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Sample records for malariae blood-stage dynamics

  1. Plasmodium malariae blood-stage dynamics.

    PubMed

    McKenzie, F E; Jeffery, G M; Collins, W E

    2001-06-01

    We examine the dynamics of parasitemia, fever, and gametocytemia reflected in the preintervention charts of 180 malaria-naive U.S. neurosyphilis patients infected with the USPHS strain of Plasmodium malariae, for malariatherapy, focusing on the 84 charts for which more than 35 days of patency preceded intervention and daily records encompassed 92% or more of the duration of each infection. Inoculum size did not influence any outcome variable. Fevers (days with temperatures > or =101 F) followed patterns that fit recognized brood structures more often than did our approximations of merogony cycles (via local peaks in parasitemia), but neither closely fit textbook quartan patterns. There were no discernable patterns in gametocytemia. Successful transmission to mosquitoes increased following subcurative drug treatment but did not depend on detectable gametocytemia.

  2. 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.

  3. 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

  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 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

  6. PLASMODIUM VIVAX BLOOD-STAGE DYNAMICS

    PubMed Central

    McKenzie, F. Ellis; Jeffery, Geoffrey M.; Collins, William E.

    2008-01-01

    We examine the dynamics of parasitemia and gametocytemia reflected in the preintervention charts of 221 malaria-naive U.S. neurosyphilis patients infected with the St. Elizabeth strain of Plasmodium vivax, for malariatherapy, focusing on the 109 charts for which 15 or more days of patency preceded intervention and daily records encompassed an average 98% of the duration of each infection. Our approximations of merogony cycles (via “local peaks” in parasitemia) seldom fit patterns that correspond to “textbook” tertian brood structures. Peak parasitemia was higher in trophozoite-induced infections than in sporozoite-induced ones. Relative densities of male and female gametocytes appeared to alternate, though without a discernably regular period. Successful transmission to mosquitoes did not depend on detectable gametocytemia or on absence of fever. When gametocytes were detected, transmission success depended on densities of only male gametocytes. Successful feeds occurred on average 4.7 days later in an infection than did failures. Parasitemia was lower in homologous reinfection, gametocytemia lower or absent. PMID:12099421

  7. Hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection.

    PubMed

    Wang, Hai-Zhen; He, Ying-Xin; Yang, Chun-Ju; Zhou, Wei; Zou, Cheng-Gang

    2011-12-15

    Hepcidin is one of the regulators of iron metabolism. The expression of hepcidin is induced in spleens and livers of mice infected with pathogenic bacteria. Recent studies have indicated that serum hepcidin level is also increased in human subjects infected with Plasmodium falciparum. The mechanism of the regulation of hepcidin expression and its role in the infection of malaria remains unknown. In this study, we determined the expression of hepcidin in livers of mice infected with Plasmodium berghei. The expression of hepcidin in the liver was upregulated and downregulated during the early and late stages of malaria infection, respectively. Inflammation and erythropoietin, rather than the iron-sensing pathway, are involved in the regulation of hepcidin expression in livers of infected mice. Meanwhile, we investigated the effect of hepcidin on the survival of mice infected with P. berghei. Treatment of malaria-infected mice with anti-hepcidin neutralizing Abs promoted the rates of parasitemia and mortality. In contrast, lentiviral vector-mediated overexpression of hepcidin improved the outcome of P. berghei infection in mice. Our data demonstrate an important role of hepcidin in modulating the course and outcome of blood-stage malaria.

  8. Can growth inhibition assays (GIA) predict blood-stage malaria vaccine efficacy?

    PubMed

    Duncan, Christopher J A; Hill, Adrian V S; Ellis, Ruth D

    2012-06-01

    An effective vaccine against P. falciparum malaria remains a global health priority. Blood-stage vaccines are an important component of this effort, with some indications of recent progress. However only a fraction of potential blood-stage antigens have been tested, highlighting a critical need for efficient down-selection strategies. Functional in vitro assays such as the growth/invasion inhibition assays (GIA) are widely used, but it is unclear whether GIA activity correlates with protection or predicts vaccine efficacy. While preliminary data in controlled human malaria infection (CHMI) studies indicate a possible association between in vitro and in vivo parasite growth rates, there have been conflicting results of immunoepidemiology studies, where associations with exposure rather than protection have been observed. In addition, GIA-interfering antibodies in vaccinated individuals from endemic regions may limit assay sensitivity in heavily malaria-exposed populations. More work is needed to establish the utility of GIA for blood-stage vaccine development.

  9. Examining cellular immune responses to inform development of a blood-stage malaria vaccine.

    PubMed

    Stanisic, Danielle I; Good, Michael F

    2016-02-01

    Naturally acquired immunity to the blood-stage of the malaria parasite develops slowly in areas of high endemicity, but is not sterilizing. It manifests as a reduction in parasite density and clinical symptoms. Immunity as a result of blood-stage vaccination has not yet been achieved in humans, although there are many animal models where vaccination has been successful. The development of a blood-stage vaccine has been complicated by a number of factors including limited knowledge of human-parasite interactions and which antigens and immune responses are critical for protection. Opinion is divided as to whether this vaccine should aim to accelerate the acquisition of responses acquired following natural exposure, or whether it should induce a different response. Animal and experimental human models suggest that cell-mediated immune responses can control parasite growth, but these responses can also contribute to significant immunopathology if unregulated. They are largely ignored in most blood-stage malaria vaccine development strategies. Here, we discuss key observations relating to cell-mediated immune responses in the context of experimental human systems and field studies involving naturally exposed individuals and how this may inform the development of a blood-stage malaria vaccine.

  10. [Cesarean section in a woman with acute blood-stage malaria].

    PubMed

    Fornet, I; Palacio, F J; López, M A; Morillas, P; Ortiz-Gómez, J R

    2007-12-01

    Malaria infection during pregnancy is a serious health problem in most of the world's tropical regions. The disease has also been imported into Western countries, however, as an increasing number of infected women, who may become pregnant, emigrate from areas where malaria is endemic. Infection during pregnancy can have serious repercussions for both mother and fetus. Early diagnosis and multidisciplinary management are essential. We report the case of a woman from Guinea who debuted with severe, acute blood-stage malaria in the 32nd week of pregnancy and was admitted to the recovery care unit.

  11. 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.

  12. 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

  13. Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria.

    PubMed

    Sponaas, Anne-Marit; Freitas do Rosario, Ana Paula; Voisine, Cecile; Mastelic, Beatris; Thompson, Joanne; Koernig, Sandra; Jarra, William; Renia, Laurent; Mauduit, Marjorie; Potocnik, Alexandre J; Langhorne, Jean

    2009-12-24

    Host responses controlling blood-stage malaria include both innate and acquired immune effector mechanisms. During Plasmodium chabaudi infection in mice, a population of CD11b(high)Ly6C(+) monocytes are generated in bone marrow, most of which depend on the chemokine receptor CCR2 for migration from bone marrow to the spleen. In the absence of this receptor mice harbor higher parasitemias. Most importantly, splenic CD11b(high)Ly6C(+) cells from P chabaudi-infected wild-type mice significantly reduce acute-stage parasitemia in CCR2(-/-) mice. The CD11b(high)Ly6C(+) cells in this malaria infection display effector functions such as production of inducible nitric oxide synthase and reactive oxygen intermediates, and phagocytose P chabaudi parasites in vitro, and in a proportion of the cells, in vivo in the spleen, suggesting possible mechanisms of parasite killing. In contrast to monocyte-derived dendritic cells, CD11b(high)Ly6C(+) cells isolated from malaria-infected mice express low levels of major histocompatibility complex II and have limited ability to present the P chabaudi antigen, merozoite surface protein-1, to specific T-cell receptor transgenic CD4 T cells and fail to activate these T cells. We propose that these monocytes, which are rapidly produced in the bone marrow as part of the early defense mechanism against invading pathogens, are important for controlling blood-stage malaria parasites.

  14. Shared Consensus Machine Learning Models for Predicting Blood Stage Malaria Inhibition.

    PubMed

    Verras, Andreas; Waller, Christopher Lee; Gedeck, Peter; Green, Darren; Kogej, Thierry; Raichurkar, Anandkumar V; Panda, Manoranjan; Shelat, Anang A; Clark, Julie A; Guy, R Kiplin; Papadatos, George; Burrows, Jeremy N

    2017-03-03

    The development of new antimalarial therapies is essential and lowering the barrier of entry for the screening and discovery of new lead compound classes can spur drug development at organizations that may not have large compound screening libraries or resources to conduct high throughput screens. Machine learning models have been long established to be more robust and have a larger domain of applicability with larger training sets. Screens over multiple data sets to find compounds with potential malaria blood stage inhibitory activity have been used to generate multiple Bayesian models. Here we describe a method by which Bayesian QSAR models, which contain information on thousands to millions of proprietary compounds, can be shared between collaborators at both for-profit and not-for-profit institutions. This model-sharing paradigm allows for the development of consensus models that have increased predictive power over any single model, and yet does not reveal the identity of any compounds in the training sets.

  15. Molecular basis of allele-specific efficacy of a blood-stage malaria vaccine: vaccine development implications.

    PubMed

    Ouattara, Amed; Takala-Harrison, Shannon; Thera, Mahamadou A; Coulibaly, Drissa; Niangaly, Amadou; Saye, Renion; Tolo, Youssouf; Dutta, Sheetij; Heppner, D Gray; Soisson, Lorraine; Diggs, Carter L; Vekemans, Johan; Cohen, Joe; Blackwelder, William C; Dube, Tina; Laurens, Matthew B; Doumbo, Ogobara K; Plowe, Christopher V

    2013-02-01

    The disappointing efficacy of blood-stage malaria vaccines may be explained in part by allele-specific immune responses that are directed against polymorphic epitopes on blood-stage antigens. FMP2.1/AS02(A), a blood-stage candidate vaccine based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, had allele-specific efficacy against clinical malaria in a phase II trial in Malian children. We assessed the cross-protective efficacy of the malaria vaccine and inferred which polymorphic amino acid positions in AMA1 were the targets of protective allele-specific immune responses. FMP2.1/AS02(A) had the highest efficacy against AMA1 alleles that were identical to the 3D7 vaccine-type allele at 8 highly polymorphic amino acid positions in the cluster 1 loop (c1L) but differed from 3D7 elsewhere in the molecule. Comparison of the incidence of vaccine-type alleles before and after vaccination in the malaria vaccine and control groups and examination of the patterns of allele change at polymorphic positions in consecutive malaria episodes suggest that the highly polymorphic amino acid position 197 in c1L was the most critical determinant of allele-specific efficacy. These results indicate that a multivalent AMA1 vaccine with broad efficacy could include only a limited set of key alleles of this extremely polymorphic antigen.

  16. 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

  17. 43 kDa and 66 kDa, two blood stage antigens induce immune response in Plasmodium berghei malaria.

    PubMed

    Pirta, Chhaya; Banyal, H S

    2014-08-01

    The hunt for an effective vaccine against malaria still continues. Several new target antigens as candidates for vaccine design are being explored and tested for their efficacy. In the present study the sera from mice immunized with 24,000 x g fraction of Plasmodium berghei has been used to identify highly immunogenic blood stage antigens. The protective antibodies present in immune sera were covalently immobilized on CNBr activated sepharose 4B and used for affinity chromatography purification of antigens present in blood stages of P. berghei. Two polypeptides of 66 and 43 kDa molecular weights proved to be highly immunogenic. They exhibited a strong humoral immune response in mice as evident by high titres in ELISA and IFA. Protective immunity by these two antigens was apparent by in vivo and in vitro studies. These two proteins could further be analysed and used as antigens in malaria vaccine design.

  18. 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

  19. Inhibition of the SR protein-phosphorylating CLK kinases of Plasmodium falciparum impairs blood stage replication and malaria transmission.

    PubMed

    Kern, Selina; Agarwal, Shruti; Huber, Kilian; Gehring, André P; Strödke, Benjamin; Wirth, Christine C; Brügl, Thomas; Abodo, Liliane Onambele; Dandekar, Thomas; Doerig, Christian; Fischer, Rainer; Tobin, Andrew B; Alam, Mahmood M; Bracher, Franz; Pradel, Gabriele

    2014-01-01

    Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-β-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.

  20. Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine

    PubMed Central

    Kouriba, Bourema; Bergmann-Leitner, Elke; Angov, Evelina; Coulibaly, Drissa; Diarra, Issa; Daou, Modibo; Niangaly, Amadou; Blackwelder, William C.; Wu, Yukun; Cohen, Joe; Ballou, W. Ripley; Vekemans, Johan; Lanar, David E.; Dutta, Sheetij; Diggs, Carter; Soisson, Lorraine; Heppner, D. Gray; Doumbo, Ogobara K.; Plowe, Christopher V.; Thera, Mahamadou A.

    2017-01-01

    The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90) (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02). From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001). In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials.gov, registry

  1. 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

  2. Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stage Plasmodium berghei ANKA.

    PubMed

    Palomo, Jennifer; Fauconnier, Mathilde; Coquard, Laurie; Gilles, Maïlys; Meme, Sandra; Szeremeta, Frederic; Fick, Lizette; Franetich, Jean-François; Jacobs, Muazzam; Togbe, Dieudonnée; Beloeil, Jean-Claude; Mazier, Dominique; Ryffel, Bernhard; Quesniaux, Valerie F J

    2013-10-01

    Cerebral malaria is a severe complication of Plasmodium falciparum infection. Although T-cell activation and type II IFN-γ are required for Plasmodium berghei ANKA (PbA)-induced murine experimental cerebral malaria (ECM), the role of type I IFN-α/β in ECM development remains unclear. Here, we address the role of the IFN-α/β pathway in ECM devel-opment in response to hepatic or blood-stage PbA infection, using mice deficient for types I or II IFN receptors. While IFN-γR1⁻/⁻ mice were fully resistant, IFNAR1⁻/⁻ mice showed delayed and partial protection to ECM after PbA infection. ECM resistance in IFN-γR1⁻/⁻ mice correlated with unaltered cerebral microcirculation and absence of ischemia, while WT and IFNAR1⁻/⁻ mice developed distinct microvascular pathologies. ECM resistance appeared to be independent of parasitemia. Instead, key mediators of ECM were attenuated in the absence of IFNAR1, including PbA-induced brain sequestration of CXCR3⁺-activated CD8⁺ T cells. This was associated with reduced expression of Granzyme B, IFN-γ, IL-12Rβ2, and T-cell-attracting chemokines CXCL9 and CXCL10 in IFNAR1⁻/⁻ mice, more so in the absence of IFN-γR1. Therefore, the type I IFN-α/β receptor pathway contributes to brain T-cell responses and microvascular pathology, although it is not as essential as IFN-γ for the development of cerebral malaria upon hepatic or blood-stage PbA infection.

  3. Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism.

