack of resilience in stressed systems, as a biological principle that unifies the importance of climatic and other environmental factors in driving malaria patterns across different spatio-temporal scales. PMID:20337259

  20. Conflict in Neighboring Countries, a Great Risk for Malaria Elimination in Southwestern Iran: Narrative Review Article.

    PubMed

    Molaee Zadeh, Maryam; Shahandeh, Khandan; Bigdeli, Shahla; Basseri, Hamid Reza

    2014-12-01

    The intensity of the conflict such as war is one of the determinants of the flow of migrants and refuges with consequence of introducing infectious disease to other countries. This paper investigates the relationship between malaria incidence and forced immigration due to war from neighboring countries in Dezful district, southwestern Iran. All available data and accessible archived documentary records on malaria cases in the period 1988-2011 in Dezful Health Centers were reviewed. Retrospective analysis of routine surveillance data from the Health authority of Dezful district was conducted to assess the trend of malaria incidence and prevalence in the last two decades. Malaria transmission dynamics was described using surveillance indicators viz, Annual Parasite Incidence (API), Slide Positivity Rate (SPR), Annual Blood Examination Rate (ABER) and based on personal information of patients. Two peaks of malaria incidence occurred during past two decades. The first one arisen by Iran-Iraq war due to residential instability in Dezful while the API reached to 8 per 1000. The second peak happened after to civil war of Afghanistan began which caused large immigrates moved into the study area. During the second peak, API reached 1.7 per 1000 at maximum and the majority of patients were immigrants. This study describes the linkage between incidence and prevalence of malaria and immigration due to civil conflict. Therefore, malaria screening of immigrants and early warning programme are effective to prevent outbreak of disease in a potential risk area such Dezful. PMID:26171354

  1. Testing Local Adaptation in a Natural Great Tit-Malaria System: An Experimental Approach

    PubMed Central

    Jenkins, Tania; Delhaye, Jessica; Christe, Philippe

    2015-01-01

    Finding out whether Plasmodium spp. are coevolving with their vertebrate hosts is of both theoretical and applied interest and can influence our understanding of the effects and dynamics of malaria infection. In this study, we tested for local adaptation as a signature of coevolution between malaria blood parasites, Plasmodium spp. and its host, the great tit, Parus major. We conducted a reciprocal transplant experiment of birds in the field, where we exposed birds from two populations to Plasmodium parasites. This experimental set-up also provided a unique opportunity to study the natural history of malaria infection in the wild and to assess the effects of primary malaria infection on juvenile birds. We present three main findings: i) there was no support for local adaptation; ii) there was a male-biased infection rate; iii) infection occurred towards the end of the summer and differed between sites. There were also site-specific effects of malaria infection on the hosts. Taken together, we present one of the few experimental studies of parasite-host local adaptation in a natural malaria system, and our results shed light on the effects of avian malaria infection in the wild. PMID:26555892

  2. Plant-Mediated Effects on Mosquito Capacity to Transmit Human Malaria.

    PubMed

    Hien, Domonbabele F D S; Dabiré, Kounbobr R; Roche, Benjamin; Diabaté, Abdoulaye; Yerbanga, Rakiswende S; Cohuet, Anna; Yameogo, Bienvenue K; Gouagna, Louis-Clément; Hopkins, Richard J; Ouedraogo, Georges A; Simard, Frédéric; Ouedraogo, Jean-Bosco; Ignell, Rickard; Lefevre, Thierry

    2016-08-01

    The ecological context in which mosquitoes and malaria parasites interact has received little attention, compared to the genetic and molecular aspects of malaria transmission. Plant nectar and fruits are important for the nutritional ecology of malaria vectors, but how the natural diversity of plant-derived sugar sources affects mosquito competence for malaria parasites is unclear. To test this, we infected Anopheles coluzzi, an important African malaria vector, with sympatric field isolates of Plasmodium falciparum, using direct membrane feeding assays. Through a series of experiments, we then examined the effects of sugar meals from Thevetia neriifolia and Barleria lupilina cuttings that included flowers, and fruit from Lannea microcarpa and Mangifera indica on parasite and mosquito traits that are key for determining the intensity of malaria transmission. We found that the source of plant sugar meal differentially affected infection prevalence and intensity, the development duration of the parasites, as well as the survival and fecundity of the vector. These effects are likely the result of complex interactions between toxic secondary metabolites and the nutritional quality of the plant sugar source, as well as of host resource availability and parasite growth. Using an epidemiological model, we show that plant sugar source can be a significant driver of malaria transmission dynamics, with some plant species exhibiting either transmission-reducing or -enhancing activities. PMID:27490374

  3. Endothelial Glycocalyx: Shedding Light on Malaria Pathogenesis.

    PubMed

    Hempel, Casper; Pasini, Erica M; Kurtzhals, Jørgen A L

    2016-06-01

    Malaria is estimated to kill 438 000 people annually, mostly due to severe malaria, which is closely associated with microcirculatory vasculopathy, although its pathogenesis remains incompletely understood. Here, we propose that the largely ignored glycocalyx of the vascular endothelium plays an important role in facilitating the pathogenesis of severe malaria. PMID:27161599

  4. Averting a malaria disaster: will insecticide resistance derail malaria control?

    PubMed

    Hemingway, Janet; Ranson, Hilary; Magill, Alan; Kolaczinski, Jan; Fornadel, Christen; Gimnig, John; Coetzee, Maureen; Simard, Frederic; Roch, Dabiré K; Hinzoumbe, Clément Kerah; Pickett, John; Schellenberg, David; Gething, Peter; Hoppé, Mark; Hamon, Nicholas

    2016-04-23

    World Malaria Day 2015 highlighted the progress made in the development of new methods of prevention (vaccines and insecticides) and treatment (single dose drugs) of the disease. However, increasing drug and insecticide resistance threatens the successes made with existing methods. Insecticide resistance has decreased the efficacy of the most commonly used insecticide class of pyrethroids. This decreased efficacy has increased mosquito survival, which is a prelude to rising incidence of malaria and fatalities. Despite intensive research efforts, new insecticides will not reach the market for at least 5 years. Elimination of malaria is not possible without effective mosquito control. Therefore, to combat the threat of resistance, key stakeholders need to rapidly embrace a multifaceted approach including a reduction in the cost of bringing new resistance management methods to market and the streamlining of associated development, policy, and implementation pathways to counter this looming public health catastrophe. PMID:26880124

  5. Anaemia of Plasmodium falciparum malaria.

    PubMed

    Phillips, R E; Pasvol, G

    1992-04-01

    The pathophysiology of the anaemia of falciparum malaria is both complex and multifactorial, and results in a condition which is a major cause of mortality and morbidity in patients, especially children and pregnant women, living in malarial endemic areas. The importance of anaemia as a cause of death in malaria may well be underestimated because of difficulty in diagnosis, especially where parasitaemia may be low and the clinical picture may be confused with other causes of anaemia. Two clinical presentations predominate: severe acute malaria in which anaemia supervenes, and severe anaemia in patients in whom there have been repeated attacks of malaria. The major mechanisms are those of red cell destruction and decreased red cell production. Potential causes of haemolysis include loss of infected cells by rupture or phagocytosis, removal of uninfected cells due to antibody sensitization or other physicochemical membrane changes, and increased reticuloendothelial activity, particularly in organs such as the spleen. Decreased production results from marrow hypoplasia seen in acute infections, and dyserythropoiesis, a morphological appearance, which in functional terms results in ineffective erythropoiesis. The role of parvovirus B19 as a possible cause of bone marrow aplasia in a few cases is postulated. Finally, there is now evidence which points to genetic factors, HLA associated, which may protect against the development of malarial anaemia and which has become common in areas endemic for malaria. PMID:1511178

  6. [Malaria in Poland in 2009].

    PubMed

    Stepiń, Małgorzata

    2011-01-01

    In Poland in 2009 were reported 22 malaria cases confirmed according to the EU case definition for the purposes of routine surveillance system. All of them were imported, including 1 case of recrudescence, 86% from Africa. In 18 cases P falciparum etiology was confirmed and in 2--P vivax, in 1--P ovale and 1 P malariae. Most cases occurred in the age group 21-40 years, there were 21 cases in males and 1 in female. Common reasons for travel to endemic countries were work-related visits (14 cases) and tourism (6 cases), one person who visited the family and in one case unknown reason for travel. Three persons used chemoprophylaxis during their travel but only one of them appropriately, relevant information was missing in 5 cases. Clinical course was severe in 7 cases of P falciparum malaria and medium-severe in one case. In 2009, there were no malaria deaths in Poland. Education on the prevention of malaria and pretravel health advising is still greatly needed. PMID:21913479

  7. Immuno-epidemiology of malaria

    PubMed Central

    van der Kaay, H. J.; Klein, F.; Hagenaar—de Weerdt, M.; Meuwissen, J. H. E. T.

    1973-01-01

    An investigation of malariometric indices in relation to immunoglobulin levels, rheumatoid factors, and antithyroglobulins was carried out on 78 members of the Arfak tribe near Manokwari in Western New Guinea, in the course of a WHO assessment of malaria control activities in that region. The population investigated had been exposed to a period of epidemic malaria, as indicated by the small differences in malariometric indices between consecutive age groups. Typically high spleen sizes were recorded, as found generally among Papuans in similar situations. Falciparum malaria was most prevalent, almost equal to cases of vivax and malariae malaria together. IgM levels were very high, while those of IgG, IgA and IgD were not elevated. Total serum protein was rather low. No correlation between malariometric indices, autoantibodies, and immunoglobulin levels could be found. In particular there was no correlation between IgM levels and spleen indices, such as has been found in many other surveys. It is suggested that splenomegaly may show no correlation with the IgM level in Papuan populations without previous selection. PMID:4211055

  8. Rifampicin/Cotrimoxazole/Isoniazid Versus Mefloquine or Quinine + Sulfadoxine- Pyrimethamine for Malaria: A Randomized Trial

    PubMed Central

    Genton, Blaise; Mueller, Ivo; Betuela, Inoni; Casey, Gerard; Ginny, Meza; Alpers, Michael P; Reeder, John C

    2006-01-01

    Objectives: Previous studies of a fixed combination including cotrimoxazole, rifampicin, and isoniazid (Cotrifazid) showed efficacy against resistant strains of Plasmodium falciparum in animal models and in small-scale human studies. We conducted a multicentric noninferiority trial to assess the safety and efficacy of Cotrifazid against drug-resistant malaria in Papua New Guinea. Design: The trial design was open-label, block-randomised, comparative, and multicentric. Setting: The trial was conducted in four primary care health facilities, two in urban and two in rural areas of Madang and East Sepik Province, Papua New Guinea. Participants: Patients of all ages with recurrent uncomplicated malaria were included. Interventions: Patients were randomly assigned to receive Cotrifazid, mefloquine, or the standard treatment of quinine with sulfadoxine–pyrimethamine (SP). Outcome Measures: Incidence of clinical and laboratory adverse events and rate of clinical and/or parasitological failure at day 14 were recorded. Results: The safety analysis population included 123 patients assigned to Cotrifazid, 123 to mefloquine, and 123 to quinine + SP. The Cotrifazid group experienced lower overall incidence of adverse events than the other groups. Among the efficacy analysis population (72 Cotrifazid, 71 mefloquine, and 75 quinine + SP), clinical failure rate (symptoms and parasite load) on day 14 was equivalent for the three groups (0% for Cotrifazid and mefloquine; 1% for quinine + SP), but parasitological failure rate (P. falciparum asexual blood-stage) was higher for Cotrifazid than for mefloquine or quinine + SP (9% [PCR corrected 8%] versus 0% and 3%, respectively [p = 0.02]). Conclusion: Despite what appears to be short-term clinical equivalence, the notable parasitological failure at day 14 in both P. falciparum and P. vivax makes Cotrifazid in its current formulation and regimen a poor alternative combination therapy for malaria. PMID:17192794

  9. Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

    PubMed Central

    Yuan, Lili; Wang, Ying; Parker, Daniel M.; Gupta, Bhavna; Yang, Zhaoqing; Liu, Huaie; Fan, Qi; Cao, Yaming; Xiao, Yuping; Lee, Ming-chieh; Zhou, Guofa; Yan, Guiyun; Baird, J. Kevin

    2014-01-01

    Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating. PMID:25512415

  10. [Malaria, anopheles, the anti-malaria campaign in French Guyana: between dogmatism and judgment].