    PubMed

    Zhao, Hong; Konishi, Aki; Fujita, Yukiko; Yagi, Masanori; Ohata, Keiichi; Aoshi, Taiki; Itagaki, Sawako; Sato, Shintaro; Narita, Hirotaka; Abdelgelil, Noha H; Inoue, Megumi; Culleton, Richard; Kaneko, Osamu; Nakagawa, Atsushi; Horii, Toshihiro; Akira, Shizuo; Ishii, Ken J; Coban, Cevayir

    2012-11-15

    Plasmodium parasites multiply within host erythrocytes, which contain high levels of iron, and parasite egress from these cells results in iron release and host anemia. Although Plasmodium requires host iron for replication, how host iron homeostasis and responses to these fluxes affect Plasmodium infection are incompletely understood. We determined that Lipocalin 2 (Lcn2), a host protein that sequesters iron, is abundantly secreted during human (P. vivax) and mouse (P. yoeliiNL) blood-stage malaria infections and is essential to control P. yoeliiNL parasitemia, anemia, and host survival. During infection, Lcn2 bolsters both host macrophage function and granulocyte recruitment and limits reticulocytosis, or the expansion of immature erythrocytes, which are the preferred target cell of P. yoeliiNL. Additionally, a chronic iron imbalance due to Lcn2 deficiency results in impaired adaptive immune responses against Plasmodium parasites. Thus, Lcn2 exerts antiparasitic effects by maintaining iron homeostasis and promoting innate and adaptive immune responses.

  4. 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

  5. Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

    PubMed

    Biswas, Sumi; Choudhary, Prateek; 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 diseases

  6. Regulating the adaptive immune response to blood-stage malaria: role of dendritic cells and CD4⁺Foxp3⁺ regulatory T cells.

    PubMed

    Stevenson, Mary M; Ing, Rebecca; Berretta, Floriana; Miu, Jenny

    2011-01-01

    Although a clearer understanding of the underlying mechanisms involved in protection and immunopathology during blood-stage malaria has emerged, the mechanisms involved in regulating the adaptive immune response especially those required to maintain a balance between beneficial and deleterious responses remain unclear. Recent evidence suggests the importance of CD11c⁺ dendritic cells (DC) and CD4⁺Foxp3⁺ regulatory T cells in regulating immune responses during infection and autoimmune disease, but information concerning the contribution of these cells to regulating immunity to malaria is limited. Here, we review recent findings from our laboratory and others in experimental models of malaria in mice and in Plasmodium-infected humans on the roles of DC and natural regulatory T cells in regulating adaptive immunity to blood-stage malaria.

  7. Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice.

    PubMed

    Al-Quraishy, Saleh; Dkhil, Mohamed A; Abdel-Baki, Abdel-Azeem S; Ghanjati, Foued; Erichsen, Lars; Santourlidis, Simeon; Wunderlich, Frank; Araúzo-Bravo, Marcos J

    2017-03-18

    Epigenetic mechanisms such as DNA methylation are increasingly recognized to be critical for vaccination efficacy and outcome of different infectious diseases, but corresponding information is scarcely available for host defense against malaria. In the experimental blood-stage malaria Plasmodium chabaudi, we investigate the possible effects of a blood-stage vaccine on DNA methylation of gene promoters in the liver, known as effector against blood-stage malaria, using DNA methylation microarrays. Naturally susceptible Balb/c mice acquire, by protective vaccination, the potency to survive P. chabaudi malaria and, concomitantly, modifications of constitutive DNA methylation of promoters of numerous genes in the liver; specifically, promoters of 256 genes are hyper(=up)- and 345 genes are hypo(=down)-methylated (p < 0.05). Protective vaccination also leads to changes in promoter DNA methylation upon challenge with P. chabaudi at peak parasitemia on day 8 post infection (p.i.), when 571 and 1013 gene promoters are up- and down-methylated, respectively, in relation to constitutive DNA methylation (p < 0.05). Gene set enrichment analyses reveal that both vaccination and P. chabaudi infections mainly modify promoters of those genes which are most statistically enriched with functions relating to regulation of transcription. Genes with down-methylated promoters encompass those encoding CX3CL1, GP130, and GATA2, known to be involved in monocyte recruitment, IL-6 trans-signaling, and onset of erythropoiesis, respectively. Our data suggest that vaccination may epigenetically improve parts of several effector functions of the liver against blood-stage malaria, as, e.g., recruitment of monocyte/macrophage to the liver accelerated liver regeneration and extramedullary hepatic erythropoiesis, thus leading to self-healing of otherwise lethal P. chabaudi blood-stage malaria.

  8. Magnetic Nanovectors for the Development of DNA Blood-Stage Malaria Vaccines

    PubMed Central

    Al-Deen, Fatin M. Nawwab; Xiang, Sue D.; Ma, Charles; Wilson, Kirsty; Coppel, Ross L.; Selomulya, Cordelia; Plebanski, Magdalena

    2017-01-01

    DNA vaccines offer cost, flexibility, and stability advantages, but administered alone have limited immunogenicity. Previously, we identified optimal configurations of magnetic vectors comprising superparamagnetic iron oxide nanoparticles (SPIONs), polyethylenimine (PEI), and hyaluronic acid (HA) to deliver malaria DNA encoding Plasmodium yoelii (Py) merozoite surface protein MSP119 (SPIONs/PEI/DNA + HA gene complex) to dendritic cells and transfect them with high efficiency in vitro. Herein, we evaluate their immunogenicity in vivo by administering these potential vaccine complexes into BALB/c mice. The complexes induced antibodies against PyMSP119, with higher responses induced intraperitoneally than intramuscularly, and antibody levels further enhanced by applying an external magnetic field. The predominant IgG subclasses induced were IgG2a followed by IgG1 and IgG2b. The complexes further elicited high levels of interferon gamma (IFN-γ), and moderate levels of interleukin (IL)-4 and IL-17 antigen-specific splenocytes, indicating induction of T helper 1 (Th1), Th2, and Th17 cell mediated immunity. The ability of such DNA/nanoparticle complexes to induce cytophilic antibodies together with broad spectrum cellular immunity may benefit malaria vaccines. PMID:28336871

  9. 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.

  10. A Plasmodium vivax plasmid DNA- and adenovirus-vectored malaria vaccine encoding blood stage antigens AMA1 and MSP142 in a prime/boost heterologous immunization regimen partially protects Aotus monkeys against blood stage challenge.

    PubMed

    Obaldia, Nicanor; Stockelman, Michael G; Otero, William; Cockrill, Jennifer A; Ganeshan, Harini; Abot, Esteban N; Zhang, Jianfeng; Limbach, Keith; Charoenvit, Yupin; Doolan, Denise L; Tang, De-Chu C; Richie, Thomas L

    2017-02-08

    Malaria is caused by parasites of the genus Plasmodium that are transmitted to humans by the bites of Anopheles mosquitoes. After the elimination of P. falciparum it is predicted that Plasmodium vivax will remain an important cause of morbidity and mortality outside of Africa, stressing the importance of developing a vaccine against malaria. In this study we assess the immunogenicity and protective efficacy of two P. vivax antigens, AMA1 and MSP142 in a recombinant DNA plasmid prime/adenoviral vector (Ad) boost regimen in Aotus monkeys. Groups of 4 to 5 monkeys were immunized with DNA alone, Ad alone, prime/boost regimens of each antigen, prime/boost with both antigens, and empty vector controls, and then subjected to blood stage challenge. The heterologous immunization regimen with the antigen pair was more protective than either antigen alone or both antigens delivered with a single vaccine platform, based on their ability to induced the longest pre-patent period and time to peak parasitemia; the lowest peak and mean parasitemia; the smallest area under the parasitemia curve and the highest self-cured rate. Overall, pre-challenge MSP1 antibody titers strongly correlated with decreased parasite burden. Nevertheless, a significant proportion of immunized animals developed anemia. In conclusion, P. vivax plasmid DNA/Ad5 vaccine encoding blood stage parasite antigens AMA1 and MSP142 in a heterologous prime/boost immunization regimen, provided significant protection against blood-stage challenge in Aotus monkeys, indicating the suitability of these antigens and regimen for further development.

  11. Assessment of immune interference, antagonism, and diversion following human immunization with biallelic blood-stage malaria viral-vectored vaccines and controlled malaria infection.

    PubMed

    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

    2013-02-01

    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 Ag variants in subunit vaccine candidates is one strategy that has aimed to overcome this problem for the leading blood-stage malaria vaccine targets, that is, merozoite surface protein 1 (MSP1) and apical membrane Ag 1 (AMA1). However, previous studies, utilizing malaria Ags, have concluded that inclusion of multiple allelic variants, encoding altered peptide ligands, in such a vaccine may be detrimental to both the priming and in vivo restimulation of Ag-experienced T cells. In this study, we analyze the T cell responses to two alleles of MSP1 and AMA1 induced by vaccination of malaria-naive adult volunteers with bivalent viral-vectored vaccine candidates. We show a significant bias to the 3D7/MAD20 allele compared with the Wellcome allele for the 33 kDa region of MSP1, but not for the 19 kDa fragment or the AMA1 Ag. Although this bias could be caused by "immune interference" at priming, the data do not support a significant role for "immune antagonism" during memory T cell restimulation, 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 toward the Wellcome allele.

  12. Differential miRNA Expression in the Liver of Balb/c Mice Protected by Vaccination during Crisis of Plasmodium chabaudi Blood-Stage Malaria

    PubMed Central

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

    2017-01-01

    MicroRNAs are increasingly recognized as epigenetic regulators for outcome of diverse infectious diseases and vaccination efficacy, but little information referring to this exists for malaria. This study investigates possible effects of both protective vaccination and P. chabaudi malaria on the miRNome of the liver as an effector against blood-stage malaria using miRNA microarrays and quantitative PCR. Plasmodium chabaudi blood-stage malaria takes a lethal outcome in female Balb/c mice, but a self-healing course after immunization with a non-infectious blood-stage vaccine. The liver robustly expresses 71 miRNA species at varying levels, among which 65 miRNA species respond to malaria evidenced as steadily increasing or decreasing expressions reaching highest or lowest levels toward the end of the crisis phase on day 11 p.i. in lethal malaria. Protective vaccination does not affect constitutive miRNA expression, but leads to significant (p < 0.05) changes in the expression of 41 miRNA species, however evidenced only during crisis. In vaccination-induced self-healing infections, 18 miRNA-species are up- and 14 miRNA-species are down-regulated by more than 50% during crisis in relation to non-vaccinated mice. Vaccination-induced self-healing and survival of otherwise lethal infections of P. chabaudi activate epigenetic miRNA-regulated remodeling processes in the liver manifesting themselves during crisis. Especially, liver regeneration is accelerated as suggested by upregulation of let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-26a, miR-122-5p, miR30a, miR27a, and mir-29a, whereas the up-regulated expression of miR-142-3p by more than 100% is compatible with the view of enhanced hepatic erythropoiesis, possibly at expense of megakaryopoiesis, during crisis of P. chabaudi blood-stage malaria. PMID:28123381

  13. The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses.

    PubMed

    Zhou, Lian-di; Zhang, Qi-hui; Zhang, Ying; Liu, Jun; Cao, Ya-ming

    2009-04-01

    Lentinan, a (1-3)-beta glucan from Lentinus edodes, is an effective immunostimulatory drug. We tested the effects of lentinan during blood-stage infection by Plasmodium yoelii 17XL (P.y17XL). Pre-treatment of mice with lentinan significantly decreased the parasitemia and increased their survival after infection. Enhanced IL-12, IFN-gamma and NO production induced by lentinan in spleen cells of infected mice revealed that the Th1 immune response was stimulated against malaria infection. In vitro and in vivo, lentinan can result in enhanced expression of MHC II, CD80/CD86, and Toll-like receptors (TLR2/TLR4), and increased production of IL-12 in spleen dendritic cells (DCs) co-cultured with parasitized red blood cells (pRBCs). Moreover, both the number of CD4(+)CD25(+) regulatory T cells (Tregs) and the levels of IL-10 secreted by Tregs were reduced by pre-treatment with lentinan in the spleen of malaria-infected mice. Meanwhile, apoptosis of CD4(+) T cell in spleens of mice pretreated with lentinan was significantly reduced. In summary, lentinan can induce protective Th1 immune responses to control the proliferation of malaria parasites during the blood-stage of P.y17XL infection by stimulating maturation of DCs to inhibit negative regulation of the Th1 immune response by Tregs. Taken together, our findings suggest that lentinan has prophylactic potential for the treatment of malaria.

  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 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

  15. Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8+ T Cells during Blood-Stage Malaria

    PubMed Central

    Silva-Filho, João L.; Caruso-Neves, Celso; Pinheiro, Ana A. S.

    2017-01-01

    CD8+ T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT1 (AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT1R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT1R in inducing the pathogenic activity of Plasmodium-specific CD8+ T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response of Plasmodium-specific CD8+ T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R−/− Plasmodium-specific CD8+ T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium-specific CD8+ T cells were treated with losartan (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R−/− OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT1R−/− OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT1R−/− OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT1R-induced harmful phenotype of Plasmodium-specific CD8+ T cells during blood-stage malaria. PMID:28261571

  16. Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8(+) T Cells during Blood-Stage Malaria.

    PubMed

    Silva-Filho, João L; Caruso-Neves, Celso; Pinheiro, Ana A S

    2017-01-01

    CD8(+) T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT1 (AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT1R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT1R in inducing the pathogenic activity of Plasmodium-specific CD8(+) T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response of Plasmodium-specific CD8(+) T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R(-/-)Plasmodium-specific CD8(+) T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium-specific CD8(+) T cells were treated with losartan (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R(-/-) OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT1R(-/-) OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT1R(-/-) OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT1R-induced harmful phenotype of Plasmodium-specific CD8(+) T cells during blood-stage malaria.

  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. 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

    2016-03-17

    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.

  19. Pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of Actelion‐451840 in an induced blood stage malaria study in healthy subjects

    PubMed Central

    Dingemanse, Jasper; Mathis, Alexandre; Marquart, Louise; Möhrle, Jörg J.; McCarthy, James S.

    2016-01-01

    Aims The aim of this study was to use data from an experimental induced blood stage malaria clinical trial to characterize the antimalarial activity of the new compound Actelion‐451840 using pharmacokinetic/pharmacodynamic (PK/PD) modelling. Then, using simulations from the model, the dose and dosing regimen necessary to achieve cure of infection were derived. Methods Eight healthy male subjects were infected with blood stage P. falciparum. After 7 days, a single dose of 500 mg of Actelion‐451840 was administered under fed conditions. Parasite and drug concentrations were sampled frequently. Parasite growth and the relation to drug exposure were estimated using PK/PD modelling. Simulations were then undertaken to derive estimates of the likelihood of achieving cure in different scenarios. Results Actelion‐451840 was safe and well tolerated. Single dose treatment markedly reduced the level of P. falciparum parasitaemia, with a weighted average parasite reduction rate of 73.6 (95% CI 56.1, 96.5) and parasite clearance half‐life of 7.7 h (95% CI 7.3, 8.3). A two compartment PK/PD model with a steep concentration−kill effect predicted maximum effect with a sustained concentration of 10–15 ng ml−1 and cure achieved in 90% of subjects with six once daily doses of 300 mg once daily. Conclusions Actelion‐451840 shows clinical efficacy against P. falciparum infections. The PK/PD model developed from a single proof‐of‐concept study with eight healthy subjects enabled prediction of therapeutic effects, with cure rates with seven daily doses predicted to be equivalent to artesunate monotherapy. Larger doses or more frequent dosing are not predicted to achieve more rapid cure. PMID:27062080

  20. Phase 1 Trial of the Plasmodium falciparum Blood Stage Vaccine MSP142-C1/Alhydrogel with and without CPG 7909 in Malaria Naïve Adults

    PubMed Central

    Ellis, Ruth D.; Martin, Laura B.; Shaffer, Donna; Long, Carole A.; Miura, Kazutoyo; Fay, Michael P.; Narum, David L.; Zhu, Daming; Mullen, Gregory E. D.; Mahanty, Siddhartha; Miller, Louis H.; Durbin, Anna P.

    2010-01-01

    Background Merozoite surface protein 142 (MSP142) is a leading blood stage malaria vaccine candidate. In order to induce immune responses that cover the major antigenic polymorphisms, FVO and 3D7 recombinant proteins of MSP142 were mixed (MSP142-C1). To improve the level of antibody response, MSP142-C1 was formulated with Alhydrogel plus the novel adjuvant CPG 7909. Methods A Phase 1 clinical trial was conducted in healthy malaria-naïve adults at the Center for Immunization Research in Washington, D.C., to evaluate the safety and immunogenicity of MSP142-C1/Alhydrogel +/− CPG 7909. Sixty volunteers were enrolled in dose escalating cohorts and randomized to receive three vaccinations of either 40 or 160 µg protein adsorbed to Alhydrogel +/− 560 µg CPG 7909 at 0, 1 and 2 months. Results Vaccinations were well tolerated, with only one related adverse event graded as severe (Grade 3 injection site erythema) and all other vaccine related adverse events graded as either mild or moderate. Local adverse events were more frequent and severe in the groups receiving CPG. The addition of CPG enhanced anti-MSP142 antibody responses following vaccination by up to 49-fold two weeks after second immunization and 8-fold two weeks after the third immunization when compared to MSP142-C1/Alhydrogel alone (p<0.0001). After the third immunization, functionality of the antibody was tested by an in vitro growth inhibition assay. Inhibition was a function of antibody titer, with an average of 3% (range −2 to 10%) in the non CPG groups versus 14% (3 to 32%) in the CPG groups. Conclusion/Significance The favorable safety profile and high antibody responses induced with MSP142-C1/Alhydrogel + CPG 7909 are encouraging. MSP142-C1/Alhydrogel is being combined with other blood stage antigens and will be taken forward in a formulation adjuvanted with CPG 7909. Trial Registration ClinicalTrials.gov Identifier: NCT00320658 PMID:20107498

  1. Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission

    PubMed Central

    Elliott, Suzanne; Sekuloski, Silvana; Sikulu, Maggy; Hugo, Leon; Khoury, David; Cromer, Deborah; Davenport, Miles; Sattabongkot, Jetsumon; Ivinson, Karen; Ockenhouse, Christian; McCarthy, James

    2016-01-01

    Background Interventions to interrupt transmission of malaria from humans to mosquitoes represent an appealing approach to assist malaria elimination. A limitation has been the lack of systems to test the efficacy of such interventions before proceeding to efficacy trials in the field. We have previously demonstrated the feasibility of induced blood stage malaria (IBSM) infection with Plasmodium vivax. In this study, we report further validation of the IBSM model, and its evaluation for assessment of transmission of P. vivax to Anopheles stephensi mosquitoes. Methods Six healthy subjects (three cohorts, n = 2 per cohort) were infected with P. vivax by inoculation with parasitized erythrocytes. Parasite growth was monitored by quantitative PCR, and gametocytemia by quantitative reverse transcriptase PCR (qRT-PCR) for the mRNA pvs25. Parasite multiplication rate (PMR) and size of inoculum were calculated by linear regression. Mosquito transmission studies were undertaken by direct and membrane feeding assays over 3 days prior to commencement of antimalarial treatment, and midguts of blood fed mosquitoes dissected and checked for presence of oocysts after 7–9 days. Results The clinical course and parasitemia were consistent across cohorts, with all subjects developing mild to moderate symptoms of malaria. No serious adverse events were reported. Asymptomatic elevated liver function tests were detected in four of six subjects; these resolved without treatment. Direct feeding of mosquitoes was well tolerated. The estimated PMR was 9.9 fold per cycle. Low prevalence of mosquito infection was observed (1.8%; n = 32/1801) from both direct (4.5%; n = 20/411) and membrane (0.9%; n = 12/1360) feeds. Conclusion The P. vivax IBSM model proved safe and reliable. The clinical course and PMR were reproducible when compared with the previous study using this model. The IBSM model presented in this report shows promise as a system to test transmission-blocking interventions

  2. 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.

  3. 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

  4. Protective immune responses elicited by immunization with a chimeric blood-stage malaria vaccine persist but are not boosted by Plasmodium yoelii challenge infection

    PubMed Central

    Alaro, James R.; Lynch, Michele M.; Burns, James M.

    2010-01-01

    An efficacious malaria vaccine remains elusive despite concerted efforts. Using the Plasmodium yoelii murine model, we previously reported that immunization with the C-terminal 19 kDa domain of merozoite surface protein 1 (MSP119) fused to full-length MSP8 protected against lethal P. yoelii 17XL, well beyond that achieved by single or combined immunizations with the component antigens. Here, we continue the evaluation of the chimeric PyMSP1/8 vaccine. We show that immunization with rPyMSP1/8 vaccine elicited an MSP8-restricted T cell response that was sufficient to provide help for both PyMSP119 and PyMSP8 specific B cells to produce high and sustained levels of protective antibodies. The enhanced efficacy of immunization with rPyMSP1/8, in comparison to a combined formulation of rPyMSP142 and rPyMSP8, was not due to improved conformation of protective B cell epitopes in the chimeric molecule. Unexpectedly, rPyMSP1/8 vaccine-induced antibody responses were not boosted by exposure to P. yoelii 17XL infected RBCs. However, rPyMSP1/8 immunized and infected mice mounted robust responses to a diverse set of blood-stage antigens. The data support the further development of an MSP1/8 chimeric vaccine but also suggest that vaccines that prime for responses to a diverse set of parasite proteins will be required to maximize vaccine efficacy. PMID:20709001

  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

    Lau, Lei Shong; Fernandez-Ruiz, Daniel; 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

    2014-05-01

    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.

  6. Dynamic RNA profiling in Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate

    PubMed Central

    Natalang, Onguma; Bischoff, Emmanuel; Deplaine, Guillaume; Proux, Caroline; Dillies, Marie-Agnès; Sismeiro, Odile; Guigon, Ghislaine; Bonnefoy, Serge; Patarapotikul, Jintana; Mercereau-Puijalon, Odile; Coppée, Jean-Yves; David, Peter H

    2008-01-01

    Background Translation of the genome sequence of Plasmodium sp. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of P. falciparum parasites exposed to antimalarial drugs. Results The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole. Conclusion The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular

  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 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

  8. Parasite-Specific CD4+ IFN-γ+ IL-10+ T Cells Distribute within Both Lymphoid and Nonlymphoid Compartments and Are Controlled Systemically by Interleukin-27 and ICOS during Blood-Stage Malaria Infection

    PubMed Central

    Villegas-Mendez, Ana; Shaw, Tovah N.; Inkson, Colette A.; Strangward, Patrick; de Souza, J. Brian

    2015-01-01

    Immune-mediated pathology in interleukin-10 (IL-10)-deficient mice during blood-stage malaria infection typically manifests in nonlymphoid organs, such as the liver and lung. Thus, it is critical to define the cellular sources of IL-10 in these sensitive nonlymphoid compartments during infection. Moreover, it is important to determine if IL-10 production is controlled through conserved or disparate molecular programs in distinct anatomical locations during malaria infection, as this may enable spatiotemporal tuning of the regulatory immune response. In this study, using dual gamma interferon (IFN-γ)–yellow fluorescent protein (YFP) and IL-10–green fluorescent protein (GFP) reporter mice, we show that CD4+ YFP+ T cells are the major source of IL-10 in both lymphoid and nonlymphoid compartments throughout the course of blood-stage Plasmodium yoelii infection. Mature splenic CD4+ YFP+ GFP+ T cells, which preferentially expressed high levels of CCR5, were capable of migrating to and seeding the nonlymphoid tissues, indicating that the systemically distributed host-protective cells have a common developmental history. Despite exhibiting comparable phenotypes, CD4+ YFP+ GFP+ T cells from the liver and lung produced significantly larger quantities of IL-10 than their splenic counterparts, showing that the CD4+ YFP+ GFP+ T cells exert graded functions in distinct tissue locations during infection. Unexpectedly, given the unique environmental conditions within discrete nonlymphoid and lymphoid organs, we show that IL-10 production by CD4+ YFP+ T cells is controlled systemically during malaria infection through IL-27 receptor signaling that is supported after CD4+ T cell priming by ICOS signaling. The results in this study substantially improve our understanding of the systemic IL-10 response to malaria infection, particularly within sensitive nonlymphoid organs. PMID:26459508

  9. The spleen CD4+ T cell response to blood-stage Plasmodium chabaudi malaria develops in two phases characterized by different properties.

    PubMed

    Muxel, Sandra Marcia; Freitas do Rosário, Ana Paula; Zago, Cláudia Augusta; Castillo-Méndez, Sheyla Inés; Sardinha, Luiz Roberto; Rodriguez-Málaga, Sérgio Marcelo; Câmara, Niels Olsen Saraiva; Álvarez, José Maria; Lima, Maria Regina D'Império

    2011-01-01

    The pivotal role of spleen CD4(+) T cells in the development of both malaria pathogenesis and protective immunity makes necessary a profound comprehension of the mechanisms involved in their activation and regulation during Plasmodium infection. Herein, we examined in detail the behaviour of non-conventional and conventional splenic CD4(+) T cells during P. chabaudi malaria. We took advantage of the fact that a great proportion of CD4(+) T cells generated in CD1d(-/-) mice are I-A(b)-restricted (conventional cells), while their counterparts in I-A(b-/-) mice are restricted by CD1d and other class IB major histocompatibility complex (MHC) molecules (non-conventional cells). We found that conventional CD4(+) T cells are the main protagonists of the immune response to infection, which develops in two consecutive phases concomitant with acute and chronic parasitaemias. The early phase of the conventional CD4(+) T cell response is intense and short lasting, rapidly providing large amounts of proinflammatory cytokines and helping follicular and marginal zone B cells to secrete polyclonal immunoglobulin. Both TNF-α and IFN-γ production depend mostly on conventional CD4(+) T cells. IFN-γ is produced simultaneously by non-conventional and conventional CD4(+) T cells. The early phase of the response finishes after a week of infection, with the elimination of a large proportion of CD4(+) T cells, which then gives opportunity to the development of acquired immunity. Unexpectedly, the major contribution of CD1d-restricted CD4(+) T cells occurs at the beginning of the second phase of the response, but not earlier, helping both IFN-γ and parasite-specific antibody production. We concluded that conventional CD4(+) T cells have a central role from the onset of P. chabaudi malaria, acting in parallel with non-conventional CD4(+) T cells as a link between innate and acquired immunity. This study contributes to the understanding of malaria immunology and opens a perspective for

  10. IL-2 contributes to maintaining a balance between CD4+Foxp3+ regulatory T cells and effector CD4+ T cells required for immune control of blood-stage malaria infection.

    PubMed

    Berretta, Floriana; St-Pierre, Jessica; Piccirillo, Ciriaco A; Stevenson, Mary M

    2011-04-15

    To investigate the role of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in blood-stage malaria, we compared Plasmodium chabaudi AS infection in wild-type (WT) C57BL/6 and transgenic mice overexpressing the transcription factor Foxp3 (Foxp3Tg) and observed that Foxp3Tg mice experienced lethal infection and deficient malaria-specific immune responses. Adoptive transfer of total CD4(+) T cells from Foxp3Tg mice or CD4(+)CD25(+) T cells from WT mice to naive WT recipients confirmed that high numbers of Treg cells compromised immune control of malaria. Transfer of GFP(+)CD4(+)CD25(+) T cells to naive WT recipients together with immunohistochemical staining of spleens from infected WT mice demonstrated that Foxp3(+) Treg cells localized in the T cell area of the spleen. Determination of CD4(+)Foxp3(+) Treg cell responses in the spleen of infected WT mice revealed a significant but transient increase in CD4(+)Foxp3(+) Treg cells early in infection. This was followed by a significant and sustained decrease due to reduced proliferation and apoptosis of CD4(+)Foxp3(+) Treg cells. Importantly, the kinetics of IL-2 secretion by effector CD4(+)Foxp3(-) T cells coincided with changes in CD4(+)Foxp3(+) cells and the differentiation of CD4(+)T-bet(+)IFN-γ(+) cells required for immune control of infection. Administration of the IL-2/anti-IL-2 mAb (clone JES6-1) complex to infected WT mice increased the severity of P. chabaudi AS infection and promoted expansion of Foxp3(+) Treg cells. Collectively, these data demonstrate that the ability to control and eliminate P. chabaudi AS infection is due to a tight balance between natural Treg cells and effector CD4(+) Th1 cells, a balance regulated in part by IL-2.

  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).

  12. The within-host dynamics of malaria infection with immune response.

    PubMed

    Li, Yilong; Ruan, Shigui; Xiao, Dongmei

    2011-10-01

    Malaria infection is one of the most serious global health problems of our time. In this article the blood-stage dynamics of malaria in an infected host are studied by incorporating red blood cells, malaria parasitemia and immune effectors into a mathematical model with nonlinear bounded Michaelis-Menten-Monod functions describing how immune cells interact with infected red blood cells and merozoites. By a theoretical analysis of this model, we show that there exists a threshold value R0, namely the basic reproduction number, for the malaria infection. The malaria-free equilibrium is global asymptotically stable if R0 < 1. If R0 > 1, there exist two kinds of infection equilibria: malaria infection equilibrium (without specific immune response) and positive equilibrium (with specific immune response). Conditions on the existence and stability of both infection equilibria are given. Moreover, it has been showed that the model can undergo Hopf bifurcation at the positive equilibrium and exhibit periodic oscillations. Numerical simulations are also provided to demonstrate these theoretical results.

  13. On global stability of the intra-host dynamics of malaria and the immune system

    NASA Astrophysics Data System (ADS)

    Tumwiine, J.; Mugisha, J. Y. T.; Luboobi, L. S.

    2008-05-01

    In this paper we consider an intra-host model for the dynamics of malaria. The model describes the dynamics of the blood stage malaria parasites and their interaction with host cells, in particular red blood cells (RBC) and immune effectors. We establish the equilibrium points of the system and analyze their stability using the theory of competitive systems, compound matrices and stability of periodic orbits. We established that the disease-free equilibrium is globally stable if and only if the basic reproduction number satisfies R0[less-than-or-equals, slant]1 and the parasite will be cleared out of the host. If R0>1, a unique endemic equilibrium is globally stable and the parasites persist at the endemic steady state. In the presence of the immune response, the numerical analysis of the model shows that the endemic equilibrium is unstable.