    PubMed

    Raccurt, C P

    1997-01-01

    The recrudescence of malaria in French Guiana involves both border regions. One notes the predominance of Plasmodium falciparum along the Maroni River on the Surinam frontier and the transmission of both Plasmodium falciparum and Plasmodium vivax in amerindian settlements along the Oyapock River on the Brazilian frontier. The main mosquito vector is the endoexophile species, Anopheles darlingi. The role of man-biting forest anophelines in malaria transmission is still unclear. At the present time, malaria control is based on curative treatment of the confirmed cases (approximately 4,000 cases a year by active and passive screening). Vector control is supported by annual houses insecticides spraying and, to a lesser degree, use of insecticide-impregnated bednets. The main limiting factors for successful control have been difficulty in implementing a strategy adapted to the cultures of the amerindian and bushnegro populations living on either side of the river-frontiers and in organizing effective cross-border cooperation. The alleged role of immigration in transmission dynamics has been more speculative than real. However the growth of the population and the increase of human activities inside rain forest areas have favorized Anopheles darlingi breeding by uncontrolled deforestation. This situation need to be monitored closely. Information campaigns to improve public awareness could be useful. Following measures could improve control in sparsely populated, remote areas: to promote an integrated preventive program for a real community-wide distribution of primary health care; to discontinue insecticides spraying in houses which is poorly accepted by the bushnegro population and unsuitable to the amerindian dwellings; to support the use of personal protection; to initiate an effective anopheline larvae control; to determine the impact of the transmission during day-time activities especially among very small settlements far from the main villages where members of the

  11. Malaria in the WHO Southeast Asia region.

    PubMed

    Kondrashin, A V

    1992-09-01

    Malaria endemic countries in the southeast Asia region include Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, and Thailand. Population movement and rapid urbanization, both largely caused by unemployment, and environmental deterioration change the malaria pattern. They also increase the incidence of drug-resistant malaria, especially resistance to 4-aminoquinolines. In India, Plasmodium falciparum is linked to the density and distribution of tribals, and, in southern Thailand, rubber tappers have the highest malaria incidence rate (46.29%). Since the population is young and the young are highly sensitive to malaria infection, the region has low community immunity. High malaria priority areas are forests, forested hills, forest fringe areas, developmental project sites, and border areas. High risk groups include infants, young children, pregnant women, and mobile population groups. Malaria incidence is between 2.5-2.8 million cases, and the slide positivity rate is about 3%. P. falciparum constitutes 40% for all malaria cases. In 1988 in India, there were 222 malaria deaths. Malaria is the 7th most common cause of death in Thailand. 3 of the 19 Anopheline species are resistant to at least 1 insecticide, particularly DDT. Posteradication epidemics surfaced in the mid-1970s. Malaria control programs tend to use the primary health care and integration approach to malaria control. Antiparasite measures range from a single-dose of an antimalarial to mass drug administration. Residual spraying continues to be the main strategy of vector control. Some other vector control measures are fish feeding on mosquito larvae, insecticide impregnated mosquito nets, and repellents. Control programs also have health education activities. India allocates the highest percentage of its total health budget to malaria control (21.54%). Few malariology training programs exist in the region. Slowly processed surveillance data limit the countries' ability to

  12. Three-dimensional analysis of morphological changes in the malaria parasite infected red blood cell by serial block-face scanning electron microscopy.

    PubMed

    Sakaguchi, Miako; Miyazaki, Naoyuki; Fujioka, Hisashi; Kaneko, Osamu; Murata, Kazuyoshi

    2016-03-01

    The human malaria parasite, Plasmodium falciparum, exhibits morphological changes during the blood stage cycle in vertebrate hosts. Here, we used serial block-face scanning electron microscopy (SBF-SEM) to visualize the entire structures of P. falciparum-infected red blood cells (iRBCs) and to examine their morphological and volumetric changes at different stages. During developmental stages, the parasite forms Maurer's clefts and vesicles in the iRBC cytoplasm and knobs on the iRBC surface, and extensively remodels the iRBC structure for proliferation of the parasite. In our observations, the Maurer's clefts and vesicles in the P. falciparum-iRBCs, resembling the so-called tubovesicular network (TVN), were not connected to each other, and continuous membrane networks were not observed between the parasitophorous vacuole membrane (PVM) and the iRBC cytoplasmic membrane. In the volumetric analysis, the iRBC volume initially increased and then decreased to the end of the blood stage cycle. This suggests that it is necessary to absorb a substantial amount of nutrients from outside the iRBC during the initial stage, but to release waste materials from inside the iRBC at the multinucleate stage. Transportation of the materials may be through the iRBC membrane, rather than a special structure formed by the parasite, because there is no direct connection between the iRBC membrane and the parasite. These results provide new insights as to how the malaria parasite grows in the iRBC and remodels iRBC structure during developmental stages; these observation can serve as a baseline for further experiments on the effects of therapeutic agents on malaria. PMID:26772147

  13. Molecular Approaches to Malaria 2000.

    PubMed

    Cowman, Alan F.; Cooke, Brian M.

    2000-04-01

    For more than 20 years now, Australia has been officially free of endemic malaria, but this devastating disease once again made a major impact on the continent in February 2000 when Melbourne hosted Australia's first major international conference on 'Molecular Approaches to Malaria' (Lorne, Australia, 2-5 February 2000). The global research effort toward our increased understanding of the pathogenesis and control of malaria in the post-genomics era was discussed and debated at length over 4 days packed with science encompassing molecular biology, cell biology, clinical studies, genomics, vaccines and pathogenic mechanisms. More than 260 researchers from 18 countries worldwide participated in this interdisciplinary meeting which comprised 57 oral presentations and 122 posters. Here we summarize some presentations pertinent to the field of drug action and resistance. Copyright 2000 Harcourt Publishers Ltd. PMID:11498369

  14. A perspective on malaria vaccines

    PubMed Central

    Desowitz, R. S.; Miller, L. H.

    1980-01-01

    The data obtained with adjuvant—antigen vaccines against asexual malaria parasites in different host—parasite systems are reviewed. From these data the problems associated with antimalarial vaccine development and testing are considered. The requirement for an adjuvant to induce immunity and the type of adjuvant required depends primarily on the host. Since the immune response of man to malaria vaccines is unknown, it is impossible to predict which animal infection is most likely to be a faithful model of malaria in man although it is generally assumed that the monkey is the most appropriate analogue. Therefore careful studies of the immune response of monkeys to purified malarial antigens are needed to develop vaccines for testing in man. PMID:6783333

  15. Exchange Transfusion in Severe Falciparum Malaria

    PubMed Central

    Khatib, Khalid Ismail

    2016-01-01

    Malaria is endemic in India with the incidence of P. falciparum Malaria increasing gradually over the last decade. Severe malaria is an acute disease, caused by P. falciparum, but increasingly also by P. vivax with major signs of organ dysfunction and/or high levels of parasitaemia (>10%) in blood smear. Use of exchange transfusion with antimalarial drug therapy as an additional modality of treatment in severe Falciparum malaria is controversial and is unclear. We report a case of severe malaria complicated by multiorgan failure and ARDS. Patient responded well to manual exchange transfusion with standard artesunate-based chemotherapy. PMID:27042503

  16. [Agricultural activities and epidemiology of malaria in Soudano-Sahelian zone in Cameroon].

    PubMed

    Atangana, J; Fomena, A; Tamesse, J Lebel; Fondjo, E

    2012-02-01

    We have comparatively studied the dynamics of malaria transmission in the villages of Mokolo-Douvar located in the rural area with traditional agriculture and Gounougou irrigated rice area, in 2004 August and November and 2006 May and October, to assess vectors biting habits, and malaria inoculation rate and malaria parasite prevalence in cohort of children from 0 to 15 years. Mosquitoes were collected by landing catches on volunteers and by pyrethrum spray collections. A total of 5961 Anopheles were collected. Seven Anopheles species were identified: Anopheles gambiae s.s., Anopheles arabiensis, Anopheles funestus, Anopheles pharoensis, Anopheles rufipes, Anopheles ziemanni and Anopheles squamosus. A. arabiensis was the major species (56.2%) and the main malaria vector in both study sites, followed by A. funestus (32.6%). Malaria transmission was high in the irrigated area of Gounougou (1.42 infection bites per man per night) whereas in the non-irrigated zone of Mokolo-Douvar, it was below detection level during the rainy season (0,245 ib/h/n). In Gounougou, a total of 655 children were examined. The mean plasmodic index was 21.1%. Our findings confirm that changes in irrigated rice agriculture influence malaria transmission dynamics, and call for control measures that are readily adapted to local eco-epidemiological settings. PMID:22294407

  17. Clinical Aspects of Uncomplicated and Severe Malaria

    PubMed Central

    Bartoloni, Alessandro; Zammarchi, Lorenzo

    2012-01-01

    The first symptoms of malaria, common to all the different malaria species, are nonspecific and mimic a flu-like syndrome. Although fever represents the cardinal feature, clinical findings in malaria are extremely diverse and may range in severity from mild headache to serious complications leading to death, particularly in falciparum malaria. As the progression to these complications can be rapid, any malaria patient must be assessed and treated rapidly, and frequent observations are needed to look for early signs of systemic complications. In fact, severe malaria is a life threatening but treatable disease. The protean and nonspecific clinical findings occurring in malaria (fever, malaise, headache, myalgias, jaundice and sometimes gastrointestinal symptoms of nausea, vomiting and diarrhoea) may lead physicians who see malaria infrequently to a wrong diagnosis, such as influenza (particularly during the seasonal epidemic flu), dengue, gastroenteritis, typhoid fever, viral hepatitis, encephalitis. Physicians should be aware that malaria is not a clinical diagnosis but must be diagnosed, or excluded, by performing microscopic examination of blood films. Prompt diagnosis and appropriate treatment are then crucial to prevent morbidity and fatal outcomes. Although Plasmodium falciparum malaria is the major cause of severe malaria and death, increasing evidence has recently emerged that Plasmodium vivax and Plasmodium knowlesi can also be severe and even fatal. PMID:22708041

  18. Protease-associated cellular networks in malaria parasite Plasmodium falciparum

    PubMed Central

    2011-01-01

    Background Malaria continues to be one of the most severe global infectious diseases, responsible for 1-2 million deaths yearly. The rapid evolution and spread of drug resistance in parasites has led to an urgent need for the development of novel antimalarial targets. Proteases are a group of enzymes that play essential roles in parasite growth and invasion. The possibility of designing specific inhibitors for proteases makes them promising drug targets. Previously, combining a comparative genomics approach and a machine learning approach, we identified the complement of proteases (degradome) in the malaria parasite Plasmodium falciparum and its sibling species [1-3], providing a catalog of targets for functional characterization and rational inhibitor design. Network analysis represents another route to revealing the role of proteins in the biology of parasites and we use this approach here to expand our understanding of the systems involving the proteases of P. falciparum. Results We investigated the roles of proteases in the parasite life cycle by constructing a network using protein-protein association data from the STRING database [4], and analyzing these data, in conjunction with the data from protein-protein interaction assays using the yeast 2-hybrid (Y2H) system [5], blood stage microarray experiments [6-8], proteomics [9-12], literature text mining, and sequence homology analysis. Seventy-seven (77) out of 124 predicted proteases were associated with at least one other protein, constituting 2,431 protein-protein interactions (PPIs). These proteases appear to play diverse roles in metabolism, cell cycle regulation, invasion and infection. Their degrees of connectivity (i.e., connections to other proteins), range from one to 143. The largest protease-associated sub-network is the ubiquitin-proteasome system which is crucial for protein recycling and stress response. Proteases are also implicated in heat shock response, signal peptide processing, cell cycle

  19. Serological investigations in retrospective diagnosis of malaria.

    PubMed

    Draper, C C; Sirr, S S

    1980-06-28

    Sera were obtained in 415 known cases of malaria (88 residents, 327 immigrants) at different times after diagnosis. Three antigens were used in the indirect fluorscence antibody test to detect antibodies to either Plasmodium falciparum or P vivax. Results in residents and immigrants were analysed separately. Most residents had detectable antibodies within one week after an attack, which began to wane after a month. The strongest reactions were obtained in cases of falciparum malaria with the homologous antigen and in cases of vivax malaria with P fieldi. The overall pattern of results was the same in the immigrants but the proportions positive for malaria antibodies, mean titres, persistence of antibodies, and the cross-reaction were usually greater. Testing for malaria antibodies is probably of value in the retrospective differential diagnosis of malaria in patients who have not been exposed to malaria before but must be interpreted with caution in others. PMID:7000244

  20. Managing malaria in the intensive care unit

    PubMed Central

    Marks, M.; Gupta-Wright, A.; Doherty, J. F.; Singer, M.; Walker, D.