  14. 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

  15. H2O2 dynamics in the malaria parasite Plasmodium falciparum

    PubMed Central

    Rahbari, Mahsa; Bogeski, Ivan

    2017-01-01

    Hydrogen peroxide is an important antimicrobial agent but is also crucially involved in redox signaling and pathogen-host cell interactions. As a basis for systematically investigating intracellular H2O2 dynamics and regulation in living malaria parasites, we established the genetically encoded fluorescent H2O2 sensors roGFP2-Orp1 and HyPer-3 in Plasmodium falciparum. Both ratiometric redox probes as well as the pH control SypHer were expressed in the cytosol of blood-stage parasites. Both redox sensors showed reproducible sensitivity towards H2O2 in the lower micromolar range in vitro and in the parasites. Due to the pH sensitivity of HyPer-3, we used parasites expressing roGFP2-Orp1 for evaluation of short-, medium-, and long-term effects of antimalarial drugs on H2O2 levels and detoxification in Plasmodium. None of the quinolines or artemisinins tested had detectable direct effects on the H2O2 homeostasis at pharmacologically relevant concentrations. However, pre-treatment of the cells with antimalarial drugs or heat shock led to a higher tolerance towards exogenous H2O2. The systematic evaluation and comparison of the two genetically encoded cytosolic H2O2 probes in malaria parasites provides a basis for studying parasite-host cell interactions or drug effects with spatio-temporal resolution while preserving cell integrity. PMID:28369083

  16. Modeling malaria and typhoid fever co-infection dynamics.

    PubMed

    Mutua, Jones M; Wang, Feng-Bin; Vaidya, Naveen K

    2015-06-01

    Malaria and typhoid are among the most endemic diseases, and thus, of major public health concerns in tropical developing countries. In addition to true co-infection of malaria and typhoid, false diagnoses due to similar signs and symptoms and false positive results in testing methods, leading to improper controls, are the major challenges on managing these diseases. In this study, we develop novel mathematical models describing the co-infection dynamics of malaria and typhoid. Through mathematical analyses of our models, we identify distinct features of typhoid and malaria infection dynamics as well as relationships associated to their co-infection. The global dynamics of typhoid can be determined by a single threshold (the typhoid basic reproduction number, R0(T)) while two thresholds (the malaria basic reproduction number, R0(M), and the extinction index, R0(MM)) are needed to determine the global dynamics of malaria. We demonstrate that by using efficient simultaneous prevention programs, the co-infection basic reproduction number, R0, can be brought down to below one, thereby eradicating the diseases. Using our model, we present illustrative numerical results with a case study in the Eastern Province of Kenya to quantify the possible false diagnosis resulting from this co-infection. In Kenya, despite having higher prevalence of typhoid, malaria is more problematic in terms of new infections and disease deaths. We find that false diagnosis-with higher possible cases for typhoid than malaria-cause significant devastating impacts on Kenyan societies. Our results demonstrate that both diseases need to be simultaneously managed for successful control of co-epidemics.

  17. Malaria

    MedlinePlus

    ... common?Malaria is a health problem in many tropical and subtropical countries, including portions of Central and ... these countries. If you are traveling to a tropical area or to a country where malaria is ...

  18. 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…

  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. Biology and dynamics of potential malaria vectors in Southern France

    PubMed Central

    Ponçon, Nicolas; Toty, Céline; L'Ambert, Grégory; Le Goff, Gilbert; Brengues, Cécile; Schaffner, Francis; Fontenille, Didier

    2007-01-01

    Background Malaria is a former endemic problem in the Camargue, South East France, an area from where very few recent data concerning Anopheles are available. A study was undertaken in 2005 to establish potential malaria vector biology and dynamics and evaluate the risk of malaria re-emergence. Methods Mosquitoes were collected in two study areas, from March to October 2005, one week every two weeks, using light traps+CO2, horse bait traps, human bait catch, and by collecting females in resting sites. Results Anopheles hyrcanus was the most abundant Anopheles species. Anopheles melanoon was less abundant, and Anopheles atroparvus and Anopheles algeriensis were rare. Anopheles hyrcanus and An. melanoon were present in summer, whereas An. atroparvus was present in autumn and winter. A large number of An. hyrcanus females was collected on humans, whereas almost exclusively animals attracted An. melanoon. Based on an enzyme-linked immunosorbent assay, almost 90% of An. melanoon blood meals analysed had been taken on horse or bovine. Anopheles hyrcanus and An. melanoon parity rates showed huge variations according to the date and the trapping method. Conclusion Anopheles hyrcanus seems to be the only Culicidae likely to play a role in malaria transmission in the Camargue, as it is abundant and anthropophilic. PMID:17313664

  1. Two putative protein export regulators promote Plasmodium blood stage development in vivo.

    PubMed

    Matz, Joachim M; Matuschewski, Kai; Kooij, Taco W A

    2013-09-01

    Protein export is considered an essential feature of malaria parasite blood stage development. Here, we examined five components of the candidate Plasmodium translocon of exported proteins (PTEX), a complex thought to mediate protein export across the parasitophorous vacuole membrane into the host cell. Using the murine malaria model parasite Plasmodium berghei, we succeeded in generating parasite lines lacking PTEX88 and thioredoxin 2 (TRX2). Repeated attempts to delete the remaining three translocon components failed, suggesting essential functions for EXP2, PTEX150, and heat shock protein 101 (HSP101) during blood stage development. To analyze blood infections of the null-mutants, we established a flow cytometry-assisted intravital competition assay using three novel high fluorescent lines (Bergreen, Beryellow, and Berred). Although blood stage development of parasites lacking TRX2 was affected, the deficit was much more striking in PTEX88 null-mutants. The multiplication rate of PTEX88-deficient parasites was strongly reduced resulting in out-competition by wild-type parasites. Endogenous tagging revealed that TRX2::tag resides in distinct punctate organelles of unknown identity. PTEX88::tag shows a diffuse intraparasitic pattern in blood stage parasites. In trophozoites, PTEX88::tag also localized to previously unrecognized extensions reaching from the parasite surface into the erythrocyte cytoplasm. Together, our results indicate auxiliary roles for TRX2 and PTEX88 and central roles for EXP2, PTEX150, and HSP101 during P. berghei blood infection.

  2. Therapeutic PD-L1 and LAG-3 blockade rapidly clears established blood-stage Plasmodium infection

    PubMed Central

    Butler, Noah S.; Moebius, Jacqueline; Pewe, Lecia L.; Traore, Boubacar; Doumbo, Ogobara K.; Tygrett, Lorraine T.; Waldschmidt, Thomas J.; Crompton, Peter D.; Harty, John T.

    2011-01-01

    Plasmodium infection of erythrocytes induces clinical malaria. Parasite-specific CD4+ T cells correlate with reduced parasite burdens and severity of human malaria, and are required to control blood-stage infection in mice. However, the characteristics of CD4+ T cells that determine protection or parasite persistence remain unknown. Here we show that P. falciparum infection of humans increased expression of an inhibitory receptor (PD-1) associated with T cell dysfunction. In vivo blockade of PD-L1 and LAG-3 restored CD4+ T cell function, amplified T follicular helper cell and germinal center B cell and plasmablast numbers, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, which can be rescued to enhance parasite control using inhibitory therapies. PMID:22157630

  3. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection.

    PubMed

    Butler, Noah S; Moebius, Jacqueline; Pewe, Lecia L; Traore, Boubacar; Doumbo, Ogobara K; Tygrett, Lorraine T; Waldschmidt, Thomas J; Crompton, Peter D; Harty, John T

    2011-12-11

    Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.

  4. 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

  5. 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 ...

  6. Malaria

    DTIC Science & Technology

    2011-06-01

    established, the infection is classi- fied as cryptic malaria. A large majority of infections are transmitted by the bite of an infected female ... female anopheline mosquitoes. Plasmodium sp infecting humans include Plasmodium vivax, Plasmodium falci- parum, Plasmodium malariae, and Plasmodium ovale...paled and pigment formed within them. Later he observed male gametes form by exflagellation and described the male and female gam- etes, the

  7. Malaria.

    PubMed

    Heck, J E

    1991-03-01

    Human malaria is caused by four species of the genus plasmodium. The sexual stage of the parasite occurs in the mosquito and asexual reproduction occurs in man. Symptoms of fever, chills, headache, and myalgia result from the invasion and rupture of erythrocytes. Merozoites are released from erythrocytes and invade other cells, thus propagating the infection. The most vulnerable hosts are nonimmune travelers, young children living in the tropics, and pregnant women. P. falciparum causes the most severe infections because it infects RBCs of all ages and has the propensity to develop resistance to antimalarials. Rapid diagnosis can be made with a malarial smear, and treatment should be initiated promptly. In some regions (Mexico, Central America except Panama, and North Africa) chloroquine phosphate is effective therapy. In subsaharan Africa, South America, and Southeast Asia, chloroquine resistance has become widespread, and other antimalarials are necessary. The primary care physician should have a high index of suspicion for malaria in the traveler returning from the tropics. Malaria should also be suspected in the febrile transfusion recipient and newborns of mothers with malaria.

  8. 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.

  9. 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

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

    PubMed

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

    2015-07-14

    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.

  11. Miniaturized Growth Inhibition Assay to Assess the Anti-blood Stage Activity of Antibodies.

    PubMed

    Duncan, Elizabeth H; Bergmann-Leitner, Elke S

    2015-01-01

    While no immune correlate for blood-stage specific immunity against Plasmodium falciparum malaria has been identified, there is strong evidence that antibodies directed to various malarial antigens play a crucial role. In an effort to evaluate the role of antibodies in inhibiting growth and/or invasion of erythrocytic stages of the malaria parasite it will be necessary to test large sample sets from Phase 2a/b trials as well as epidemiological studies. The major constraints for such analyses are (1) availability of sufficient sample quantities (especially from infants and small children) and (2) the throughput of standard growth inhibition assays. The method described here assesses growth- and invasion inhibition by measuring the metabolic activity and viability of the parasite (by using a parasite lactate dehydrogenase-specific substrate) in a 384-microtiter plate format. This culture method can be extended beyond the described detection system to accommodate other techniques commonly used for growth/invasion-inhibition.

  12. 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.

  13. Dynamics of positional warfare malaria: Finland and Korea compared

    PubMed Central

    Huldén, Lena; Huldén, Larry

    2008-01-01

    Background A sudden outbreak of vivax malaria among Finnish troops in SE-Finland and along the front line in Hanko peninsula in the southwest occurred in 1941 during World War II. The common explanation has been an invasion of infective Anopheles mosquitoes from the Russian troops crossing the front line between Finland and Soviet Union. A revised explanation is presented based on recent studies of Finnish malaria. Methods The exact start of the epidemic and the phenology of malaria cases among the Finnish soldiers were reanalyzed. The results were compared with the declining malaria in Finland. A comparison with a corresponding situation starting in the 1990's in Korea was performed. Results and discussion The malaria cases occurred in July in 1941 when it was by far too early for infective mosquitoes to be present. The first Anopheles mosquitoes hatched at about the same time as the first malaria cases were observed among the Finnish soldiers. It takes about 3 – 6 weeks for the completion of the sporogony in Finland. The new explanation is that soldiers in war conditions were suddenly exposed to uninfected mosquitoes and those who still were carriers of hypnozoites developed relapses triggered by these mosquitoes. It is estimated that about 0.5% of the Finnish population still were carriers of hypnozoites in the 1940's. A corresponding outbreak of vivax malaria in Korea in the 1990's is similarly interpreted as relapses from activated hypnozoites among Korean soldiers. The significance of the mosquito induced relapses is emphasized by two benefits for the Plasmodium. There is a synchronous increase of gametocytes when new mosquitoes emerge. It also enables meiotic recombination between different strains of the Plasmodium. Conclusion The malaria peak during the positional warfare in the 1940's was a short outbreak during the last phase of declining indigenous malaria in Finland. The activation of hypnozoites among a large number of soldiers and subsequent

  14. 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.

  15. The importance of temperature fluctuations in understanding mosquito population dynamics and malaria risk

    PubMed Central

    Nelson, William A.; Paaijmans, Krijn P.; Thomas, Matthew B.; Bjørnstad, Ottar N.

    2017-01-01

    Temperature is a key environmental driver of Anopheles mosquito population dynamics; understanding its central role is important for these malaria vectors. Mosquito population responses to temperature fluctuations, though important across the life history, are poorly understood at a population level. We used stage-structured, temperature-dependent delay-differential equations to conduct a detailed exploration of the impacts of diurnal and annual temperature fluctuations on mosquito population dynamics. The model allows exploration of temperature-driven temporal changes in adult age structure, giving insights into the population’s capacity to vector malaria parasites. Because of temperature-dependent shifts in age structure, the abundance of potentially infectious mosquitoes varies temporally, and does not necessarily mirror the dynamics of the total adult population. In addition to conducting the first comprehensive theoretical exploration of fluctuating temperatures on mosquito population dynamics, we analysed observed temperatures at four locations in Africa covering a range of environmental conditions. We found both temperature and precipitation are needed to explain the observed malaria season in these locations, enhancing our understanding of the drivers of malaria seasonality and how temporal disease risk may shift in response to temperature changes. This approach, tracking both mosquito abundance and age structure, may be a powerful tool for understanding current and future malaria risk.

  16. Dynamics of climate-based malaria transmission model with age-structured human population

    NASA Astrophysics Data System (ADS)

    Addawe, Joel; Pajimola, Aprimelle Kris

    2016-10-01

    In this paper, we proposed to study the dynamics of malaria transmission with periodic birth rate of the vector and an age-structure for the human population. The human population is divided into two compartments: pre-school (0-5 years) and the rest of the human population. We showed the existence of a disease-free equilibrium point. Using published epidemiological parameters, we use numerical simulations to show potential effect of climate change in the dynamics of age-structured malaria transmission. Numerical simulations suggest that there exists an asymptotically attractive solution that is positive and periodic.

  17. Variation in Malaria Transmission Dynamics in Three Different Sites in Western Kenya

    PubMed Central

    Imbahale, S. S.; Mukabana, W. R.; Orindi, B.; Githeko, A. K.; Takken, W.

    2012-01-01

    The main objective was to investigate malaria transmission dynamics in three different sites, two highland villages (Fort Ternan and Lunyerere) and a lowland peri-urban area (Nyalenda) of Kisumu city. Adult mosquitoes were collected using PSC and CDC light trap while malaria parasite incidence data was collected from a cohort of children on monthly basis. Rainfall, humidity and temperature data were collected by automated weather stations. Negative binomial and Poisson generalized additive models were used to examine the risk of being infected, as well as the association with the weather variables. Anopheles gambiae s.s. was most abundant in Lunyerere, An. arabiensis in Nyalenda and An. funestus in Fort Ternan. The CDC light traps caught a higher proportion of mosquitoes (52.3%) than PSC (47.7%), although not significantly different (P = 0.689). The EIR's were 0, 61.79 and 6.91 bites/person/year for Fort Ternan, Lunyerere and Nyalenda. Site, month and core body temperature were all associated with the risk of having malaria parasites (P < 0.0001). Rainfall was found to be significantly associated with the occurrence of P. falciparum malaria parasites, but not relative humidity and air temperature. The presence of malaria parasite-infected children in all the study sites provides evidence of local malaria transmission. PMID:22988466

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. MAPK phosphotase 5 deficiency contributes to protection against blood-stage Plasmodium yoelii 17XL infection in mice.

    PubMed

    Cheng, Qianqian; Zhang, Qingfeng; Xu, Xindong; Yin, Lan; Sun, Lin; Lin, Xin; Dong, Chen; Pan, Weiqing

    2014-04-15

    Cell-mediated immunity plays a crucial role in the development of host resistance to asexual blood-stage malaria infection. However, little is known of the regulatory factors involved in this process. In this study, we investigated the impact of MAPK phosphotase 5 (MKP5) on protective immunity against a lethal Plasmodium yoelii 17XL blood-stage infection using MKP5 knockout C57BL/6 mice. Compared with wild-type control mice, MKP5 knockout mice developed significantly lower parasite burdens with prolonged survival times. We found that this phenomenon correlated with a rapid and strong IFN-γ-dependent cellular immune response during the acute phase of infection. Inactivation of IFN-γ by the administration of a neutralizing Ab significantly reduced the protective effects in MKP5 knockout mice. By analyzing IFN-γ production in innate and adaptive lymphocyte subsets, we observed that MKP5 deficiency specifically enhanced the IFN-γ response mediated by CD4+ T cells, which was attributable to the increased stimulatory capacity of splenic CD11c+ dendritic cells. Furthermore, following vaccination with whole blood-stage soluble plasmodial Ag, MKP5 knockout mice acquired strongly enhanced Ag-specific immune responses and a higher level of protection against subsequent P. yoelii 17XL challenge. Finally, we found the enhanced response mediated by MKP5 deficiency resulted in a lethal consequence in mice when infected with nonlethal P. yoelii 17XNL. Thus, our data indicate that MKP5 is a potential regulator of immune resistance against Plasmodium infection in mice, and that an understanding of the role of MKP5 in manipulating anti-malaria immunity may provide valuable information on the development of better control strategies for human malaria.

  3. 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.

  4. 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.

  5. A whole parasite vaccine to control the blood stages of Plasmodium: the case for lateral thinking.

    PubMed

    Good, Michael F

    2011-08-01

    Now, 27 years following the cloning of malaria antigens with the promise of the rapid development of a malaria vaccine, we face significant obstacles that are belatedly being addressed. Poor immunogenicity of subunit vaccine antigens and significant antigenic diversity of target epitopes represent major hurdles for which there are no clear strategies for a way forward within the current paradigm. Thus, a different paradigm - a vaccine that uses the whole organism - is now being examined. Although most advances in this approach relate to a vaccine for the pre-erythrocytic stages (sporozoites, liver stages), this opinion paper will outline the possibilities of developing a whole parasite vaccine for the blood stage and address some of the challenges for this strategy, which are entirely different to the challenges for a subunit vaccine. It is the view of the author that both vaccine paradigms should be pursued, but that success will come more quickly using the paranormal approach of exposing individuals to ultra-low doses of whole attenuated or killed parasites.

  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. Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum

    PubMed Central

    Dickerman, Benjamin K.; Elsworth, Brendan; Cobbold, Simon A.; Nie, Catherine Q.; McConville, Malcolm J.; Crabb, Brendan S.; Gilson, Paul R.

    2016-01-01

    Plasmodium parasites are responsible for the devastating disease malaria that affects hundreds of millions of people each year. Blood stage parasites establish new permeability pathways (NPPs) in infected red blood cell membranes to facilitate the uptake of nutrients and removal of parasite waste products. Pharmacological inhibition of the NPPs is expected to lead to nutrient starvation and accumulation of toxic metabolites resulting in parasite death. Here, we have screened a curated library of antimalarial compounds, the MMV Malaria Box, identifying two compounds that inhibit NPP function. Unexpectedly, metabolic profiling suggested that both compounds also inhibit dihydroorotate dehydrogense (DHODH), which is required for pyrimidine synthesis and is a validated drug target in its own right. Expression of yeast DHODH, which bypasses the need for the parasite DHODH, increased parasite resistance to these compounds. These studies identify two potential candidates for therapeutic development that simultaneously target two essential pathways in Plasmodium, NPP and DHODH. PMID:27874068

  8. 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

  9. 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

  10. 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

  11. IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

    PubMed Central

    Sebina, Ismail; James, Kylie R.; Soon, Megan S. F.; Best, Shannon E.; Montes de Oca, Marcela; Amante, Fiona H.; Thomas, Bryce S.; Beattie, Lynette; Souza-Fonseca-Guimaraes, Fernando; Smyth, Mark J.; Hertzog, Paul J.; Hill, Geoffrey R.; Engwerda, Christian R.

    2016-01-01

    Parasite-specific antibodies protect against blood-stage Plasmodium infection. However, in malaria-endemic regions, it takes many months for naturally-exposed individuals to develop robust humoral immunity. Explanations for this have focused on antigenic variation by Plasmodium, but have considered less whether host production of parasite-specific antibody is sub-optimal. In particular, it is unclear whether host immune factors might limit antibody responses. Here, we explored the effect of Type I Interferon signalling via IFNAR1 on CD4+ T-cell and B-cell responses in two non-lethal murine models of malaria, P. chabaudi chabaudi AS (PcAS) and P. yoelii 17XNL (Py17XNL) infection. Firstly, we demonstrated that CD4+ T-cells and ICOS-signalling were crucial for generating germinal centre (GC) B-cells, plasmablasts and parasite-specific antibodies, and likewise that T follicular helper (Tfh) cell responses relied on B cells. Next, we found that IFNAR1-signalling impeded the resolution of non-lethal blood-stage infection, which was associated with impaired production of parasite-specific IgM and several IgG sub-classes. Consistent with this, GC B-cell formation, Ig-class switching, plasmablast and Tfh differentiation were all impaired by IFNAR1-signalling. IFNAR1-signalling proceeded via conventional dendritic cells, and acted early by limiting activation, proliferation and ICOS expression by CD4+ T-cells, by restricting the localization of activated CD4+ T-cells adjacent to and within B-cell areas of the spleen, and by simultaneously suppressing Th1 and Tfh responses. Finally, IFNAR1-deficiency accelerated humoral immune responses and parasite control by boosting ICOS-signalling. Thus, we provide evidence of a host innate cytokine response that impedes the onset of humoral immunity during experimental malaria. PMID:27812214

  12. Type I Interferons Regulate Immune Responses in Humans with Blood-Stage Plasmodium falciparum Infection

    PubMed Central

    Montes de Oca, Marcela; Kumar, Rajiv; de Labastida Rivera, Fabian; Amante, Fiona H.; Sheel, Meru; Faleiro, Rebecca J.; Bunn, Patrick T.; Best, Shannon E.; Beattie, Lynette; Ng, Susanna S.; Edwards, Chelsea L.; Boyle, Glen M.; Price, Ric N.; Anstey, Nicholas M.; Loughland, Jessica R.; Burel, Julie; Doolan, Denise L.; Haque, Ashraful; McCarthy, James S.; Engwerda, Christian R.

    2016-01-01

    Summary The development of immunoregulatory networks is important to prevent disease. However, these same networks allow pathogens to persist and reduce vaccine efficacy. Here, we identify type I interferons (IFNs) as important regulators in developing anti-parasitic immunity in healthy volunteers infected for the first time with Plasmodium falciparum. Type I IFNs suppressed innate immune cell function and parasitic-specific CD4+ T cell IFNγ production, and they promoted the development of parasitic-specific IL-10-producing Th1 (Tr1) cells. Type I IFN-dependent, parasite-specific IL-10 production was also observed in P. falciparum malaria patients in the field following chemoprophylaxis. Parasite-induced IL-10 suppressed inflammatory cytokine production, and IL-10 levels after drug treatment were positively associated with parasite burdens before anti-parasitic drug administration. These findings have important implications for understanding the development of host immune responses following blood-stage P. falciparum infection, and they identify type I IFNs and related signaling pathways as potential targets for therapies or vaccine efficacy improvement. PMID:27705789

  13. Discovery of GAMA, a Plasmodium falciparum merozoite micronemal protein, as a novel blood-stage vaccine candidate antigen.

    PubMed

    Arumugam, Thangavelu U; Takeo, Satoru; Yamasaki, Tsutomu; Thonkukiatkul, Amporn; Miura, Kazutoyo; Otsuki, Hitoshi; Zhou, Hong; Long, Carole A; Sattabongkot, Jetsumon; Thompson, Jennifer; Wilson, Danny W; Beeson, James G; Healer, Julie; Crabb, Brendan S; Cowman, Alan F; Torii, Motomi; Tsuboi, Takafumi

    2011-11-01

    One of the solutions for reducing the global mortality and morbidity due to malaria is multivalent vaccines comprising antigens of several life cycle stages of the malarial parasite. Hence, there is a need for supplementing the current set of malaria vaccine candidate antigens. Here, we aimed to characterize glycosylphosphatidylinositol (GPI)-anchored micronemal antigen (GAMA) encoded by the PF08_0008 gene in Plasmodium falciparum. Antibodies were raised against recombinant GAMA synthesized by using a wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that GAMA is a microneme protein of the merozoite. Erythrocyte binding assays revealed that GAMA possesses an erythrocyte binding epitope in the C-terminal region and it binds a nonsialylated protein receptor on human erythrocytes. Growth inhibition assays revealed that anti-GAMA antibodies can inhibit P. falciparum invasion in a dose-dependent manner and GAMA plays a role in the sialic acid (SA)-independent invasion pathway. Anti-GAMA antibodies in combination with anti-erythrocyte binding antigen 175 exhibited a significantly higher level of invasion inhibition, supporting the rationale that targeting of both SA-dependent and SA-independent ligands/pathways is better than targeting either of them alone. Human sera collected from areas of malaria endemicity in Mali and Thailand recognized GAMA. Since GAMA in P. falciparum is refractory to gene knockout attempts, it is essential to parasite invasion. Overall, our study indicates that GAMA is a novel blood-stage vaccine candidate antigen.

  14. 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.

  15. Protective immunity against malaria after vaccination.

    PubMed

    de Souza, J B

    2014-03-01

    A good understanding of the immunological correlates of protective immunity is an important requirement for the development of effective vaccines against malaria. However, this concern has received little attention even in the face of two decades of intensive vaccine research. Here, we review the immune response to blood-stage malaria, with a particular focus on the type of vaccine most likely to induce the kind of response required to give strong protection against infection.

  16. Genetic diversity and natural selection of three blood-stage 6-Cys proteins in Plasmodium vivax populations from the China-Myanmar endemic border.

    PubMed

    Wang, Yue; Ma, An; Chen, Shen-Bo; Yang, Ying-Chao; Chen, Jun-Hu; Yin, Ming-Bo

    2014-12-01

    Pv12, Pv38 and Pv41, the three 6-Cys family proteins which are expressed in the blood-stage of vivax malaria, might be involved in merozoite invasion activity and thus be potential vaccine candidate antigens of Plasmodium vivax. However, little information is available concerning the genetic diversity and natural selection of these three proteins. In the present study, we analyzed the amino acid sequences of P. vivax blood-stage 6-Cys family proteins in comparison with the homologue proteins of Plasmodium cynomolgi strain B using bioinformatic methods. We also investigated genetic polymorphisms and natural selection of these three genes in P. vivax populations from the China-Myanmar endemic border. The three P. vivax blood-stage 6-Cys proteins were shown to possess a signal peptide at the N-terminus, containing two s48/45 domains, and Pv12 and Pv38 have a GPI-anchor motif at the C-terminus. Then, 22, 21 and 29 haplotypes of pv12, pv38 and pv41 were identified out of 45, 38 and 40 isolates, respectively. The dN/dS values for Domain II of pv38 and pv41 were 3.33880 and 5.99829, respectively, suggesting positive balancing selection for these regions. Meanwhile, the C-terminus of pv41 showed high nucleotide diversity, and Tajima's D test suggested that this fragment could be under positive balancing selection. Overall, our results have significant implications, providing a genetic basis for blood-stage malaria vaccine development based on these three 6-Cys proteins.

  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. Malaria Elimination Campaigns in the Lake Kariba Region of Zambia: A Spatial Dynamical Model

    PubMed Central

    Nikolov, Milen; Bever, Caitlin A.; Upfill-Brown, Alexander; Hamainza, Busiku; Miller, John M.; Eckhoff, Philip A.; Wenger, Edward A.; Gerardin, Jaline

    2016-01-01

    As more regions approach malaria elimination, understanding how different interventions interact to reduce transmission becomes critical. The Lake Kariba area of Southern Province, Zambia, is part of a multi-country elimination effort and presents a particular challenge as it is an interconnected region of variable transmission intensities. In 2012–13, six rounds of mass test-and-treat drug campaigns were carried out in the Lake Kariba region. A spatial dynamical model of malaria transmission in the Lake Kariba area, with transmission and climate modeled at the village scale, was calibrated to the 2012–13 prevalence survey data, with case management rates, insecticide-treated net usage, and drug campaign coverage informed by surveillance. The model captured the spatio-temporal trends of decline and rebound in malaria prevalence in 2012–13 at the village scale. Various interventions implemented between 2016–22 were simulated to compare their effects on reducing regional transmission and achieving and maintaining elimination through 2030. Simulations predict that elimination requires sustaining high coverage with vector control over several years. When vector control measures are well-implemented, targeted mass drug campaigns in high-burden areas further increase the likelihood of elimination, although drug campaigns cannot compensate for insufficient vector control. If infections are regularly imported from outside the region into highly receptive areas, vector control must be maintained within the region until importations cease. Elimination in the Lake Kariba region is possible, although human movement both within and from outside the region risk damaging the success of elimination programs. PMID:27880764

  19. Malaria Elimination Campaigns in the Lake Kariba Region of Zambia: A Spatial Dynamical Model.

    PubMed

    Nikolov, Milen; Bever, Caitlin A; Upfill-Brown, Alexander; Hamainza, Busiku; Miller, John M; Eckhoff, Philip A; Wenger, Edward A; Gerardin, Jaline

    2016-11-01

    As more regions approach malaria elimination, understanding how different interventions interact to reduce transmission becomes critical. The Lake Kariba area of Southern Province, Zambia, is part of a multi-country elimination effort and presents a particular challenge as it is an interconnected region of variable transmission intensities. In 2012-13, six rounds of mass test-and-treat drug campaigns were carried out in the Lake Kariba region. A spatial dynamical model of malaria transmission in the Lake Kariba area, with transmission and climate modeled at the village scale, was calibrated to the 2012-13 prevalence survey data, with case management rates, insecticide-treated net usage, and drug campaign coverage informed by surveillance. The model captured the spatio-temporal trends of decline and rebound in malaria prevalence in 2012-13 at the village scale. Various interventions implemented between 2016-22 were simulated to compare their effects on reducing regional transmission and achieving and maintaining elimination through 2030. Simulations predict that elimination requires sustaining high coverage with vector control over several years. When vector control measures are well-implemented, targeted mass drug campaigns in high-burden areas further increase the likelihood of elimination, although drug campaigns cannot compensate for insufficient vector control. If infections are regularly imported from outside the region into highly receptive areas, vector control must be maintained within the region until importations cease. Elimination in the Lake Kariba region is possible, although human movement both within and from outside the region risk damaging the success of elimination programs.

  20. 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.