    2014-01-01

    The number of people travelling to malaria-endemic countries continues to increase, and malaria remains the commonest cause of serious imported infection in non-endemic areas. Severe malaria, mostly caused by Plasmodium falciparum, often requires intensive care unit (ICU) admission and can be complicated by cerebral malaria, respiratory distress, acute kidney injury, bleeding complications, and co-infection. The mortality from imported malaria remains significant. This article reviews the manifestations, complications and principles of management of severe malaria as relevant to critical care clinicians, incorporating recent studies of anti-malarial and adjunctive treatment. Effective management of severe malaria includes prompt diagnosis and early institution of effective anti-malarial therapy, recognition of complications, and appropriate supportive management in an ICU. All cases should be discussed with a specialist unit and transfer of the patient considered. PMID:24946778

  1. The Economic Case for Combating Malaria

    PubMed Central

    Purdy, Mark; Robinson, Matthew; Wei, Kuangyi; Rublin, David

    2013-01-01

    To date, existing studies focus largely on the economic detriments of malaria. However, if we are to create suitable incentives for larger-scale, more sustained anti-malaria efforts from a wider group of stakeholders, we need a much better understanding of the economic benefits of malaria reduction and elimination. Our report seeks to rectify this disjuncture by showing how attaining the funding needed to meet internationally agreed targets for malaria elimination would, on conservative assumptions, generate enormous economic improvements. We use a cost-benefit analysis anchored in Global Malaria Action Plan projections of malaria eradication based on fully met funding goals. By calculating the value of economic output accrued caused by work years saved and subtracting the costs of intervention, we find that malaria reduction and elimination during 2013–2035 has a 2013 net present value of US $208.6 billion. PMID:24197172

  2. The economic case for combating malaria.

    PubMed

    Purdy, Mark; Robinson, Matthew; Wei, Kuangyi; Rublin, David

    2013-11-01

    To date, existing studies focus largely on the economic detriments of malaria. However, if we are to create suitable incentives for larger-scale, more sustained anti-malaria efforts from a wider group of stakeholders, we need a much better understanding of the economic benefits of malaria reduction and elimination. Our report seeks to rectify this disjuncture by showing how attaining the funding needed to meet internationally agreed targets for malaria elimination would, on conservative assumptions, generate enormous economic improvements. We use a cost-benefit analysis anchored in Global Malaria Action Plan projections of malaria eradication based on fully met funding goals. By calculating the value of economic output accrued caused by work years saved and subtracting the costs of intervention, we find that malaria reduction and elimination during 2013-2035 has a 2013 net present value of US $208.6 billion. PMID:24197172

  3. The Suf Iron-Sulfur Cluster Synthesis Pathway Is Required for Apicoplast Maintenance in Malaria Parasites

    PubMed Central

    Gisselberg, Jolyn E.; Dellibovi-Ragheb, Teegan A.; Matthews, Krista A.; Bosch, Gundula; Prigge, Sean T.

    2013-01-01

    The apicoplast organelle of the malaria parasite Plasmodium falciparum contains metabolic pathways critical for liver-stage and blood-stage development. During the blood stages, parasites lacking an apicoplast can grow in the presence of isopentenyl pyrophosphate (IPP), demonstrating that isoprenoids are the only metabolites produced in the apicoplast which are needed outside of the organelle. Two of the isoprenoid biosynthesis enzymes are predicted to rely on iron-sulfur (FeS) cluster cofactors, however, little is known about FeS cluster synthesis in the parasite or the roles that FeS cluster proteins play in parasite biology. We investigated two putative FeS cluster synthesis pathways (Isc and Suf) focusing on the initial step of sulfur acquisition. In other eukaryotes, these proteins can be located in multiple subcellular compartments, raising the possibility of cross-talk between the pathways or redundant functions. In P. falciparum, SufS and its partner SufE were found exclusively the apicoplast and SufS was shown to have cysteine desulfurase activity in a complementation assay. IscS and its effector Isd11 were solely mitochondrial, suggesting that the Isc pathway cannot contribute to apicoplast FeS cluster synthesis. The Suf pathway was disrupted with a dominant negative mutant resulting in parasites that were only viable when supplemented with IPP. These parasites lacked the apicoplast organelle and its organellar genome – a phenotype not observed when isoprenoid biosynthesis was specifically inhibited with fosmidomycin. Taken together, these results demonstrate that the Suf pathway is essential for parasite survival and has a fundamental role in maintaining the apicoplast organelle in addition to any role in isoprenoid biosynthesis. PMID:24086138

  4. PTEX is an essential nexus for protein export in malaria parasites.

    PubMed

    Elsworth, Brendan; Matthews, Kathryn; Nie, Catherine Q; Kalanon, Ming; Charnaud, Sarah C; Sanders, Paul R; Chisholm, Scott A; Counihan, Natalie A; Shaw, Philip J; Pino, Paco; Chan, Jo-Anne; Azevedo, Mauro F; Rogerson, Stephen J; Beeson, James G; Crabb, Brendan S; Gilson, Paul R; de Koning-Ward, Tania F

    2014-07-31

    During the blood stages of malaria, several hundred parasite-encoded proteins are exported beyond the double-membrane barrier that separates the parasite from the host cell cytosol. These proteins have a variety of roles that are essential to virulence or parasite growth. There is keen interest in understanding how proteins are exported and whether common machineries are involved in trafficking the different classes of exported proteins. One potential trafficking machine is a protein complex known as the Plasmodium translocon of exported proteins (PTEX). Although PTEX has been linked to the export of one class of exported proteins, there has been no direct evidence for its role and scope in protein translocation. Here we show, through the generation of two parasite lines defective for essential PTEX components (HSP101 or PTEX150), and analysis of a line lacking the non-essential component TRX2 (ref. 12), greatly reduced trafficking of all classes of exported proteins beyond the double membrane barrier enveloping the parasite. This includes proteins containing the PEXEL motif (RxLxE/Q/D) and PEXEL-negative exported proteins (PNEPs). Moreover, the export of proteins destined for expression on the infected erythrocyte surface, including the major virulence factor PfEMP1 in Plasmodium falciparum, was significantly reduced in PTEX knockdown parasites. PTEX function was also essential for blood-stage growth, because even a modest knockdown of PTEX components had a strong effect on the parasite's capacity to complete the erythrocytic cycle both in vitro and in vivo. Hence, as the only known nexus for protein export in Plasmodium parasites, and an essential enzymic machine, PTEX is a prime drug target. PMID:25043043

  5. Direct Tests of Enzymatic Heme Degradation by the Malaria Parasite Plasmodium falciparum*

    PubMed Central

    Sigala, Paul A.; Crowley, Jan R.; Hsieh, Samantha; Henderson, Jeffrey P.; Goldberg, Daniel E.

    2012-01-01

    Malaria parasites generate vast quantities of heme during blood stage infection via hemoglobin digestion and limited de novo biosynthesis, but it remains unclear if parasites metabolize heme for utilization or disposal. Recent in vitro experiments with a heme oxygenase (HO)-like protein from Plasmodium falciparum suggested that parasites may enzymatically degrade some heme to the canonical HO product, biliverdin (BV), or its downstream metabolite, bilirubin (BR). To directly test for BV and BR production by P. falciparum parasites, we DMSO-extracted equal numbers of infected and uninfected erythrocytes and developed a sensitive LC-MS/MS assay to quantify these tetrapyrroles. We found comparable low levels of BV and BR in both samples, suggesting the absence of HO activity in parasites. We further tested live parasites by targeted expression of a fluorescent BV-binding protein within the parasite cytosol, mitochondrion, and plant-like plastid. This probe could detect exogenously added BV but gave no signal indicative of endogenous BV production within parasites. Finally, we recombinantly expressed and tested the proposed heme degrading activity of the HO-like protein, PfHO. Although PfHO bound heme and protoporphyrin IX with modest affinity, it did not catalyze heme degradation in vivo within bacteria or in vitro in UV absorbance and HPLC assays. These observations are consistent with PfHO's lack of a heme-coordinating His residue and suggest an alternative function within parasites. We conclude that P. falciparum parasites lack a canonical HO pathway for heme degradation and thus rely fully on alternative mechanisms for heme detoxification and iron acquisition during blood stage infection. PMID:22992734

  6. Interplay between insecticide-treated bed-nets and mosquito demography: implications for malaria control.

    PubMed

    Ngonghala, Calistus N; Mohammed-Awel, Jemal; Zhao, Ruijun; Prosper, Olivia

    2016-05-21

    Although malaria prevalence has witnessed a significant reduction within the past decade, malaria still constitutes a major health and economic problem, especially to low-income countries. Insecticide-treated nets (ITNs) remain one of the primary measures for preventing the malignant disease. Unfortunately, the success of ITN campaigns is hampered by improper use and natural decay in ITN-efficacy over time. Many models aimed at studying malaria transmission and control fail to account for this decay, as well as mosquito demography and feeding preferences exhibited by mosquitoes towards humans. Omitting these factors can misrepresent disease risk, while understanding their effects on malaria dynamics can inform control policy. We present a model for malaria dynamics that incorporates these factors, and a systematic analysis, including stability and sensitivity analyses of the model under different conditions. The model with constant ITN-efficacy exhibits a backward bifurcation emphasizing the need for sustained control measures until the basic reproduction number, R0, drops below a critical value at which control is feasible. The infectious and partially immune human populations and R0 are highly sensitive to the probability that a mosquito feeds successfully on a human, ITN coverage and the maximum biting rate of mosquitoes, irrespective of whether ITN-efficacy is constant or declines over time. This implies that ITNs play an important role in disease control. When ITN-efficacy wanes over time, we identify disease risks and corresponding ITN coverage, as well as feeding preference levels for which the disease can be controlled or eradicated. Our study leads to important insights that could assist in the design and implementation of better malaria control strategies. We conclude that ITNs that can retain their effectiveness for longer periods will be more appropriate in the fight against malaria and that making more ITNs available to highly endemic regions is

  7. DC8 and DC13 var Genes Associated with Severe Malaria Bind Avidly to Diverse Endothelial Cells

    PubMed Central

    Avril, Marion; Brazier, Andrew J.; Melcher, Martin; Sampath, Sowmya; Smith, Joseph D.

    2013-01-01

    During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels. This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host. Adhesion of infected erythrocytes is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a family of polymorphic adhesion proteins encoded by var genes. Whereas cerebral binding and severe malaria are associated with parasites expressing DC8 and DC13 var genes, relatively little is known about the non-brain endothelial selection on severe malaria adhesive types. In this study, we selected P. falciparum-IEs on diverse endothelial cell types and demonstrate that DC8 and DC13 var genes were consistently among the major var transcripts selected on non-brain endothelial cells (lung, heart, bone marrow). To investigate the molecular basis for this avid endothelial binding activity, recombinant proteins were expressed from the predominant upregulated DC8 transcript, IT4var19. In-depth binding comparisons revealed that multiple extracellular domains from this protein bound brain and non-brain endothelial cells, and individual domains largely did not discriminate between different endothelial cell types. Additionally, we found that recombinant DC8 and DC13 CIDR1 domains exhibited a widespread endothelial binding activity and could compete for DC8-IE binding to brain endothelial cells, suggesting they may bind the same host receptor. Our findings provide new insights into the interaction of severe malaria adhesive types and host blood vessels and support the hypothesis that parasites causing severe malaria express PfEMP1 variants with a superior ability to adhere to diverse endothelial cell types, and may therefore endow these parasites with a growth and transmission advantage. PMID:23825944

  8. Malaria: prevention in travellers

    PubMed Central

    2007-01-01

    Introduction Malaria transmission occurs most frequently in environments with humidity over 60% and ambient temperature of 25-30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10-14 days but can be up to 18 months depending on the strain of parasite. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in adult travellers? What are the effects of drug prophylaxis in adult travellers? What are the effects of antimalaria vaccines in travellers? What are the effects of antimalaria interventions in child travellers, pregnant travellers, and in airline pilots? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: acoustic buzzers, aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), doxycycline, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vaporising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines. PMID:19450348

  9. Malaria successes and challenges in Asia.

    PubMed

    Bhatia, Rajesh; Rastogi, Rakesh Mani; Ortega, Leonard

    2013-12-01

    Asia ranks second to Africa in terms of malaria burden. In 19 countries of Asia, malaria is endemic and 2.31 billion people or 62% of the total population in these countries are at risk of malaria. In 2010, WHO estimated around 34.8 million cases and 45,600 deaths due to malaria in Asia. In 2011, 2.7 million cases and > 2000 deaths were reported. India, Indonesia, Myanmar and Pakistan are responsible for >85% of the reported cases (confirmed) and deaths in Asia. In last 10 yr, due to availability of donor's fund specially from Global fund, significant progress has been made by the countries in Asia in scaling-up malaria control interventions which were instrumental in reducing malaria morbidity and mortality significantly. There is a large heterogeneity in malaria epidemiology in Asia. As a result, the success in malaria control/elimination is also diverse. As compared to the data of the year 2000, out of 19 malaria endemic countries, 12 countries were able to reduce malaria incidence (microscopically confirmed cases only) by 75%. Two countries, namely Bangladesh and Malaysia are projected to reach 75% reduction by 2015 while India is projected to reach 50-75% only by 2015. The trend could not be assessed in four countries, namely Indonesia, Myanmar, Pakistan and Timor-Leste due to insufficient consistent data. Numerous key challenges need to be addressed to sustain the gains and eliminate malaria in most parts of Asia. Some of these are to control the spread of resistance in Plasmodium falciparum to artemisinin, control of outdoor transmission, control of vivax malaria and ensuring universal coverage of key interventions. Asia has the potential to influence the malaria epidemiology all over the world as well as to support the global efforts in controlling and eliminating malaria through production of quality-assured ACTs, RDTs and long-lasting insecticidal nets. PMID:24499845

  10. Ongoing challenges in the management of malaria

    PubMed Central

    Kokwaro, Gilbert

    2009-01-01

    This article gives an overview of some of the ongoing challenges that are faced in the prevention, diagnosis and treatment of malaria. Malaria causes approximately 881,000 deaths every year, with nine out of ten deaths occurring in sub-Saharan Africa. In addition to the human burden of malaria, the economic burden is vast. It is thought to cost African countries more than US$12 billion every year in direct losses. However, great progress in malaria control has been made in some highly endemic countries. Vector control is assuming a new importance with the significant reductions in malaria burden achieved using combined malaria control interventions in countries such as Zanzibar, Zambia and Rwanda. The proportion of patients treated for malaria who have a confirmed diagnosis is low in Africa compared with other regions of the world, with the result that anti-malarials could be used to treat patients without malaria, especially in areas where progress has been made in reducing the malaria burden and malaria epidemiology is changing. Inappropriate administration of anti-malarials could contribute to the spread of resistance and incurs unnecessary costs. Parasite resistance to almost all commonly used anti-malarials has been observed in the most lethal parasite species, Plasmodium falciparum. This has presented a major barrier to successful disease management in malaria-endemic areas. ACT (artemisinin-based combination therapy) has made a significant contribution to malaria control and to reducing disease transmission through reducing gametocyte carriage. Administering ACT to infants and small children can be difficult and time consuming. Specially formulating anti-malarials for this vulnerable population is vital to ease administration and help ensure that an accurate dose is received. Education of healthworkers and communities about malaria prevention, diagnosis and treatment is a vital component of effective case management, especially as diagnostic policies change

  11. An Open Source Business Model for Malaria

    PubMed Central

    Årdal, Christine; Røttingen, John-Arne

    2015-01-01

    Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, ‘closed’ publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more “open source” approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.’ President’s Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new

  12. An open source business model for malaria.

    PubMed

    Årdal, Christine; Røttingen, John-Arne

    2015-01-01

    Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new malaria

  13. Malaria Molecular Epidemiology: Lessons from the International Centers of Excellence for Malaria Research Network

    PubMed Central

    Escalante, Ananias A.; Ferreira, Marcelo U.; Vinetz, Joseph M.; Volkman, Sarah K.; Cui, Liwang; Gamboa, Dionicia; Krogstad, Donald J.; Barry, Alyssa E.; Carlton, Jane M.; van Eijk, Anna Maria; Pradhan, Khageswar; Mueller, Ivo; Greenhouse, Bryan; Andreina Pacheco, M.; Vallejo, Andres F.; Herrera, Socrates; Felger, Ingrid

    2015-01-01

    Molecular epidemiology leverages genetic information to study the risk factors that affect the frequency and distribution of malaria cases. This article describes molecular epidemiologic investigations currently being carried out by the International Centers of Excellence for Malaria Research (ICEMR) network in a variety of malaria-endemic settings. First, we discuss various novel approaches to understand malaria incidence and gametocytemia, focusing on Plasmodium falciparum and Plasmodium vivax. Second, we describe and compare different parasite genotyping methods commonly used in malaria epidemiology and population genetics. Finally, we discuss potential applications of molecular epidemiological tools and methods toward malaria control and elimination efforts. PMID:26259945

  14. 'Who's who' in renal sphaerosporids (Bivalvulida: Myxozoa) from common carp, Prussian carp and goldfish--molecular identification of cryptic species, blood stages and new members of Sphaerospora sensu stricto.

    PubMed

    Holzer, Astrid Sibylle; Bartošová, P; Pecková, H; Tyml, T; Atkinson, S; Bartholomew, J; Sipos, D; Eszterbauer, E; Dyková, I

    2013-01-01

    Myxozoans are a group of diverse, spore-forming metazoan microparasites bound to aquatic environments. Sphaerospora dykovae (previously S. renicola) causes renal sphaerosporosis and acute swim bladder inflammation (SBI) in juvenile Cyprinus carpio carpio, in central Europe. A morphologically similar species with comparably low pathogenicity, S. angulata has been described from C. c. carpio, Carassius auratus auratus and Carassius gibelio. To clarify uncertainties and ambiguities in taxon identification in these hosts we decided to re-investigate differences in spore morphology using a statistical approach, in combination with SSU and LSU rDNA sequence analyses. We found that developing spores of S. angulata and S. dykovae cannot be distinguished morphologically and designed a duplex PCR assay for the cryptic species that demonstrated S. dykovae is specific to C. c. carpio, whereas S. angulata infects C. a. auratus and C. gibelio. The molecular identification of myxozoan blood stages in common carp and goldfish, which had previously been ascribed to Sphaerospora spp. showed that approximately 75% of blood stages were from non-sphaerosporid coelozoic species infecting these cyprinids and more than 10% were from an alien species, Myxobilatus gasterostei, developing in sticklebacks. We hereby report non-selective myxozoan host invasion and multi-species infections, whose role in SBI still requires clarification. PMID:22917178

  15. Malaria epidemiological trends in Italy.

    PubMed

    Sabatinelli, G; Majori, G; D'Ancona, F; Romi, R

    1994-08-01

    Based on the official reports received from local health laboratories, an epidemiological analysis of malaria cases reported in Italy from 1989 to 1992 is presented. A total of 1,941 cases were reported, 1,287 among Italians and 654 among foreigners. The incidence of cases was on average 500 per year with a maximum in 1990. A slight, but constant decrease of incidence of malaria cases was recorded in this period among Italian citizens (-21.5%), while the incidence among foreigners increased (+80%). Plasmodium falciparum accounted for 74.2% of total infections, followed by P. vivax (19%). The highest number of cases was imported from Africa (86.5%), followed by Asia, South America, and Oceania. 11 cases were contracted in Europe (transfusion, airport and cryptic malaria). 26 people died from malaria during the four years, with a fatality rate of 2.3% among Italians. Other epidemiological features concerning incidence in the different categories of travellers, countries of infection, clinical and therapeutic aspects of cases, are also discussed. PMID:7843343

  16. [Malaria in Poland in 2007].

    PubMed

    Rosińska, Magdalena

    2009-01-01

    In Poland in 2007 there were 11 malaria cases confirmed according to the European Union cases definition reported through the routine surveillance system. All of them were imported, 82% from Africa, including 2 cases of relapse. Invasion with Plasmodium falciparum was diagnosed in 7 cases, mixed invasion in 2 cases and P. vivax- in one case. The majority of cases were in the age group 35-45 (8 cases) and were males (10 cases). Common reasons for travel to endemic countries were work-related (5 cases) and tourism or family visits (4 cases). Approximately half of the cases for whom the information was available used malaria chemoprophylaxis during their travel. Clinical course was severe in one case of P. falciparum malaria and the person died of the disease. The decreasing trend in malaria incidence in Poland is likely related to incomplete reporting as tourist and professional travel to endemic areas has not decreased and there is no indication of wider use ofchemoprophylaxis. PMID:19799261

  17. The Origin of Malignant Malaria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasmodium falciparum is the causative agent of malignant malaria, which is among the most severe human infectious diseases. Despite its overwhelming significance to human health, the parasite’s origins remain unclear. The favored origin hypothesis holds that P. falciparum and its closest known rel...

  18. Chemical biology: Knockout for malaria

    NASA Astrophysics Data System (ADS)

    Krysiak, Joanna; Sieber, Stephan A.

    2014-02-01

    Discovering and validating new targets is urgently required to tackle the rise in resistance to antimalarial drugs. Now, inhibition of the enzyme N-myristoyltransferase has been shown to prevent the formation of a critical subcellular organelle in the parasite that causes malaria, leading to death of the parasite.

  19. Confidential inquiry into malaria deaths.

    PubMed Central

    Dürrheim, D. N.; Frieremans, S.; Kruger, P.; Mabuza, A.; de Bruyn, J. C.

    1999-01-01

    The results of a confidential inquiry into mortality attributed to malaria in South Africa's Mpumalanga Province are being used to guide the design of strategies for improving the management of cases and reducing the probability of deaths from the disease. PMID:10212518

  20. Characterization of imported malaria, the largest threat to sustained malaria elimination from Sri Lanka.

    PubMed

    Dharmawardena, Priyani; Premaratne, Risintha G; Gunasekera, W M Kumudunayana T de A W; Hewawitarane, Mihirini; Mendis, Kamini; Fernando, Deepika

    2015-01-01

    Sri Lanka has reached zero indigenous malaria cases in November 2012, two years before its targeted deadline for elimination. Currently, the biggest threat to the elimination efforts are the risk of resurgence of malaria due to imported cases. This paper describes two clusters of imported malaria infections reported in 2013 and 2014, one among a group of Pakistani asylum-seekers resident in Sri Lanka, and the other amongst local fishermen who returned from Sierra Leone. The two clusters studied reveal the potential impact of imported malaria on the risk of reintroducing the disease, as importation is the only source of malaria in the country at present. In the event of a case occurring, detection is a major challenge both amongst individuals returning from malaria endemic countries and the local population, as malaria is fast becoming a "forgotten" disease amongst health care providers. In spite of a very good coverage of diagnostic services (microscopy and rapid diagnostic tests) throughout the country, malaria is being repeatedly overlooked by health care providers even when individuals present with fever and a recent history of travel to a malaria endemic country. Given the high receptivity to malaria in previously endemic areas of the country due to the prevalence of the vector mosquito, such cases pose a significant threat for the reintroduction of malaria to Sri Lanka. The challenges faced by the Anti Malaria Campaign and measures taken to prevent the resurgence of malaria are discussed here. PMID:25902716

  1. Ethical aspects of malaria control and research.

    PubMed

    Jamrozik, Euzebiusz; de la Fuente-Núñez, Vânia; Reis, Andreas; Ringwald, Pascal; Selgelid, Michael J

    2015-01-01

    Malaria currently causes more harm to human beings than any other parasitic disease, and disproportionally affects low-income populations. The ethical issues raised by efforts to control or eliminate malaria have received little explicit analysis, in comparison with other major diseases of poverty. While some ethical issues associated with malaria are similar to those that have been the subject of debate in the context of other infectious diseases, malaria also raises distinct ethical issues in virtue of its unique history, epidemiology, and biology. This paper provides preliminary ethical analyses of the especially salient issues of: (i) global health justice, (ii) universal access to malaria control initiatives, (iii) multidrug resistance, including artemisinin-based combination therapy (ACT) resistance, (iv) mandatory screening, (v) mass drug administration, (vi) benefits and risks of primaquine, and (vii) malaria in the context of blood donation and transfusion. Several ethical issues are also raised by past, present and future malaria research initiatives, in particular: (i) controlled infection studies, (ii) human landing catches, (iii) transmission-blocking vaccines, and (iv) genetically-modified mosquitoes. This article maps the terrain of these major ethical issues surrounding malaria control and elimination. Its objective is to motivate further research and discussion of ethical issues associated with malaria--and to assist health workers, researchers, and policy makers in pursuit of ethically sound malaria control practice and policy. PMID:26693920