  1. 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

  2. Dynamics of Plasmodium falciparum parasitemia regarding combined treatment regimens for acute uncomplicated malaria, Antioquia, Colombia.

    PubMed

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

    2010-07-01

    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.

  3. Unstable, low-level transmission of malaria on the Colombian Pacific Coast.

    PubMed

    González, J M; Olano, V; Vergara, J; Arévalo-Herrera, M; Carrasquilla, G; Herrera, S; López, J A

    1997-06-01

    The development of immune responses to malarial infection in inhabitants of endemic areas differs according to the level of exposure to the parasite. Adults living in a region where the level of malaria transmission is low (Colombia) have been shown to exhibit a similar response to each of the three regions of the circumsporozoite protein (the central repeated NANP region, and the flanking N- and C-termini). Conversely, donors exposed to a frequent sporozoite challenge in areas of high malaria transmission (Mali) exhibit antibodies predominantly to the NANP repeated domain. Malaria in the people of Zacarías, a community on the Pacific Coast of Colombia where malaria transmission is low and unstable, was the subject of the present study. Within a 9-year period, a negative correlation between rainfall and documented malaria cases was recorded for this area. Thick smears of blood samples of 319 individuals revealed that 8.5% had malarial infections. As most (67%) of the smear-positive cases were asymptomatic, it seems that, despite the low prevalence of malaria in this area, the establishment of clinical symptoms is attenuated, probably because of the acquisition of premunition. Within this region, the most commonly found Anopheles species (representing 61.1% of the mosquitoes caught) and that giving the highest monthly biting rate (4.0 bites/man) was An. neivai. Most (90%) of the human sera tested possessed antibodies to blood-stage forms of Plasmodium falciparum, and 18% had antibodies to sporozoites. More than half (58%) of the adults had been in contact with hepatitis B virus, 7.2% carried hepatitis B surface antigen, and syphilis was common but no subject was found to be seropositive for HIV. A better understanding of the dynamics of the different elements influencing malaria in areas of low, unstable transmission, such as the one described here, is essential for the design of new malaria-control strategies.

  4. Protective immunity to liver-stage malaria

    PubMed Central

    Holz, Lauren E; Fernandez-Ruiz, Daniel; Heath, William R

    2016-01-01

    Despite decades of research and recent clinical trials, an efficacious long-lasting preventative vaccine for malaria remains elusive. This parasite infects mammals via mosquito bites, progressing through several stages including the relatively short asymptomatic liver stage followed by the more persistent cyclic blood stage, the latter of which is responsible for all disease symptoms. As the liver acts as a bottleneck to blood-stage infection, it represents a potential site for parasite and disease control. In this review, we discuss immunity to liver-stage malaria. It is hoped that the knowledge gained from animal models of malaria immunity will translate into a more powerful and effective vaccine to reduce this global health problem. PMID:27867517

  5. Protective immunity to liver-stage malaria.

    PubMed

    Holz, Lauren E; Fernandez-Ruiz, Daniel; Heath, William R

    2016-10-01

    Despite decades of research and recent clinical trials, an efficacious long-lasting preventative vaccine for malaria remains elusive. This parasite infects mammals via mosquito bites, progressing through several stages including the relatively short asymptomatic liver stage followed by the more persistent cyclic blood stage, the latter of which is responsible for all disease symptoms. As the liver acts as a bottleneck to blood-stage infection, it represents a potential site for parasite and disease control. In this review, we discuss immunity to liver-stage malaria. It is hoped that the knowledge gained from animal models of malaria immunity will translate into a more powerful and effective vaccine to reduce this global health problem.

  6. 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

  7. 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

  8. The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages.

    PubMed

    Sanz, Sílvia; López-Gutiérrez, Borja; Bandini, Giulia; Damerow, Sebastian; Absalon, Sabrina; Dinglasan, Rhoel R; Samuelson, John; Izquierdo, Luis

    2016-11-16

    Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito.

  9. The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages

    PubMed Central

    Sanz, Sílvia; López-Gutiérrez, Borja; Bandini, Giulia; Damerow, Sebastian; Absalon, Sabrina; Dinglasan, Rhoel R.; Samuelson, John; Izquierdo, Luis

    2016-01-01

    Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito. PMID:27849032

  10. Ecological transition from natural forest to tea plantations: effect on the dynamics of malaria vectors in the highlands of Cameroon.

    PubMed

    Tanga, M C; Ngundu, W I

    2010-10-01

    From October 2002 to September 2003, an entomological survey was carried out in a rural forested fringed village in the highlands of Mount Cameroon region to determine the temporal dynamics of the anopheline population and the intensity of malaria transmission. A total of 2387 Anopheles spp. were collected, with A. funestus predominating (59.9%), followed by A. hancocki (24.4%) and A. gambiae s.l. (15.7%). Considerable differences were observed in the nocturnal biting cycles of parous mosquitoes, with peak activity in the latter part of the night. PCR revealed that all specimens of the A. funestus group were A. funestus s.s. and all specimens from the A. gambiae complex were A. gambiae s.s. of the S molecular form. Plasmodium falciparum sporozoite rates of 17.3% and 8.5% were recorded for A. funestus and A. hancocki, respectively, with an anthropophilic rate of 96.3%. A strong positive correlation (r=0.996) was found between the human-biting rate and the entomological inoculation rate (EIR). Malaria transmission was very high and perennial, with an estimated annual EIR of 460.1 infective bites per person per year. These results confirm that in high agricultural activity areas, A. funestus can be by far the major malaria vector responsible for malaria transmission.

  11. Targeting a dynamic protein-protein interaction: fragment screening against the malaria myosin A motor complex.

    PubMed

    Douse, Christopher H; Vrielink, Nina; Wenlin, Zhang; Cota, Ernesto; Tate, Edward W

    2015-01-01

    Motility is a vital feature of the complex life cycle of Plasmodium falciparum, the apicomplexan parasite that causes human malaria. Processes such as host cell invasion are thought to be powered by a conserved actomyosin motor (containing myosin A or myoA), correct localization of which is dependent on a tight interaction with myosin A tail domain interacting protein (MTIP) at the inner membrane of the parasite. Although disruption of this protein-protein interaction represents an attractive means to investigate the putative roles of myoA-based motility and to inhibit the parasitic life cycle, no small molecules have been identified that bind to MTIP. Furthermore, it has not been possible to obtain a crystal structure of the free protein, which is highly dynamic and unstable in the absence of its natural myoA tail partner. Herein we report the de novo identification of the first molecules that bind to and stabilize MTIP via a fragment-based, integrated biophysical approach and structural investigations to examine the binding modes of hit compounds. The challenges of targeting such a dynamic system with traditional fragment screening workflows are addressed throughout.

  12. 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

  13. Space-time clustering of childhood malaria at the household level: a dynamic cohort in a Mali village

    PubMed Central

    Gaudart, Jean; Poudiougou, Belco; Dicko, Alassane; Ranque, Stéphane; Toure, Ousmane; Sagara, Issaka; Diallo, Mouctar; Diawara, Sory; Ouattara, Amed; Diakite, Mahamadou; Doumbo, Ogobara K

    2006-01-01

    Background Spatial and temporal heterogeneities in the risk of malaria have led the WHO to recommend fine-scale stratification of the epidemiological situation, making it possible to set up actions and clinical or basic researches targeting high-risk zones. Before initiating such studies it is necessary to define local patterns of malaria transmission and infection (in time and in space) in order to facilitate selection of the appropriate study population and the intervention allocation. The aim of this study was to identify, spatially and temporally, high-risk zones of malaria, at the household level (resolution of 1 to 3 m). Methods This study took place in a Malian village with hyperendemic seasonal transmission as part of Mali-Tulane Tropical Medicine Research Center (NIAID/NIH). The study design was a dynamic cohort (22 surveys, from June 1996 to June 2001) on about 1300 children (<12 years) distributed between 173 households localized by GPS. We used the computed parasitological data to analyzed levels of Plasmodium falciparum, P. malariae and P. ovale infection and P. falciparum gametocyte carriage by means of time series and Kulldorff's scan statistic for space-time cluster detection. Results The time series analysis determined that malaria parasitemia (primarily P. falciparum) was persistently present throughout the population with the expected seasonal variability pattern and a downward temporal trend. We identified six high-risk clusters of P. falciparum infection, some of which persisted despite an overall tendency towards a decrease in risk. The first high-risk cluster of P. falciparum infection (rate ratio = 14.161) was detected from September 1996 to October 1996, in the north of the village. Conclusion This study showed that, although infection proportions tended to decrease, high-risk zones persisted in the village particularly near temporal backwaters. Analysis of this heterogeneity at the household scale by GIS methods lead to target preventive

  14. 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

  15. 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

  16. Modeling the effects of relapse in the transmission dynamics of malaria parasites.

    PubMed

    Aguas, Ricardo; Ferreira, Marcelo U; Gomes, M Gabriela M

    2012-01-01

    Often regarded as "benign," Plasmodium vivax infections lay in the shadows of the much more virulent P. falciparum infections. However, about 1.98 billion people are at risk of both parasites worldwide, stressing the need to understand the epidemiology of Plasmodium vivax, particularly under the scope of decreasing P. falciparum prevalence and ecological interactions between both species. Two epidemiological observations put the dynamics of both species into perspective: (1) ACT campaigns have had a greater impact on P. falciparum prevalence. (2) Complete clinical immunity is attained at younger ages for P. vivax, under similar infection rates. We systematically compared two mathematical models of transmission for both Plasmodium species. Simulations suggest that an ACT therapy combined with a hypnozoite killing drug would eliminate both species. However, P. vivax elimination is predicted to be unstable. Differences in age profiles of clinical malaria can be explained solely by P. vivax's ability to relapse, which accelerates the acquisition of clinical immunity and serves as an immunity boosting mechanism. P. vivax transmission can subsist in areas of low mosquito abundance and is robust to drug administration initiatives due to relapse, making it an inconvenient and cumbersome, yet less lethal alternative to P. falciparum.

  17. Pilot survey of expressed sequence tags (ESTs) from the asexual blood stages of Plasmodium vivax in human patients

    PubMed Central

    Merino, Emilio F; Fernandez-Becerra, Carmen; Madeira, Alda MBN; Machado, Ariane L; Durham, Alan; Gruber, Arthur; Hall, Neil; del Portillo, Hernando A

    2003-01-01

    Background Plasmodium vivax is the most widely distributed human malaria, responsible for 70–80 million clinical cases each year and large socio-economical burdens for countries such as Brazil where it is the most prevalent species. Unfortunately, due to the impossibility of growing this parasite in continuous in vitro culture, research on P. vivax remains largely neglected. Methods A pilot survey of expressed sequence tags (ESTs) from the asexual blood stages of P. vivax was performed. To do so, 1,184 clones from a cDNA library constructed with parasites obtained from 10 different human patients in the Brazilian Amazon were sequenced. Sequences were automatedly processed to remove contaminants and low quality reads. A total of 806 sequences with an average length of 586 bp met such criteria and their clustering revealed 666 distinct events. The consensus sequence of each cluster and the unique sequences of the singlets were used in similarity searches against different databases that included P. vivax, Plasmodium falciparum, Plasmodium yoelii, Plasmodium knowlesi, Apicomplexa and the GenBank non-redundant database. An E-value of <10-30 was used to define a significant database match. ESTs were manually assigned a gene ontology (GO) terminology Results A total of 769 ESTs could be assigned a putative identity based upon sequence similarity to known proteins in GenBank. Moreover, 292 ESTs were annotated and a GO terminology was assigned to 164 of them. Conclusion These are the first ESTs reported for P. vivax and, as such, they represent a valuable resource to assist in the annotation of the P. vivax genome currently being sequenced. Moreover, since the GC-content of the P. vivax genome is strikingly different from that of P. falciparum, these ESTs will help in the validation of gene predictions for P. vivax and to create a gene index of this malaria parasite. PMID:12914668

  18. Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics.

    PubMed

    Eckhoff, Philip A; Wenger, Edward A; Godfray, H Charles J; Burt, Austin

    2017-01-10

    The renewed effort to eliminate malaria and permanently remove its tremendous burden highlights questions of what combination of tools would be sufficient in various settings and what new tools need to be developed. Gene drive mosquitoes constitute a promising set of tools, with multiple different possible approaches including population replacement with introduced genes limiting malaria transmission, driving-Y chromosomes to collapse a mosquito population, and gene drive disrupting a fertility gene and thereby achieving population suppression or collapse. Each of these approaches has had recent success and advances under laboratory conditions, raising the urgency for understanding how each could be deployed in the real world and the potential impacts of each. New analyses are needed as existing models of gene drive primarily focus on nonseasonal or nonspatial dynamics. We use a mechanistic, spatially explicit, stochastic, individual-based mathematical model to simulate each gene drive approach in a variety of sub-Saharan African settings. Each approach exhibits a broad region of gene construct parameter space with successful elimination of malaria transmission due to the targeted vector species. The introduction of realistic seasonality in vector population dynamics facilitates gene drive success compared with nonseasonal analyses. Spatial simulations illustrate constraints on release timing, frequency, and spatial density in the most challenging settings for construct success. Within its parameter space for success, each gene drive approach provides a tool for malaria elimination unlike anything presently available. Provided potential barriers to success are surmounted, each achieves high efficacy at reducing transmission potential and lower delivery requirements in logistically challenged settings.

  19. Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics

    PubMed Central

    Eckhoff, Philip A.; Wenger, Edward A.; Godfray, H. Charles J.; Burt, Austin

    2017-01-01

    The renewed effort to eliminate malaria and permanently remove its tremendous burden highlights questions of what combination of tools would be sufficient in various settings and what new tools need to be developed. Gene drive mosquitoes constitute a promising set of tools, with multiple different possible approaches including population replacement with introduced genes limiting malaria transmission, driving-Y chromosomes to collapse a mosquito population, and gene drive disrupting a fertility gene and thereby achieving population suppression or collapse. Each of these approaches has had recent success and advances under laboratory conditions, raising the urgency for understanding how each could be deployed in the real world and the potential impacts of each. New analyses are needed as existing models of gene drive primarily focus on nonseasonal or nonspatial dynamics. We use a mechanistic, spatially explicit, stochastic, individual-based mathematical model to simulate each gene drive approach in a variety of sub-Saharan African settings. Each approach exhibits a broad region of gene construct parameter space with successful elimination of malaria transmission due to the targeted vector species. The introduction of realistic seasonality in vector population dynamics facilitates gene drive success compared with nonseasonal analyses. Spatial simulations illustrate constraints on release timing, frequency, and spatial density in the most challenging settings for construct success. Within its parameter space for success, each gene drive approach provides a tool for malaria elimination unlike anything presently available. Provided potential barriers to success are surmounted, each achieves high efficacy at reducing transmission potential and lower delivery requirements in logistically challenged settings. PMID:28028208

  20. Optimal control analysis of malaria-schistosomiasis co-infection dynamics.

    PubMed

    Okosun, Kazeem Oare; Smith, Robert

    2017-04-01

    This paper presents a mathematical model for malaria--schistosomiasis co-infection in order to investigate their synergistic relationship in the presence of treatment. We first analyse the single infection steady states, then investigate the existence and stability of equilibria and then calculate the basic reproduction numbers. Both the single-infection models and the co-infection model exhibit backward bifurcations. We carrying out a sensitivity analysis of the co-infection model and show that schistosomiasis infection may not be associated with an increased risk of malaria. Conversely, malaria infection may be associated with an increased risk of schistosomiasis. Furthermore, we found that effective treatment and prevention of schistosomiasis infection would also assist in the effective control and eradication of malaria. Finally, we apply Pontryagin's Maximum Principle to the model in order to determine optimal strategies for control of both diseases.