  2. Urbanization and the global malaria recession

    PubMed Central

    2013-01-01

    Background The past century has seen a significant contraction in the global extent of malaria transmission, resulting in over 50 countries being declared malaria free, and many regions of currently endemic countries eliminating the disease. Moreover, substantial reductions in transmission have been seen since 1900 in those areas that remain endemic today. Recent work showed that this malaria recession was unlikely to have been driven by climatic factors, and that control measures likely played a significant role. It has long been considered, however, that economic development, and particularly urbanization, has also been a causal factor. The urbanization process results in profound socio-economic and landscape changes that reduce malaria transmission, but the magnitude and extent of these effects on global endemicity reductions are poorly understood. Methods Global data at subnational spatial resolution on changes in malaria transmission intensity and urbanization trends over the past century were combined to examine the relationships seen over a range of spatial and temporal scales. Results/Conclusions A consistent pattern of increased urbanization coincident with decreasing malaria transmission and elimination over the past century was found. Whilst it remains challenging to untangle whether this increased urbanization resulted in decreased transmission, or that malaria reductions promoted development, the results point to a close relationship between the two, irrespective of national wealth. The continuing rapid urbanization in malaria-endemic regions suggests that such malaria declines are likely to continue, particularly catalyzed by increasing levels of direct malaria control. PMID:23594701

  3. Genetic polymorphisms linked to susceptibility to malaria

    PubMed Central

    2011-01-01

    The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature. Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria. PMID:21929748

  4. Integrated Approach to Malaria Control

    PubMed Central

    Shiff, Clive

    2002-01-01

    Malaria draws global attention in a cyclic manner, with interest and associated financing waxing and waning according to political and humanitarian concerns. Currently we are on an upswing, which should be carefully developed. Malaria parasites have been eliminated from Europe and North America through the use of residual insecticides and manipulation of environmental and ecological characteristics; however, in many tropical and some temperate areas the incidence of disease is increasing dramatically. Much of this increase results from a breakdown of effective control methods developed and implemented in the 1960s, but it has also occurred because of a lack of trained scientists and control specialists who live and work in the areas of endemic infection. Add to this the widespread resistance to the most effective antimalarial drug, chloroquine, developing resistance to other first-line drugs such as sulfadoxine-pyrimethamine, and resistance of certain vector species of mosquito to some of the previously effective insecticides and we have a crisis situation. Vaccine research has proceeded for over 30 years, but as yet there is no effective product, although research continues in many promising areas. A global strategy for malaria control has been accepted, but there are critics who suggest that the single strategy cannot confront the wide range of conditions in which malaria exists and that reliance on chemotherapy without proper control of drug usage and diagnosis will select for drug resistant parasites, thus exacerbating the problem. An integrated approach to control using vector control strategies based on the biology of the mosquito, the epidemiology of the parasite, and human behavior patterns is needed to prevent continued upsurge in malaria in the endemic areas. PMID:11932233

  5. Using Malaria Medication for Leg Cramps Is Risky

    MedlinePlus

    ... Products Vaccines, Blood & Biologics Articulos en Espanol Using Malaria Medication for Leg Cramps is Risky Printer-friendly ... approved only to treat a certain type of malaria (uncomplicated malaria) caused by the parasite Plasmodium falciparum. ...

  6. Highly focused anopheline breeding sites and malaria transmission in Dakar

    PubMed Central

    Machault, Vanessa; Gadiaga, Libasse; Vignolles, Cécile; Jarjaval, Fanny; Bouzid, Samia; Sokhna, Cheikh; Lacaux, Jean-Pierre; Trape, Jean-François; Rogier, Christophe; Pagès, Frédéric

    2009-01-01

    Background Urbanization has a great impact on the composition of the vector system and malaria transmission dynamics. In Dakar, some malaria cases are autochthonous but parasite rates and incidences of clinical malaria attacks have been recorded at low levels. Ecological heterogeneity of malaria transmission was investigated in Dakar, in order to characterize the Anopheles breeding sites in the city and to study the dynamics of larval density and adult aggressiveness in ten characteristically different urban areas. Methods Ten study areas were sampled in Dakar and Pikine. Mosquitoes were collected by human landing collection during four nights in each area (120 person-nights). The Plasmodium falciparum circumsporozoite (CSP) index was measured by ELISA and the entomological inoculation rates (EIR) were calculated. Open water collections in the study areas were monitored weekly for physico-chemical characterization and the presence of anopheline larvae. Adult mosquitoes and hatched larvae were identified morphologically and by molecular methods. Results In September-October 2007, 19,451 adult mosquitoes were caught among which, 1,101 were Anopheles gambiae s.l. The Human Biting Rate ranged from 0.1 bites per person per night in Yoff Village to 43.7 in Almadies. Seven out of 1,101 An. gambiae s.l. were found to be positive for P. falciparum (CSP index = 0.64%). EIR ranged from 0 infected bites per person per year in Yoff Village to 16.8 in Almadies. The An. gambiae complex population was composed of Anopheles arabiensis (94.8%) and Anopheles melas (5.2%). None of the An. melas were infected with P. falciparum. Of the 54 water collection sites monitored, 33 (61.1%) served as anopheline breeding sites on at least one observation. No An. melas was identified among the larval samples. Some physico-chemical characteristics of water bodies were associated with the presence/absence of anopheline larvae and with larval density. A very close parallel between larval and adult

  7. From "forest malaria" to "bromeliad malaria": a case-study of scientific controversy and malaria control.

    PubMed

    Gadelha, P

    1994-08-01

    The article analyses the evolution of knowledge and rationale of control of a special case of malaria transmission based on Bromelia-Kerteszia complex. Since bromeliaceae function as a 'host of the carrier' and were previously associated with natural forests, the elucidation of bromeliad malaria historically elicited controversies concerning the imputation of Kertesziae as transmitters as well as over control strategies directed to bromelia eradication (manual removal, herbicides and deforestation), use of insecticides and chemoprophylaxis. Established authority, disciplinary traditions, conceptual premises and contemporary criteria for validating knowledge in the field partly explain the long time gap since Adolpho Lutz announced at the beginning of the century the existence of a new mosquito and breeding site as responsible for a 'forest malaria' epidemic occurring at a high altitude. The article brings attention to how economic, political and institutional determinants played an important role in redefining studies that led both in Trinidad and Brazil to the recognition of the importance of kerteszia transmission, including urban areas, and establishing new approaches to its study, most relevant of all the concurrence of broad ecological research. The article then describes the Brazilian campaign strategies which showed significant short-term results but had to wait four decades to achieve the goal of eradication due to the peculiar characteristics of this pathogenic complex. Finally, it brings attention to the importance of encompassing social values and discourses, in this case, environmental preservation, to understanding historical trends of malaria control programs. PMID:7898955

  8. The Plasmodium falciparum Antigen MB2 Induces Interferon-γ and Interleukin-10 Responses in Adults in Malaria Endemic Areas of Western Kenya

    PubMed Central

    Ochola, Lyticia A; Ng’wena, Gideon M; Noland, Gregory S; Ondigo, Bartholomew N; Ayodo, George; John, Chandy C

    2013-01-01

    Background: MB2 is a novel Plasmodium falciparum antigen of unknown function expressed in pre-erythrocytic and blood stages of infection in the human host. Interferon-gamma (IFN-γ) and interleukin (IL)-10 responses to other P. falciparum antigens have been associated with protection from clinical malaria, but these responses have not been studied for MB2. The present study was undertaken to characterize IFN-γ and IL-10 responses to P. falciparum MB2 antigen in adults living in areas of differing malaria transmission in Western Kenya. Materials and Methods: Cytokine responses to two 9-mer MB2 peptides predicted to be human leukocyte antigen (HLA) class I restricted T-cell epitopes were measured by enzyme-linked immunosorbent assay (ELISA) (IFN-γ and IL-10) and enzyme-linked immunosorbent spot (ELISPOT) (IFN-γ) in adults (n = 228) in areas of unstable and stable malaria transmission. HLA class I restriction of responses was assessed in a sub-group of the study population. Results: IFN-γ and IL-10 responses to MB2 peptides by ELISA were observed in both sites with no significant difference in prevalence (IFN-γ, unstable transmission area, 18.8%, stable transmission area, 27.5%, P = 0.33; IL-10, unstable transmission area, 22.5%, stable transmission area, 25.0%, P = 0.78). Prevalence of IFN-γ responses by ELISPOT was also similar in both areas (unstable, 10.8%, stable, 10.9%, P = 0.98). Neither IFN-γ nor IL-10 responses showed evidence of HLA class I restriction. Conclusions: MB2 induces IFN-γ and IL-10 responses in adults living in both stable and unstable malaria transmission areas. Future studies should assess if these responses are associated with protection from clinical malaria. PMID:24672173

  9. The Hydrology of Malaria: Model Development and Application to a Sahelian Village

    NASA Astrophysics Data System (ADS)

    Bomblies, A.; Duchemin, J.; Eltahir, E. A.

    2008-12-01

    We present a coupled hydrology and entomology model for the mechanistic simulation of local-scale response of malaria transmission to hydrological and climatological determinants in semi-arid, desert fringe environments. The model is applied to the Sahel village of Banizoumbou, Niger, to predict interannual variability in malaria vector mosquito populations which lead to variations in malaria transmission. Using a high-resolution, small-scale distributed hydrology model that incorporates remotely-sensed data for land cover and topography, we simulate the formation and persistence of the pools constituting the primary breeding habitat of Anopheles gambiae s.l. mosquitoes, the principal regional malaria vector mosquitoes. An agent-based mosquito population model is coupled to the distributed hydrology model, with aquatic stage and adult stage components. For each individual adult mosquito, the model tracks attributes relevant to population dynamics and malaria transmission, which are updated as mosquitoes interact with their environment, humans, and animals. Weekly field observations were made in 2005 and 2006. The model reproduces mosquito population variability at seasonal and interannual time scales, and highlights individual pool persistence as a dominant control. Future developments to the presented model can be used in the evaluation of impacts of climate change on malaria, as well as the a priori evaluation of environmental management-based interventions.

  10. Modeling Combinations of Pre-erythrocytic Plasmodium falciparum Malaria Vaccines.

    PubMed

    Walker, Andrew S; Lourenço, José; Hill, Adrian V S; Gupta, Sunetra

    2015-12-01

    Despite substantial progress in the control of Plasmodium falciparum infection due to the widespread deployment of insecticide-treated bed nets and artemisinin combination therapies, malaria remains a prolific killer, with over half a million deaths estimated to have occurred in 2013 alone. Recent evidence of the development of resistance to treatments in both parasites and their mosquito vectors has underscored the need for a vaccine. Here, we use a mathematical model of the within-host dynamics of P. falciparum infection, fit to data from controlled human malaria infection clinical trials, to predict the efficacy of co-administering the two most promising subunit vaccines, RTS,S/AS01 and ChAd63-MVA ME-TRAP. We conclude that currently available technologies could be combined to induce very high levels of sterile efficacy, even in immune-naive individuals. PMID:26503278

  11. Backward bifurcation and optimal control of Plasmodium Knowlesi malaria

    NASA Astrophysics Data System (ADS)

    Abdullahi, Mohammed Baba; Hasan, Yahya Abu; Abdullah, Farah Aini

    2014-07-01

    A deterministic model for the transmission dynamics of Plasmodium Knowlesi malaria with direct transmission is developed. The model is analyzed using dynamical system techniques and it shows that the backward bifurcation occurs for some range of parameters. The model is extended to assess the impact of time dependent preventive (biological and chemical control) against the mosquitoes and vaccination for susceptible humans, while treatment for infected humans. The existence of optimal control is established analytically by the use of optimal control theory. Numerical simulations of the problem, suggest that applying the four control measure can effectively reduce if not eliminate the spread of Plasmodium Knowlesi in a community.

  12. The role of ENSO in understanding changes in Colombia's annual malaria burden by region, 1960–2006

    PubMed Central

    Mantilla, Gilma; Oliveros, Hugo; Barnston, Anthony G

    2009-01-01

    malaria cases in Colombia. These results naturally point to additional needed work: (1) refining the regional and seasonal dependence of climate on the ENSO state, and of malaria on the climate variables; (2) incorporating ENSO-related climate variability into dynamic malaria models. PMID:19133152

  13. The role of vitamin D in malaria.

    PubMed

    Lương, Khanh Vinh Quốc; Nguyễn, Lan Thi Hoàng

    2015-01-01

    An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus Calmette-Guerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed. PMID:25596566

  14. Vaccines for Malaria: How Close Are We?

    PubMed Central

    Thera, Mahamadou A.; Plowe, Christopher V.

    2012-01-01

    Vaccines are the most powerful public health tools mankind has created, but malaria parasites are bigger, more complicated, and wilier than the viruses and bacteria that have been conquered or controlled with vaccines. Despite decades of research toward a vaccine for malaria, this goal has remained elusive. Nevertheless, recent advances justify optimism that a licensed malaria vaccine is within reach. A subunit recombinant protein vaccine that affords in the neighborhood of 50% protective efficacy against clinical malaria is in the late stages of clinical evaluation in Africa. Incremental improvements on this successful vaccine are possible and worth pursuing, but the best hope for a highly efficacious malaria vaccine that would improve prospects for malaria eradication may lie with the use of attenuated whole parasites and powerful immune-boosting adjuvants. PMID:22077719

  15. Evaluation of Students' Conceptual Understanding of Malaria

    NASA Astrophysics Data System (ADS)

    Poh-Ai Cheong, Irene; Treagust, David; Kyeleve, Iorhemen J.; Oh, Peck-Yoke

    2010-12-01

    In this study, a two-tier diagnostic test for understanding malaria was developed and administered to 314 Bruneian students in Year 12 and in a nursing diploma course. The validity, reliability, difficulty level, discriminant indices, and reading ability of the test were examined and found to be acceptable in terms of measuring students' understanding and identifying alternative conceptions with respect to malaria. Results showed that students' understanding of malaria was high for content, low for reasons, and limited and superficial for both content and reasons. The instrument revealed several common alternative conceptual understandings students' hold about malaria. The MalariaTT2 instrument developed could be used in classroom lessons for challenging alternative conceptions and enhancing conceptions of malaria.

  16. Acute renal failure due to falciparum malaria.

    PubMed

    Habte, B

    1990-01-01

    Seventy-two patients with severe falciparum malaria are described. Twenty-four (33.3%) were complicated by acute renal failure. Comparing patients with renal failure and those without, statistically significant differences occurred regarding presence of cerebral malaria (83% vs 46%), jaundice (92% vs 33%), and death (54% vs 17%). A significantly higher number of patients with renal failure were nonimmune visitors to malaria endemic regions. Renal failure was oliguric in 45% of cases. Dialysis was indicated in 38%, 29% died in early renal failure, and 33% recovered spontaneously. It is concluded that falciparum malaria is frequently complicated by cerebral malaria and renal failure. As nonimmune individuals are prone to develop serious complications, malaria prophylaxis and vigorous treatment of cases is mandatory. PMID:2236718

  17. [The epidemiology of malaria in Kocaeli].

    PubMed

    Sönmez Tamer, Gülden

    2008-01-01

    Malaria is a very important disease both for the world and Turkey. In this retrospective study, malaria cases detected by the Malaria Control Unit Division of the Bursa Health Directorship from 1997-2007 have been evaluated. During this ten-year period, a total of 46,959 blood specimens were examined and 64 (0.14%) malaria cases were detected. Out of the 64 cases of malaria, 63 (98.44%) were caused by Plasmodium vivax and 1 (1.56%) by Plasmodium falciparum. Of the 64 cases, 45 (70.3%) were male and (29.7%), female. Positivity rates were found to be highest in 1997 and 1998. In this study, we have reviewed the malaria cases according to age, gender, locality and source of infection. PMID:19156602

  18. Shrinking the malaria map: progress and prospects

    PubMed Central

    Feachem, Richard GA; Phillips, Allison A; Hwang, Jimee; Cotter, Chris; Wielgosz, Benjamin; Greenwood, Brian M; Sabot, Oliver; Rodriguez, Mario Henry; Abeyasinghe, Rabindra R; Ghebreyesus, Tedros Adhanom; Snow, Robert W

    2010-01-01

    Summary In the past 150 years, roughly half of the countries in the world eliminated malaria. Nowadays, there are 99 endemic countries—67 are controlling malaria and 32 are pursuing an elimination strategy. This four-part Series presents evidence about the technical, operational, and financial dimensions of malaria elimination. The first paper in this Series reviews definitions of elimination and the state that precedes it: controlled low-endemic malaria. Feasibility assessments are described as a crucial step for a country transitioning from controlled low-endemic malaria to elimination. Characteristics of the 32 malaria-eliminating countries are presented, and contrasted with countries that pursued elimination in the past. Challenges and risks of elimination are presented, including Plasmodium vivax, resistance in the parasite and mosquito populations, and potential resurgence if investment and vigilance decrease. The benefits of elimination are outlined, specifically elimination as a regional and global public good. Priorities for the next decade are described. PMID:21035842

  19. Application of in-situ hybridization for the detection and identification of avian malaria parasites in paraffin wax-embedded tissues from captive penguins

    PubMed Central

    Dinhopl, Nora; Mostegl, Meike M.; Richter, Barbara; Nedorost, Nora; Maderner, Anton; Fragner, Karin; Weissenböck, Herbert

    2011-01-01

    In captive penguins, avian malaria due to Plasmodium parasites is a well-recognized disease problem as these protozoa may cause severe losses among valuable collections of zoo birds. In blood films from naturally infected birds, identification and differentiation of malaria parasites based on morphological criteria are difficult because parasitaemia is frequently light and blood stages, which are necessary for identification of parasites, are often absent. Post-mortem diagnosis by histological examination of tissue samples is sometimes inconclusive due to the difficulties in differentiating protozoal tissue stages from fragmented nuclei in necrotic tissue. The diagnosis of avian malaria would be facilitated by a technique with the ability to specifically identify developmental stages of Plasmodium in tissue samples. Thus, a chromogenic in-situ hybridization (ISH) procedure with a digoxigenin-labelled probe, targeting a fragment of the 18S rRNA, was developed for the detection of Plasmodium parasites in paraffin wax-embedded tissues. This method was validated in comparison with traditional techniques (histology, polymerase chain reaction), on various tissues from 48 captive penguins that died at the zoological garden Schönbrunn, Vienna, Austria. Meronts of Plasmodium gave clear signals and were easily identified using ISH. Potential cross-reactivity of the probe was ruled out by the negative outcome of the ISH against a number of protozoa and fungi. Thus, ISH proved to be a powerful, specific and sensitive tool for unambiguous detection of Plasmodium parasites in paraffin wax-embedded tissue samples. PMID:21711191

  20. No more monkeying around: primate malaria model systems are key to understanding Plasmodium vivax liver-stage biology, hypnozoites, and relapses

    PubMed Central

    Joyner, Chester; Barnwell, John W.; Galinski, Mary R.

    2015-01-01

    Plasmodium vivax is a human malaria parasite responsible for significant morbidity worldwide and potentially death. This parasite possesses formidable liver-stage biology that involves the formation of dormant parasites known as hypnozoites. Hypnozoites are capable of activating weeks, months, or years after a primary blood-stage infection causing relapsing bouts of illness. Elimination of this dormant parasitic reservoir will be critical for global malaria eradication. Although hypnozoites were first discovered in 1982, few advancements have been made to understand their composition and biology. Until recently, in vitro models did not exist to study these forms and studying them from human ex vivo samples was virtually impossible. Today, non-human primate (NHP) models and modern systems biology approaches are poised as tools to enable the in-depth study of P. vivax liver-stage biology, including hypnozoites and relapses. NHP liver-stage model systems for P. vivax and the related simian malaria species P. cynomolgi are discussed along with perspectives regarding metabolite biomarker discovery, putative roles of extracellular vesicles, and relapse immunobiology. PMID:25859242

  1. Modelling entomological-climatic interactions of Plasmodium falciparum malaria transmission in two Colombian endemic-regions: contributions to a National Malaria Early Warning System

    PubMed Central

    Ruiz, Daniel; Poveda, Germán; Vélez, Iván D; Quiñones, Martha L; Rúa, Guillermo L; Velásquez, Luz E; Zuluaga, Juan S

    2006-01-01

    Background Malaria has recently re-emerged as a public health burden in Colombia. Although the problem seems to be climate-driven, there remain significant gaps of knowledge in the understanding of the complexity of malaria transmission, which have motivated attempts to develop a comprehensive model. Methods The mathematical tool was applied to represent Plasmodium falciparum malaria transmission in two endemic-areas. Entomological exogenous variables were estimated through field campaigns and laboratory experiments. Availability of breeding places was included towards representing fluctuations in vector densities. Diverse scenarios, sensitivity analyses and instabilities cases were considered during experimentation-validation process. Results Correlation coefficients and mean square errors between observed and modelled incidences reached 0.897–0.668 (P > 0.95) and 0.0002–0.0005, respectively. Temperature became the most relevant climatic parameter driving the final incidence. Accordingly, malaria outbreaks are possible during the favourable epochs following the onset of El Niño warm events. Sporogonic and gonotrophic cycles showed to be the entomological key-variables controlling the transmission potential of mosquitoes' population. Simulation results also showed that seasonality of vector density becomes an important factor towards understanding disease transmission. Conclusion The model constitutes a promising tool to deepen the understanding of the multiple interactions related to malaria transmission conducive to outbreaks. In the foreseeable future it could be implemented as a tool to diagnose possible dynamical patterns of malaria incidence under several scenarios, as well as a decision-making tool for the early detection and control of outbreaks. The model will be also able to be merged with forecasts of El Niño events to provide a National Malaria Early Warning System. PMID:16882349

  2. Measuring malaria endemicity from intense to interrupted transmission

    PubMed Central

    Hay, Simon I; Smith, David L; Snow, Robert W

    2008-01-01

    Summary The quantification of malaria transmission for the classification of malaria risk has long been a concern for epidemiologists. During the era of the Global Malaria Eradication Programme, measurements of malaria endemicity were institutionalised by their incorporation into rules outlining defined action points for malaria control programmes. We review the historical development of these indices and their contemporary relevance. This is at a time when many malaria-endemic countries are scaling-up their malaria control activities and reconsidering their prospects for elimination. These considerations are also important to an international community that has recently been challenged to revaluate the prospects for malaria eradication. PMID:18387849

  3. Malaria and the work of WHO.

    PubMed Central

    Najera, J. A.

    1989-01-01

    Malaria has been one of the main health problems demanding the attention of WHO from the time the Organization was created. This review of the historical record analyses the different approaches to the malaria problem in the past 40 years and shows how WHO tried to fulfil its constitutional mandate. The article exposes the historical roots of the present situation and helps towards an understanding of current problems and approaches to malaria control. PMID:2670294

  4. The recent malaria situation in Chittagong, Bangladesh.

    PubMed

    Hussain, S M B; Rahman, M M; Ahmed, Z; Siddique, M M

    2003-01-01

    This is a retrospective study on 7,005 cases of malaria treated in a base hospital during the period 1998 to 2001. The aim of the study is to analyze the patterns, complications and mortality rates of malaria and its response to standard anti-malarial drugs. Diagnosis of malaria was made from identification of parasites on Giemsa stained thick and thin blood slides among the febrile cases and the clinical (unspecified) malaria was diagnosed as per WHO criteria. Malaria cases accounted for 136.17 per thousand-hospital admissions. Out of 7,005 malaria cases, 54.22% were falciparum, 26.18% were vivax and 12.02% were mixed infections. The most common complications of falciparum malaria were cerebral malaria (2.80%), malarial hepatitis (1.55%), acute pneumonia and/or pulmonary edema (0.22%), acute renal failure (0.13%), algid malaria (0.13%) and black water fever (0.06%). Most of the cases (66.98%) responded (S-response) well to chloroquine. Among the rest, 11.99% required quinine, 9.79% required artemether and 0.08% required both mefloquine and artemether. The total mortality rate was 0.30% but it was 9.25% and 6.17% among complicated malaria and cerebral malaria cases, respectively. Prognosis appeared better on early recognition of complications and initiation of prompt, effective treatment and adequate nursing care. Most mortality was due to complicated falciparum malaria and the emergence of drug resistance. PMID:19238662

  5. Novel image processing approach to detect malaria

    NASA Astrophysics Data System (ADS)

    Mas, David; Ferrer, Belen; Cojoc, Dan; Finaurini, Sara; Mico, Vicente; Garcia, Javier; Zalevsky, Zeev

    2015-09-01

    In this paper we present a novel image processing algorithm providing good preliminary capabilities for in vitro detection of malaria. The proposed concept is based upon analysis of the temporal variation of each pixel. Changes in dark pixels mean that inter cellular activity happened, indicating the presence of the malaria parasite inside the cell. Preliminary experimental results involving analysis of red blood cells being either healthy or infected with malaria parasites, validated the potential benefit of the proposed numerical approach.