  1. Malaria Facts

    MedlinePlus

    ... Laveran and the Discovery of the Malaria Parasite Ross and the Discovery that Mosquitoes Transmit Malaria Parasites ... for work associated with malaria: to Sir Ronald Ross (1902), Charles Louis Alphonse Laveran (1907), Julius Wagner- ...

  2. 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.

  3. 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.

  4. Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality.

    PubMed

    Wu, Jian; Tian, Linjie; Yu, Xiao; Pattaradilokrat, Sittiporn; Li, Jian; Wang, Mingjun; Yu, Weishi; Qi, Yanwei; Zeituni, Amir E; Nair, Sethu C; Crampton, Steve P; Orandle, Marlene S; Bolland, Silvia M; Qi, Chen-Feng; Long, Carole A; Myers, Timothy G; Coligan, John E; Wang, Rongfu; Su, Xin-zhuan

    2014-01-28

    Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.

  5. Decreased growth rate of P. falciparum blood stage parasitemia with age in a holoendemic population.

    PubMed

    Pinkevych, Mykola; Petravic, Janka; Chelimo, Kiprotich; Vulule, John; Kazura, James W; Moormann, Ann M; Davenport, Miles P

    2014-04-01

    In malaria holoendemic settings, decreased parasitemia and clinical disease is associated with age and cumulative exposure. The relative contribution of acquired immunity against various stages of the parasite life cycle is not well understood. In particular, it is not known whether changes in infection dynamics can be best explained by decreasing rates of infection, or by decreased growth rates of parasites in blood. Here, we analyze the dynamics of Plasmodium falciparum infection after treatment in a cohort of 197 healthy study participants of different ages. We use both polymerase chain reaction (PCR) and microscopy detection of parasitemia in order to understand parasite growth rates and infection rates over time. The more sensitive PCR assay detects parasites earlier than microscopy, and demonstrates a higher overall prevalence of infection than microscopy alone. The delay between PCR and microscopy detection is significantly longer in adults compared with children, consistent with slower parasite growth with age. We estimated the parasite multiplication rate from delay to PCR and microscopy detections of parasitemia. We find that both the delay between PCR and microscopy infection as well as the differing reinfection dynamics in different age groups are best explained by a slowing of parasite growth with age.

  6. Epitope mapping of PfCP-2.9, an asexual blood-stage vaccine candidate of Plasmodium falciparum

    PubMed Central

    2010-01-01

    Background Apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP1) of Plasmodium falciparum are two leading blood-stage malaria vaccine candidates. A P. falciparum chimeric protein 2.9 (PfCP-2.9) has been constructed as a vaccine candidate, by fusing AMA-1 domain III (AMA-1 (III)) with a C-terminal 19 kDa fragment of MSP1 (MSP1-19) via a 28-mer peptide hinge. PfCP-2.9 was highly immunogenic in animal studies, and antibodies elicited by the PfCP-2.9 highly inhibited parasite growth in vitro. This study focused on locating the distribution of epitopes on PfCP-2.9. Methods A panel of anti-PfCP-2.9 monoclonal antibodies (mAbs) were produced and their properties were examined by Western blot as well as in vitro growth inhibition assay (GIA). In addition, a series of PfCP-2.9 mutants containing single amino acid substitution were produced in Pichia pastoris. Interaction of the mAbs with the PfCP-2.9 mutants was measured by both Western blot and enzyme-linked immunosorbent assay (ELISA). Results Twelve mAbs recognizing PfCP-2.9 chimeric protein were produced. Of them, eight mAbs recognized conformational epitopes and six mAbs showed various levels of inhibitory activities on parasite growth in vitro. In addition, seventeen PfCP-2.9 mutants with single amino acid substitution were produced in Pichia pastoris for interaction with mAbs. Reduced binding of an inhibitory mAb (mAb7G), was observed in three mutants including M62 (Phe491→Ala), M82 (Glu511→Gln) and M84 (Arg513→Lys), suggesting that these amino acid substitutions are critical to the epitope corresponding to mAb7G. The binding of two non-inhibitory mAbs (mAbG11.12 and mAbW9.10) was also reduced in the mutants of either M62 or M82. The substitution of Leu31 to Arg resulted in completely abolishing the binding of mAb1E1 (a blocking antibody) to M176 mutant, suggesting that the Leu residue at this position plays a crucial role in the formation of the epitope. In addition, the Asn15 residue may

  7. 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

  8. 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...

  9. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

    PubMed

    Fryauff, D J; Leksana, B; Masbar, S; Wiady, I; Sismadi, P; Susanti, A I; Nagesha, H S; Syafruddin; Atmosoedjono, S; Bangs, M J; Baird, J K

    2002-07-01

    Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene

  10. Widespread occurrence of lysine methylation in Plasmodium falciparum proteins at asexual blood stages

    PubMed Central

    Kaur, Inderjeet; Zeeshan, Mohammad; Saini, Ekta; Kaushik, Abhinav; Mohmmed, Asif; Gupta, Dinesh; Malhotra, Pawan

    2016-01-01

    Post-transcriptional and post-translational modifications play a major role in Plasmodium life cycle regulation. Lysine methylation of histone proteins is well documented in several organisms, however in recent years lysine methylation of proteins outside histone code is emerging out as an important post-translational modification (PTM). In the present study we have performed global analysis of lysine methylation of proteins in asexual blood stages of Plasmodium falciparum development. We immunoprecipitated stage specific Plasmodium lysates using anti-methyl lysine specific antibodies that immunostained the asexual blood stage parasites. Using liquid chromatography and tandem mass spectrometry analysis, 570 lysine methylated proteins at three different blood stages were identified. Analysis of the peptide sequences identified 605 methylated sites within 422 proteins. Functional classification of the methylated proteins revealed that the proteins are mainly involved in nucleotide metabolic processes, chromatin organization, transport, homeostatic processes and protein folding. The motif analysis of the methylated lysine peptides reveals novel motifs. Many of the identified lysine methylated proteins are also interacting partners/substrates of PfSET domain proteins as revealed by STRING database analysis. Our findings suggest that the protein methylation at lysine residues is widespread in Plasmodium and plays an important regulatory role in diverse set of the parasite pathways. PMID:27762281

  11. 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.

  12. 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

  13. Changes in Serological Immunology Measures in UK and Kenyan Adults Post-controlled Human Malaria Infection

    PubMed Central

    Hodgson, Susanne H.; Llewellyn, David; Silk, Sarah E.; Milne, Kathryn H.; Elias, Sean C.; Miura, Kazutoyo; Kamuyu, Gathoni; Juma, Elizabeth A.; Magiri, Charles; Muia, Alfred; Jin, Jing; Spencer, Alexandra J.; Longley, Rhea J.; Mercier, Thomas; Decosterd, Laurent; Long, Carole A.; Osier, Faith H.; Hoffman, Stephen L.; Ogutu, Bernhards; Hill, Adrian V. S.; Marsh, Kevin; Draper, Simon J.

    2016-01-01

    Background: The timing of infection is closely determined in controlled human malaria infection (CHMI) studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS) (Pan African Clinical Trial Registry: PACTR20121100033272) was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe (PfSPZ Challenge) and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria. Methods: We describe detailed serological and functional immunological responses pre- and post-CHMI for participants in the KCS and compare these with those from malaria-naïve UK volunteers who also underwent CHMI (VAC049) (ClinicalTrials.gov NCT01465048) using PfSPZ Challenge. We assessed antibody responses to three key blood-stage merozoite antigens [merozoite surface protein 1 (MSP1), apical membrane protein 1 (AMA1), and reticulocyte-binding protein homolog 5 (RH5)] and functional activity using two candidate measures of anti-merozoite immunity; the growth inhibition activity (GIA) assay and the antibody-dependent respiratory burst activity (ADRB) assay. Results:Clear serological differences were observed pre- and post-CHMI by ELISA between malaria-naïve UK volunteers in VAC049, and Kenyan volunteers who had prior malaria exposure. Antibodies to AMA1 and schizont extract correlated with parasite multiplication rate (PMR) post-CHMI in KCS. Serum from volunteer 110 in KCS, who demonstrated a dramatically reduced PMR in vivo, had no in vitro GIA prior to CHMI but the highest level of ADRB activity. A significant difference in ADRB activity was seen between KCS volunteers with minimal and definite prior exposure to malaria and significant increases were seen in ADRB activity post-CHMI in Kenyan

  14. Changes in Serological Immunology Measures in UK and Kenyan Adults Post-controlled Human Malaria Infection.

    PubMed

    Hodgson, Susanne H; Llewellyn, David; Silk, Sarah E; Milne, Kathryn H; Elias, Sean C; Miura, Kazutoyo; Kamuyu, Gathoni; Juma, Elizabeth A; Magiri, Charles; Muia, Alfred; Jin, Jing; Spencer, Alexandra J; Longley, Rhea J; Mercier, Thomas; Decosterd, Laurent; Long, Carole A; Osier, Faith H; Hoffman, Stephen L; Ogutu, Bernhards; Hill, Adrian V S; Marsh, Kevin; Draper, Simon J

    2016-01-01

    Background: The timing of infection is closely determined in controlled human malaria infection (CHMI) studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS) (Pan African Clinical Trial Registry: PACTR20121100033272) was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe (PfSPZ Challenge) and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria. Methods: We describe detailed serological and functional immunological responses pre- and post-CHMI for participants in the KCS and compare these with those from malaria-naïve UK volunteers who also underwent CHMI (VAC049) (ClinicalTrials.gov NCT01465048) using PfSPZ Challenge. We assessed antibody responses to three key blood-stage merozoite antigens [merozoite surface protein 1 (MSP1), apical membrane protein 1 (AMA1), and reticulocyte-binding protein homolog 5 (RH5)] and functional activity using two candidate measures of anti-merozoite immunity; the growth inhibition activity (GIA) assay and the antibody-dependent respiratory burst activity (ADRB) assay. Results:Clear serological differences were observed pre- and post-CHMI by ELISA between malaria-naïve UK volunteers in VAC049, and Kenyan volunteers who had prior malaria exposure. Antibodies to AMA1 and schizont extract correlated with parasite multiplication rate (PMR) post-CHMI in KCS. Serum from volunteer 110 in KCS, who demonstrated a dramatically reduced PMR in vivo, had no in vitro GIA prior to CHMI but the highest level of ADRB activity. A significant difference in ADRB activity was seen between KCS volunteers with minimal and definite prior exposure to malaria and significant increases were seen in ADRB activity post-CHMI in Kenyan

  15. High frequency of malaria-specific T cells in non-exposed humans.

    PubMed

    Zevering, Y; Amante, F; Smillie, A; Currier, J; Smith, G; Houghten, R A; Good, M F

    1992-03-01

    A major goal of current candidate malaria vaccines is to stimulate the expansion of clones of malaria-specific lymphocytes. We have examined the in vitro T cell responses of a group of malaria exposed and non-exposed adult Caucasian donors to recombinant circumsporozoite (CS) proteins, one of which is undergoing clinical trials, to blood-stage parasites, and to synthetic peptides copying the CS protein and defined blood-stage proteins. In nearly all individuals tested, CD4 T cell proliferation or lymphokine production occurred in response to whole parasite or CS protein stimulation, and T cells from many individuals responded to synthetic peptides. T cell responses were major histocompatibility complex-restricted, and stimulation of T cells with malaria parasites or CS protein did not appear to expand a population of T cell receptor gamma/delta cells. Malaria-specific responses were independent of prior malaria exposure, and in some cases exceeded the magnitude of response to tetanus toxoid. Specific T cells are present in high frequency in the peripheral blood of many donors who have never been exposed to malaria. Although malaria-specific CD4 T cells play an important role in immunity, these data question whether vaccines need to stimulate such cells, and focus attention on other aspects of malaria immunity which may be more critical to a successful vaccine.

  16. Landscape and Dynamics of Transcription Initiation in the Malaria Parasite Plasmodium falciparum.

    PubMed

    Adjalley, Sophie H; Chabbert, Christophe D; Klaus, Bernd; Pelechano, Vicent; Steinmetz, Lars M

    2016-03-15

    A comprehensive map of transcription start sites (TSSs) across the highly AT-rich genome of P. falciparum would aid progress toward deciphering the molecular mechanisms that underlie the timely regulation of gene expression in this malaria parasite. Using high-throughput sequencing technologies, we generated a comprehensive atlas of transcription initiation events at single-nucleotide resolution during the parasite intra-erythrocytic developmental cycle. This detailed analysis of TSS usage enabled us to define architectural features of plasmodial promoters. We demonstrate that TSS selection and strength are constrained by local nucleotide composition. Furthermore, we provide evidence for coordinate and stage-specific TSS usage from distinct sites within the same transcription unit, thereby producing transcript isoforms, a subset of which are developmentally regulated. This work offers a framework for further investigations into the interactions between genomic sequences and regulatory factors governing the complex transcriptional program of this major human pathogen.

  17. Imported malaria.

    PubMed

    Schultz, M G

    1974-01-01

    There have been 4 waves of imported malaria in the USA. They occurred during the colonization of the country and during the Second World War, the UN Police Action in Korea, and the Viet-Nam conflict. The first 3 episodes are briefly described and the data on imported malaria from Viet-Nam are discussed in detail.Endemic malaria is resurgent in many tropical countries and international travel is also on the rise. This increases the likelihood of malaria being imported from an endemic area and introduced into a receptive area. The best defence for countries threatened by imported malaria is a vigorous surveillance programme. The principles of surveillance are discussed and an example of their application is provided by a description of the methods used to conduct surveillance of malaria in the USA.

  18. Malaria Research

    MedlinePlus

    ... critical role in development of those next-generation strategies. Read more about malaria prevention, treatment and control Global Cooperation Collaboration involving scientists from diverse disciplines is ...

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

    PubMed

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

    2011-10-22

    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% wAIC(c) 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.

  20. 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

  1. Dynamical Behavior of a Malaria Model with Discrete Delay and Optimal Insecticide Control

    NASA Astrophysics Data System (ADS)

    Kar, Tuhin Kumar; Jana, Soovoojeet

    In this paper we have proposed and analyzed a simple three-dimensional mathematical model related to malaria disease. We consider three state variables associated with susceptible human population, infected human population and infected mosquitoes, respectively. A discrete delay parameter has been incorporated to take account of the time of incubation period with infected mosquitoes. We consider the effect of insecticide control, which is applied to the mosquitoes. Basic reproduction number is figured out for the proposed model and it is shown that when this threshold is less than unity then the system moves to the disease-free state whereas for higher values other than unity, the system would tend to an endemic state. On the other hand if we consider the system with delay, then there may exist some cases where the endemic equilibrium would be unstable although the numerical value of basic reproduction number may be greater than one. We formulate and solve the optimal control problem by considering insecticide as the control variable. Optimal control problem assures to obtain better result than the noncontrol situation. Numerical illustrations are provided in support of the theoretical results.