  6. [Current management of imported severe malaria].

    PubMed

    Venanzi, E; López-Vélez, R

    2016-09-01

    Severe malaria is a diagnostic and therapeutic emergency with great impact worldwide for incidence and mortality. The clinical presentation of severe malaria can be very polymorphic and rapidly progressing. Therefore a correct diagnosis and an early and adequate antiparasitic and support therapy are essential. This paper attempts to outline the diagnosis frame and the treatment of severe malaria for adults, paediatric patients and for pregnant. PMID:27608318

  7. Surveillance and Control of Malaria Transmission in Thailand using Remotely Sensed Meteorological and Environmental Parameters

    NASA Technical Reports Server (NTRS)

    Kiang, Richard K.; Adimi, Farida; Soika, Valerii; Nigro, Joseph

    2007-01-01

    These slides address the use of remote sensing in a public health application. Specifically, this discussion focuses on the of remote sensing to detect larval habitats to predict current and future endemicity and identify key factors that sustain or promote transmission of malaria in a targeted geographic area (Thailand). In the Malaria Modeling and Surveillance Project, which is part of the NASA Applied Sciences Public Health Applications Program, we have been developing techniques to enhance public health's decision capability for malaria risk assessments and controls. The main objectives are: 1) identification of the potential breeding sites for major vector species; 2) implementation of a risk algorithm to predict the occurrence of malaria and its transmission intensity; 3) implementation of a dynamic transmission model to identify the key factors that sustain or intensify malaria transmission. The potential benefits are: 1) increased warning time for public health organizations to respond to malaria outbreaks; 2) optimized utilization of pesticide and chemoprophylaxis; 3) reduced likelihood of pesticide and drug resistance; and 4) reduced damage to environment. !> Environmental parameters important to malaria transmission include temperature, relative humidity, precipitation, and vegetation conditions. The NASA Earth science data sets that have been used for malaria surveillance and risk assessment include AVHRR Pathfinder, TRMM, MODIS, NSIPP, and SIESIP. Textural-contextual classifications are used to identify small larval habitats. Neural network methods are used to model malaria cases as a function of the remotely sensed parameters. Hindcastings based on these environmental parameters have shown good agreement to epidemiological records. Discrete event simulations are used for modeling the detailed interactions among the vector life cycle, sporogonic cycle and human infection cycle, under the explicit influences of selected extrinsic and intrinsic factors

  8. Malaria Parasites Produce Volatile Mosquito Attractants

    PubMed Central

    Kelly, Megan; Su, Chih-Ying; Schaber, Chad; Crowley, Jan R.; Hsu, Fong-Fu; Carlson, John R.

    2015-01-01

    ABSTRACT The malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid organelle that possesses plant-like metabolic pathways. Plants use the plastidial isoprenoid biosynthesis pathway to produce volatile odorants, known as terpenes. In this work, we describe the volatile chemical profile of cultured malaria parasites. Among the identified compounds are several plant-like terpenes and terpene derivatives, including known mosquito attractants. We establish the molecular identity of the odorant receptors of the malaria mosquito vector Anopheles gambiae, which responds to these compounds. The malaria parasite produces volatile signals that are recognized by mosquitoes and may thereby mediate host attraction and facilitate transmission. PMID:25805727

  9. Mathematical Analysis of the Effects of HIV-Malaria Co-infection on Workplace Productivity.

    PubMed

    Seidu, Baba; Makinde, Oluwole D; Seini, Ibrahim Y

    2015-06-01

    In this paper, a nonlinear dynamical system is proposed and qualitatively analyzed to study the dynamics and effects of HIV-malaria co-infection in the workplace. Basic reproduction numbers of sub-models are derived and are shown to have LAS disease-free equilibria when their respective basic reproduction numbers are less than unity. Conditions for existence of endemic equilibria of sub-models are also derived. Unlike the HIV-only model, the malaria-only model is shown to exhibit a backward bifurcation under certain conditions. Conditions for optimal control of the co-infection are derived using the Pontryagin's maximum principle. Numerical experimentation on the resulting optimality system is performed. Using the incremental cost-effectiveness ratio, it is observed that combining preventative measures for both diseases is the best strategy for optimal control of HIV-malaria co-infection at the workplace. PMID:25980477

  10. Malaria in penguins - current perceptions.

    PubMed

    Grilo, M L; Vanstreels, R E T; Wallace, R; García-Párraga, D; Braga, É M; Chitty, J; Catão-Dias, J L; Madeira de Carvalho, L M

    2016-08-01

    Avian malaria is a mosquito-borne disease caused by protozoans of the genus Plasmodium, and it is considered one of the most important causes of morbidity and mortality in captive penguins, both in zoological gardens and rehabilitation centres. Penguins are known to be highly susceptible to this disease, and outbreaks have been associated with mortality as high as 50-80% of affected captive populations within a few weeks. The disease has also been reported in wild penguin populations, however, its impacts on the health and fitness of penguins in the wild is not clear. This review provides an overview of the aetiology, life cycle and epidemiology of avian malaria, and provides details on the strategies that can be employed for the diagnostic, treatment and prevention of this disease in captive penguins, discussing possible directions for future research. PMID:27009571

  11. [Malaria in Poland in 2008].

    PubMed

    Stepień, Małgorzata

    2010-01-01

    There were 22 malaria cases confirmed according to the European Union cases definition registered in Poland in 2008. All of them were imported, 13 cases (59%) from Africa, 3 from Asia, 5 from Oceania and 1 from South America. Invasion with Plasmodium falciparum was confirmed in 14 cases, P. vivax in 4 cases, mixed invasion in 2 cases and in 2 cases species of Plasmodium was undetermined. There were 13 cases in males and 9 in females. Age at onset ranged from 23 to 58 years and majority of cases were in the age group 25-40. Common reason for travel to endemic countries were tourism (11 cases) and work-related visits (7 cases). Clinical course was severe in 6 cases of P. falciparum malaria and 1 person died because of the disease. Nine cases used chemoprophylaxis during their travel but only one of them appropriately, relevant information was missing in 6 cases. PMID:20731236

  12. [Malaria in Poland in 2006].

    PubMed

    Rosińska, Magdalena

    2008-01-01

    There were 19 cases of malaria meeting European Union case definition for confirmed case registered in Poland in 2006. All of them were imported, including 1 case of relapse: 17 from Africa, 1 from Asia and 1 from Oceania. Species of Plasmodium was determined for 12 cases (68%): P. falciparum in 12 cases and P. vivax in one. There were 15 cases in males and 4 in females. Age at onset ranged from 17 to 59 years and a considerable number of cases occurred in persons 50 years old or older (5.26%). Common reasons for travel to endemic countries included tourism or family visits (10 cases) and professional or missionary travel (5 cases). Only four cases used chemoprophylaxis and the relevant information was missing in 4 cases. In two cases of malaria caused by Pl. falciparum the clinical course was severe and one of them died. PMID:18807482

  13. Antibody response dynamics to the Plasmodium falciparum conserved vaccine candidate antigen, merozoite surface protein-1 C-terminal 19kD (MSP1-19kD), in Peruvians exposed to hypoendemic malaria transmission

    PubMed Central

    Torres, Katherine J; Clark, Eva H; Hernandez, Jean N; Soto-Cornejo, Katherine E; Gamboa, Dionicia; Branch, OraLee H

    2008-01-01

    Background In high-transmission areas, developing immunity to symptomatic Plasmodium falciparum infections requires 2–10 years of uninterrupted exposure. Delayed malaria-immunity has been attributed to difficult-to-develop and then short-lived antibody responses. Methods In a study area with <0.5 P. falciparum infections/person/year, antibody responses to the MSP1-19kD antigen were evaluated and associations with P. falciparum infections in children and adults. In months surrounding and during the malaria seasons of 2003–2004, 1,772 participants received ≥6 active visits in one study-year. Community-wide surveys were conducted at the beginning and end of each malaria season, and weekly active visits were completed for randomly-selected individuals each month. There were 79 P. falciparum infections with serum samples collected during and approximately one month before and after infection. Anti-MSP1-19kD IgG levels were measured by ELISA. Results The infection prevalence during February-July was similar in children (0.02–0.12 infections/person/month) and adults (0.03–0.14 infections/person/month) and was negligible in the four-month dry season. In children and adults, the seroprevalence was maintained in the beginning (children = 28.9%, adults = 61.8%) versus ending malaria-season community survey (children = 26.7%, adults = 64.6%). Despite the four-month non-transmission season, the IgG levels in Plasmodium-negative adults were similar to P. falciparum-positive adults. Although children frequently responded upon infection, the transition from a negative/low level before infection to a high level during/after infection was slower in children. Adults and children IgG-positive before infection had reduced symptoms and parasite density. Conclusion Individuals in low transmission areas can rapidly develop and maintain αMSP1-19kD IgG responses for >4 months, unlike responses reported in high transmission study areas. A greater immune capacity might contribute

  14. [Microbiological diagnosis of imported malaria].

    PubMed

    Torrús, Diego; Carranza, Cristina; Manuel Ramos, José; Carlos Rodríguez, Juan; Rubio, José Miguel; Subirats, Mercedes; Ta-Tang, Thuy-Huong

    2015-07-01

    Current diagnosis of malaria is based on the combined and sequential use of rapid antigen detection tests (RDT) of Plasmodium and subsequent visualization of the parasite stained with Giemsa solution in a thin and thick blood smears. If an expert microscopist is not available, should always be a sensitive RDT to rule out infection by Plasmodium falciparum, output the result immediately and prepare thick smears (air dried) and thin extensions (fixed with methanol) for subsequent staining and review by an expert microscopist. The RDT should be used as an initial screening test, but should not replace microscopy techniques, which should be done in parallel. The diagnosis of malaria should be performed immediately after clinical suspicion. The delay in laboratory diagnosis (greater than 3 hours) should not prevent the initiation of empirical antimalarial treatment if the probability of malaria is high. If the first microscopic examination and RDT are negative, they must be repeated daily in patients with high suspicion. If suspicion remains after three negative results must be sought the opinion of an tropical diseases expert. Genomic amplification methods (PCR) are useful as confirmation of microscopic diagnosis, to characterize mixed infections undetectable by other methods, and to diagnose asymptomatic infections with submicroscopic parasitaemia. PMID:26320995

  15. Epidemiology of malaria in Malaysia.

    PubMed

    Rahman, K M

    1982-01-01

    Malaria is a major public health problem in Malaysia, particularly in peninsular Malaysia and the state of Sabah. An eradication program started in the states of Sabah and Sarawak in 1961 initially was remarkably successful. A similar but staged program was started in peninsular Malaysia in 1967 and was also quite successful. However, a marked upsurge in incidence in Sabah in 1975-1978 showed that malaria is still a major hazard. The disease leads to great economic losses in terms of the productivity of the labor force and the learning capacity of schoolchildren. The topography, the climate, and the migrations of the people due to increased economic activity are similar in peninsular Malaysia, Sabah, and Sarawak. However, the epidemiologic picture differs strikingly from area to area in terms of species of vectors, distribution of parasitic species, and resistance of Plasmodium falciparum to chloroquine. Likewise, the problems faced by the eradication or control programs in the three regions are dissimilar. Because solutions to only some of these problems are possible, the eradication of malaria in Malaysia is not likely in the near future. However, the situation offers an excellent opportunity for further studies of antimalaria measures. PMID:6755616

  16. How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

    PubMed

    Hastings, Ian M; Kay, Katherine; Hodel, Eva Maria

    2015-10-01

    Artemisinin-based combination therapies (ACTs) are currently the first-line drugs for treating uncomplicated falciparum malaria, the most deadly of the human malarias. Malaria parasite clearance rates estimated from patients' blood following ACT treatment have been widely adopted as a measure of drug effectiveness and as surveillance tools for detecting the presence of potential artemisinin resistance. This metric has not been investigated in detail, nor have its properties or potential shortcomings been identified. Herein, the pharmacology of drug treatment, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following ACT. This approach parsimoniously recovers the principal clinical features and dynamics of clearance. Human immunity is the primary determinant of clearance rates, unless or until artemisinin killing has fallen to near-ineffective levels. Clearance rates are therefore highly insensitive metrics for surveillance that may lead to overconfidence, as even quite substantial reductions in drug sensitivity may not be detected as lower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regimen changes, as this strategy will plausibly miss even very substantial increases in drug effectiveness. In particular, the malaria community may be missing the opportunity to dramatically increase ACT effectiveness through regimen changes, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears overreliant on a single metric of drug effectiveness, the parasite clearance rate, that has significant and serious shortcomings. PMID:26239987

  17. How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

    PubMed Central

    Kay, Katherine; Hodel, Eva Maria

    2015-01-01

    Artemisinin-based combination therapies (ACTs) are currently the first-line drugs for treating uncomplicated falciparum malaria, the most deadly of the human malarias. Malaria parasite clearance rates estimated from patients' blood following ACT treatment have been widely adopted as a measure of drug effectiveness and as surveillance tools for detecting the presence of potential artemisinin resistance. This metric has not been investigated in detail, nor have its properties or potential shortcomings been identified. Herein, the pharmacology of drug treatment, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following ACT. This approach parsimoniously recovers the principal clinical features and dynamics of clearance. Human immunity is the primary determinant of clearance rates, unless or until artemisinin killing has fallen to near-ineffective levels. Clearance rates are therefore highly insensitive metrics for surveillance that may lead to overconfidence, as even quite substantial reductions in drug sensitivity may not be detected as lower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regimen changes, as this strategy will plausibly miss even very substantial increases in drug effectiveness. In particular, the malaria community may be missing the opportunity to dramatically increase ACT effectiveness through regimen changes, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears overreliant on a single metric of drug effectiveness, the parasite clearance rate, that has significant and serious shortcomings. PMID:26239987

  18. Antibodies against PfEMP1, RIFIN, MSP3 and GLURP Are Acquired during Controlled Plasmodium falciparum Malaria Infections in Naïve Volunteers

    PubMed Central

    Turner, Louise; Wang, Christian W.; Lavstsen, Thomas; Mwakalinga, Steven B.; Sauerwein, Robert W.; Hermsen, Cornelus C.; Theander, Thor G.

    2011-01-01

    Antibodies to polymorphic antigens expressed during the parasites erythrocytic stages are important mediators of protective immunity against P. falciparum malaria. Therefore, polymorphic blood stage antigens like MSP3, EBA-175 and GLURP and variant surface antigens PfEMP1 and RIFIN are considered vaccine candidates. However, to what extent these antibodies to blood stage antigens are acquired during naive individuals' first infections has not been studied in depth. Using plasma samples collected from controlled experimental P. falciparum infections we show that antibodies against variant surface antigens, PfEMP1 and RIFIN as well as MSP3 and GLURP, are acquired during a single short low density P. falciparum infection in non-immune individuals including strain transcendent PfEMP1 immune responses. These data indicate that the immunogenicity of the variant surface antigens is similar to the less diverse merozoite antigens. The acquisition of a broad and strain transcendent repertoire of PfEMP1 antibodies may reflect a parasite strategy of expressing most or all PfEMP1 variants at liver release optimizing the likelihood of survival and establishment of chronic infections in the new host. PMID:22174947

  19. Neuropsychiatric Profile in Malaria: An Overview

    PubMed Central

    Singh, Veer Bahadur; Meena, Babu Lal; Chandra, Subhash; Agrawal, Jatin; Kanogiya, Naresh

    2016-01-01

    Introduction Malaria is the most important parasitic disease of humans causes clinical illness over 300-500 million people globally and over one million death every year globally. The involvement of the nervous system in malaria is studied in this paper, to help formulate a strategy for better malaria management. Aim To study the Neuropsychiatric manifestation in malaria. Materials and Methods This was a prospective observational study in 170 patients with a clinical diagnosis of malaria admitted in various medical wards of medicine department of PBM Hospital, Bikaner during epidemic of malaria. It included both sexes of all age groups except the paediatric range. The diagnosis of malaria was confirmed by examination of thick and thin smear/optimal test/strip test. Only those cases that had asexual form of parasite of malaria in the blood by smear examination or optimal test were included in the study. Results Out of total 170 patients 104 (62%) reported Plasmodium falciparum (PF), Plasmodium vivax (PV) were 57 (33.5%) followed by mixed (PF+PV) 9 (5.3%) cases. The total PBF-MP test positivity was 84.5%. Maximum patients were belonging to the age range of 21-40 year with male predominance. Neuropsychiatric manifestation seen in falciparum malaria (n=111) as follow: altered consciousness 20 (18.01%), headache 17 (15.32%), neck rigidity 5 (4.5%), convulsion 5 (4.55%), extra pyramidal rigidity 2 (1.8%), decorticate rigidity 1 (0.90%), decerebrate rigidity 1 (0.90%), cerebellar ataxia 3 (2.7%), subarachnoid haemorrhage 1 (0.90%), aphasia 2 (1.8%), subconjunctival haemorrhage 1 (0.90%), conjugate deviation of eye 1 (0.90%) and psychosis 6 (5.40%). Twenty one patients presented with cerebral malaria out of 111 patients. Most patients of cerebral malaria presented with altered level of consciousness followed by headache and psychosis. Acute confusional state with clouding of consciousness was the most common presentation of psychosis (50%). Conclusion Neuropsychiatric

  20. Climate, environment and transmission of malaria.

    PubMed

    Rossati, Antonella; Bargiacchi, Olivia; Kroumova, Vesselina; Zaramella, Marco; Caputo, Annamaria; Garavelli, Pietro Luigi

    2016-06-01

    Malaria, the most common parasitic disease in the world, is transmitted to the human host by mosquitoes of the genus Anopheles. The transmission of malaria requires the interaction between the host, the vector and the parasite.The four species of parasites responsible for human malaria are Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax. Occasionally humans can be infected by several simian species, like Plasmodium knowlesi, recognised as a major cause of human malaria in South-East Asia since 2004. While P. falciparum is responsible for most malaria cases, about 8% of estimated cases globally are caused by P. vivax. The different Plasmodia are not uniformly distributed although there are areas of species overlap. The life cycle of all species of human malaria parasites is characterised by an exogenous sexual phase in which multiplication occurs in several species of Anopheles mosquitoes, and an endogenous asexual phase in the vertebrate host. The time span required for mature oocyst development in the salivary glands is quite variable (7-30 days), characteristic of each species and influenced by ambient temperature. The vector Anopheles includes 465 formally recognised species. Approximately 70 of these species have the capacity to transmit Plasmodium spp. to humans and 41 are considered as dominant vector capable of transmitting malaria. The intensity of transmission is dependent on the vectorial capacity and competence of local mosquitoes. An efficient system for malaria transmission needs strong interaction between humans, the ecosystem and infected vectors. Global warming induced by human activities has increased the risk of vector-borne diseases such as malaria. Recent decades have witnessed changes in the ecosystem and climate without precedent in human history although the emphasis in the role of temperature on the epidemiology of malaria has given way to predisposing conditions such as ecosystem changes, political

  1. A transcriptional switch underlies commitment to sexual development in malaria parasites.

    PubMed

    Kafsack, Björn F C; Rovira-Graells, Núria; Clark, Taane G; Bancells, Cristina; Crowley, Valerie M; Campino, Susana G; Williams, April E; Drought, Laura G; Kwiatkowski, Dominic P; Baker, David A; Cortés, Alfred; Llinás, Manuel

    2014-03-13

    The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized niches. Transmission of malaria parasites (Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited, and disrupting this critical developmental transition remains a long-standing goal. Here we show that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as probable targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci prone to spontaneous activation. Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first discovery of a transcriptional switch controlling a differentiation decision in protozoan parasites. PMID:24572369

  2. A transcriptional switch underlies commitment to sexual development in human malaria parasites

    PubMed Central

    Kafsack, Björn F.C.; Rovira-Graells, Núria; Clark, Taane G.; Bancells, Cristina; Crowley, Valerie M.; Campino, Susana G.; Williams, April E.; Drought, Laura G.; Kwiatkowski, Dominic P.; Baker, David A.; Cortés, Alfred; Llinás, Manuel

    2014-01-01

    The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized niches. Transmission of malaria parasites (Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited and disrupting this critical developmental transition remains a long-standing goal1. We show here that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as likely targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci2,3 prone to spontaneous activation4. Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first identification of a transcriptional switch controlling a differentiation decision in protozoan parasites. PMID:24572369

  3. Development of malaria vaccines: Memorandum from a USAID/WHO meeting

    PubMed Central

    1983-01-01

    The fifth meeting of the Scientific Working Group on the Immunology of Malaria evaluated studies of the production and analysis of defined malarial antigens. Rapid progress has been made in the study of protective antigens on the surface of sporozoites and it is likely that a family of analogous polypeptides occurs in several species of Plasmodium. New assays have been developed for the detection of these antigens and for the detection of infected mosquitos. Exoerythrocytic stages of several parasite species can be cultivated in vitro, providing an assay system for antibody and allowing the characterization of exoerythrocytic stage antigens. Progress has also been made in the identification of species- and stage-specific antigens of the asexual blood stages of rodent, simian, and human malaria parasites. In some instances, protective immunity has been shown to be directed against polypeptides (with a high relative molecular mass) synthesized at a late stage of schizont development. Messenger RNA (mRNA) species from P. knowlesi and P. yoelii have been successfully translated in vitro to give polypeptides with a high relative molecular mass (Mr). Monoclonal antibodies have been used to identify and to purify important parasite antigens and purified P. yoelii antigens induced protective immunity. Monoclonal antibodies reactive with merozoite surface antigens have been used, as well as S-antigens, to distinguish between different isolates of P. falciparum. Recombinant DNA technology is being applied to Plasmodium: differences were found between repetitive DNA sequences from the genome of two isolates of P. falciparum; the genes for ribosomal RNA of P. falciparum and P. yoelii, and sequences homologous to the actin gene were identified in fragments of Plasmodium DNA cloned in prokaryotic vectors; by means of hybrid selection, complementary DNA (cDNA) probes were used to purify mRNAs encoding proteins of P. knowlesi of up to 100 000 Mr. PMID:6340848

  4. Revealing natural antisense transcripts from Plasmodium vivax isolates: evidence of genome regulation in complicated malaria.

    PubMed

    Boopathi, P A; Subudhi, Amit Kumar; Garg, Shilpi; Middha, Sheetal; Acharya, Jyoti; Pakalapati, Deepak; Saxena, Vishal; Aiyaz, Mohammed; Chand, Bipin; Mugasimangalam, Raja C; Kochar, Sanjay K; Sirohi, Parmendra; Kochar, Dhanpat K; Das, Ashis

    2013-12-01

    Plasmodium vivax is the most geographically widespread human malaria parasite causing approximately 130-435 million infections annually. It is an economic burden in many parts of the world and poses a public health challenge along with the other Plasmodium sp. The biology of this parasite is less studied and poorly understood, in spite of these facts. Emerging evidence of severe complications due to infections by this parasite provides an impetus to focus research on the same. Investigating the parasite directly from infected patients is the best way to study its biology and pathogenic mechanisms. Gene expression studies of this parasite directly obtained from the patients has provided evidence of gene regulation resulting in varying amount of transcript levels in the different blood stages. The mechanisms regulating gene expression in malaria parasites are not well understood. Discovery of Natural Antisense Transcripts (NATs) in Plasmodium falciparum has suggested that these might play an important role in regulating gene expression. We report here the genome-wide occurrence of NATs in P. vivax parasites from patients with differing clinical symptoms. A total of 1348 NATs against annotated gene loci have been detected using a custom designed microarray with strand specific probes. Majority of NATs identified from this study shows positive correlation with the expression pattern of the sense (S) transcript. Our data also shows condition specific expression patterns of varying S and antisense (AS) transcript levels. Genes with AS transcripts enrich to various biological processes. To our knowledge this is the first report on the presence of NATs from P. vivax obtained from infected patients with different disease complications. The data suggests differential regulation of gene expression in diverse clinical conditions, as shown by differing sense/antisense ratios and would lead to future detailed investigations of gene regulation. PMID:24121022

  5. Uncomplicated Plasmodium vivax malaria in pregnancy associated with mortality from acute respiratory distress syndrome.

    PubMed

    McGready, Rose; Wongsaen, Klanarong; Chu, Cindy S; Tun, Nay Win; Chotivanich, Kesinee; White, Nicholas J; Nosten, François

    2014-01-01

    The association between severe malaria and Plasmodium vivax species is contentious. On the Thai-Mya