  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.

  3. Impact of host nutritional status on infection dynamics and parasite virulence in a bird-malaria system.

    PubMed

    Cornet, Stéphane; Bichet, Coraline; Larcombe, Stephen; Faivre, Bruno; Sorci, Gabriele

    2014-01-01

    Host resources can drive the optimal parasite exploitation strategy by offering a good or a poor environment to pathogens. Hosts living in resource-rich habitats might offer a favourable environment to developing parasites because they provide a wealth of resources. However, hosts living in resource-rich habitats might afford a higher investment into costly immune defences providing an effective barrier against infection. Understanding how parasites can adapt to hosts living in habitats of different quality is a major challenge in the light of the current human-driven environmental changes. We studied the role of nutritional resources as a source of phenotypic variation in host exploitation by the avian malaria parasite Plasmodium relictum. We investigated how the nutritional status of birds altered parasite within-host dynamics and virulence, and how the interaction between past and current environments experienced by the parasite accounts for the variation in the infection dynamics. Experimentally infected canaries were allocated to control or supplemented diets. Plasmodium parasites experiencing the two different environments were subsequently transmitted in a full-factorial design to new hosts reared under similar control or supplemented diets. Food supplementation was effective since supplemented hosts gained body mass during a 15-day period that preceded the infection. Host nutrition had strong effects on infection dynamics and parasite virulence. Overall, parasites were more successful in control nonsupplemented birds, reaching larger population sizes and producing more sexual (transmissible) stages. However, supplemented hosts paid a higher cost of infection, and when keeping parasitaemia constant, they had lower haematocrit than control hosts. Parasites grown on control hosts were better able to exploit the subsequent hosts since they reached higher parasitaemia than parasites originating from supplemented hosts. They were also more virulent since they

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

    PubMed Central

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

    2016-01-01

    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

  5. Characterization of a glycerophosphodiesterase with an unusual tripartite distribution and an important role in the asexual blood stages of Plasmodium falciparum.

    PubMed

    Denloye, Titilola; Dalal, Seema; Klemba, Michael

    2012-11-01

    Catabolism of glycerophospholipids during the rapid growth of the asexual intraerythrocytic malaria parasite may contribute to membrane recycling and the acquisition of lipid biosynthetic precursors from the host. To better understand the scope of lipid catabolism in Plasmodium falciparum, we have characterized a malarial homolog of bacterial glycerophosphodiesterases. These enzymes catalyze the hydrolysis of glycerophosphodiesterases that are generated by phospholipase-catalyzed removal of the two acyl groups from glycerophospholipids. The P. falciparum glycerophosphodiesterase (PfGDPD) exhibits an unusual tripartite distribution during the asexual blood stage with pools of enzyme in the parasitophorous vacuole, food vacuole and cytosol. Efforts to disrupt the chromosomal PfGDPD coding sequence were unsuccessful, which implies that the enzyme is important for efficient parasite growth. Tagging of the endogenous pool of PfGDPD with a conditional aggregation domain partially perturbed the distribution of the enzyme in the parasitophorous vacuole but had no discernable effect on growth in culture. Kinetic characterization of the hydrolysis of glycerophosphocholine by recombinant PfGDPD, an Mg(2+)-dependent enzyme, yielded steady-state parameters that were comparable to those of a homologous bacterial glycerophosphodiesterase. Together, these results suggest a physiological role for PfGDPD in glycerophospholipid catabolism in multiple subcellular compartments. Possibilities for what this role might be are discussed.

  6. Tissue-specific features of the X chromosome and nucleolus spatial dynamics in a malaria mosquito, Anopheles atroparvus

    PubMed Central

    Bondarenko, Semen M.; Artemov, Gleb N.; Stegniy, Vladimir N.

    2017-01-01

    Spatial organization of chromosome territories is important for maintenance of genomic stability and regulation of gene expression. Recent studies have shown tissue-specific features of chromosome attachments to the nuclear envelope in various organisms including malaria mosquitoes. However, other spatial characteristics of nucleus organization, like volume and shape of chromosome territories, have not been studied in Anopheles. We conducted a thorough analysis of tissue-specific features of the X chromosome and nucleolus volume and shape in follicular epithelium and nurse cells of the Anopheles atroparvus ovaries using a modern open-source software. DNA of the polytene X chromosome from ovarian nurse cells was obtained by microdissection and was used as a template for amplification with degenerate oligo primers. A fluorescently labeled X chromosome painting probe was hybridized with formaldehyde-fixed ovaries of mosquitoes using a 3D-FISH method. The nucleolus was stained by immunostaining with an anti-fibrillarin antibody. The analysis was conducted with TANGO—a software for a chromosome spatial organization analysis. We show that the volume and position of the X chromosome have tissue-specific characteristics. Unlike nurse cell nuclei, the growth of follicular epithelium nuclei is not accompanied with the proportional growth of the X chromosome. However, the shape of the X chromosome does not differ between the tissues. The dynamics of the X chromosome attachment regions location is tissue-specific and it is correlated with the process of nucleus growth in follicular epithelium and nurse cells. PMID:28158219

  7. Malaria Treatment (United States)

    MedlinePlus

    ... Malaria Branch clinician. malaria@cdc.gov Malaria Treatment (United States) Recommend on Facebook Tweet Share Compartir Treatment of Malaria: Guidelines For Clinicians (United States) Download PDF version of Parts 1-3 formatted ...

  8. Malaria Pathogenesis

    NASA Astrophysics Data System (ADS)

    Miller, Louis H.; Good, Michael F.; Milon, Genevieve

    1994-06-01

    Malaria is a disease caused by repeated cycles of growth of the parasite Plasmodium in the erythrocyte. Various cellular and molecular strategies allow the parasite to evade the human immune response for many cycles of parasite multiplication. Under certain circumstances Plasmodium infection causes severe anemia or cerebral malaria; the expression of disease is influenced by both parasite and host factors, as exemplified by the exacerbation of disease during pregnancy. This article provides an overview of malaria pathogenesis, synthesizing the recent field, laboratory, and epidemiological data that will lead to the development of strategies to reduce mortality and morbidity.

  9. Behavioral heterogeneity of Anopheles darlingi (Diptera: Culicidae) and malaria transmission dynamics along the Maroni River, Suriname, French Guiana.

    PubMed

    Hiwat, H; Issaly, J; Gaborit, P; Somai, A; Samjhawan, A; Sardjoe, P; Soekhoe, T; Girod, R

    2010-03-01

    The border area between Suriname and French Guiana is considered the most affected malaria area in South America. A one-year cooperative malaria vector study was performed by the two countries, between March 2004 and February 2005, in four villages. Anopheles darlingi proved to be the most abundant anopheline species. Human biting rates differed between villages. The differential effect of high rainfall on mosquito densities in the villages suggests variation in breeding sites. Overall parity rates were low, with means varying from 0.31 to 0.56 per study site. Of the 2045 A. darlingi mosquitoes collected, 13 were found to be infected with Plasmodium: ten P. falciparum, two P. malariae and one mixed P. malariae/P. vivax. The overall annual entomological inoculation rates in the villages ranged from 8.7 to 66.4. There was an apparent lack of relationship between number of malaria cases and periods of high mosquito density. The tendency of Anopheles darlingi to bite during sleeping hours provides opportunity for malaria control using impregnated bed nets, a strategy just introduced in Suriname that may also find its way into French Guiana.

  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.

  11. Immunoscreening of Plasmodium falciparum proteins expressed in a wheat germ cell-free system reveals a novel malaria vaccine candidate

    PubMed Central

    Morita, Masayuki; Takashima, Eizo; Ito, Daisuke; Miura, Kazutoyo; Thongkukiatkul, Amporn; Diouf, Ababacar; Fairhurst, Rick M.; Diakite, Mahamadou; Long, Carole A.; Torii, Motomi; Tsuboi, Takafumi

    2017-01-01

    The number of malaria vaccine candidates in preclinical and clinical development is limited. To identify novel blood-stage malaria vaccine candidates, we constructed a library of 1,827P. falciparum proteins prepared using the wheat germ cell-free system (WGCFS). Also, a high-throughput AlphaScreen procedure was developed to measure antibody reactivity to the recombinant products. Purified IgGs from residents in malaria endemic areas have shown functional activity against blood-stage parasites as judged by an in vitro parasite Growth Inhibition Assay (GIA). Therefore, we evaluated the GIA activity of 51 plasma samples prepared from Malian adults living in a malaria endemic area against the WGCFS library. Using the AlphaScreen-based immunoreactivity measurements, antibody reactivity against 3 proteins was positively associated with GIA activity. Since anti-LSA3-C responses showed the strongest correlation with GIA activity, this protein was investigated further. Anti-LSA3-C-specific antibody purified from Malian adult plasmas showed GIA activity, and expression of LSA3 in blood-stage parasites was confirmed by western blotting. Taken together, we identified LSA3 as a novel blood-stage vaccine candidate, and we propose that this system will be useful for future vaccine candidate discovery. PMID:28378857

  12. Shifts in malaria vector species composition and transmission dynamics along the Kenyan coast over the past 20 years

    PubMed Central

    2013-01-01

    Background Over the past 20 years, numerous studies have investigated the ecology and behaviour of malaria vectors and Plasmodium falciparum malaria transmission on the coast of Kenya. Substantial progress has been made to control vector populations and reduce high malaria prevalence and severe disease. The goal of this paper was to examine trends over the past 20 years in Anopheles species composition, density, blood-feeding behaviour, and P. falciparum sporozoite transmission along the coast of Kenya. Methods Using data collected from 1990 to 2010, vector density, species composition, blood-feeding patterns, and malaria transmission intensity was examined along the Kenyan coast. Mosquitoes were identified to species, based on morphological characteristics and DNA extracted from Anopheles gambiae for amplification. Using negative binomial generalized estimating equations, mosquito abundance over the period were modelled while adjusting for season. A multiple logistic regression model was used to analyse the sporozoite rates. Results Results show that in some areas along the Kenyan coast, Anopheles arabiensis and Anopheles merus have replaced An. gambiae sensu stricto (s.s.) and Anopheles funestus as the major mosquito species. Further, there has been a shift from human to animal feeding for both An. gambiae sensu lato (s.l.) (99% to 16%) and An. funestus (100% to 3%), and P. falciparum sporozoite rates have significantly declined over the last 20 years, with the lowest sporozoite rates being observed in 2007 (0.19%) and 2008 (0.34%). There has been, on average, a significant reduction in the abundance of An. gambiae s.l. over the years (IRR = 0.94, 95% CI 0.90–0.98), with the density standing at low levels of an average 0.006 mosquitoes/house in the year 2010. Conclusion Reductions in the densities of the major malaria vectors and a shift from human to animal feeding have contributed to the decreased burden of malaria along the Kenyan coast. Vector species

  13. 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

  14. 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.

  15. 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

  16. 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

  17. Artesunate-tafenoquine combination therapy promotes clearance and abrogates transmission of the avian malaria parasite Plasmodium gallinaceum.

    PubMed

    Tasai, Suchada; Saiwichai, Tawee; Kaewthamasorn, Morakot; Tiawsirisup, Sonthaya; Buddhirakkul, Prayute; Chaichalotornkul, Sirintip; Pattaradilokrat, Sittiporn

    2017-01-15

    Clinical manifestations of malaria infection in vertebrate hosts arise from the multiplication of the asexual stage parasites in the blood, while the gametocytes are responsible for the transmission of the disease. Antimalarial drugs that target the blood stage parasites and transmissible gametocytes are rare, but are essentially needed for the effective control of malaria and for limiting the spread of resistance. Artemisinin and its derivatives are the current first-line antimalarials that are effective against the blood stage parasites and gametocytes, but resistance to artemisinin has now emerged and spread in various malaria endemic areas. Therefore, a novel antimalarial drug, or a new drug combination, is critically needed to overcome this problem. The objectives of this study were to evaluate the efficacy of a relatively new antimalarial compound, tafenoquine (TQ), and a combination of TQ and a low dose of artesunate (ATN) on the in vivo blood stage multiplication, gametocyte development and transmission of the avian malaria parasite Plasmodium gallinaceum to the vector Aedes aegypti. The results showed that a 5-d treatment with TQ alone was unable to clear the blood stage parasites, but was capable of reducing the mortality rate, while TQ monotherapy at a high dose of 30mg/kg was highly effective against the gametocytes and completely blocked the transmission of P. gallinaceum. In addition, the combination therapy of TQ+ATN completely cleared P. gallinaceum blood stages and sped up the gametocyte clearance from chickens, suggesting the synergistic effect of the two drugs. In conclusion, TQ is demonstrated to be effective for limiting avian malaria transmission and may be used in combination with a low dose of ATN for safe and effective treatment.

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

    PubMed

    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

    2015-09-16

    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.

  19. Dynamic Gut Microbiome across Life History of the Malaria Mosquito Anopheles gambiae in Kenya

    PubMed Central

    Kukutla, Phanidhar; Yan, Guiyun; Xu, Jiannong

    2011-01-01

    The mosquito gut represents an ecosystem that accommodates a complex, intimately associated microbiome. It is increasingly clear that the gut microbiome influences a wide variety of host traits, such as fitness and immunity. Understanding the microbial community structure and its dynamics across mosquito life is a prerequisite for comprehending the symbiotic relationship between the mosquito and its gut microbial residents. Here we characterized gut bacterial communities across larvae, pupae and adults of Anopheles gambiae reared in semi-natural habitats in Kenya by pyrosequencing bacterial 16S rRNA fragments. Immatures and adults showed distinctive gut community structures. Photosynthetic Cyanobacteria were predominant in the larval and pupal guts while Proteobacteria and Bacteroidetes dominated the adult guts, with core taxa of Enterobacteriaceae and Flavobacteriaceae. At the adult stage, diet regime (sugar meal and blood meal) significantly affects the microbial structure. Intriguingly, blood meals drastically reduced the community diversity and favored enteric bacteria. Comparative genomic analysis revealed that the enriched enteric bacteria possess large genetic redox capacity of coping with oxidative and nitrosative stresses that are associated with the catabolism of blood meal, suggesting a beneficial role in maintaining gut redox homeostasis. Interestingly, gut community structure was similar in the adult stage between the field and laboratory mosquitoes, indicating that mosquito gut is a selective eco-environment for its microbiome. This comprehensive gut metatgenomic profile suggests a concerted symbiotic genetic association between gut inhabitants and host. PMID:21957459

  20. Genome-wide regulatory dynamics of G-quadruplexes in human malaria parasite Plasmodium falciparum.

    PubMed

    Bhartiya, Deeksha; Chawla, Vandna; Ghosh, Sourav; Shankar, Ravi; Kumar, Niti

    2016-12-01

    The AT-rich genome of P. falciparum has uniquely localized G-rich stretches that have propensity to form G-quadruplexes. However, their global occurrence and potential biological roles in the parasite are poorly explored. Our genome-wide analysis revealed unique enrichment of quadruplexes in P. falciparum genome which was remarkably different from other Plasmodium species. A distinct predominance of quadruplexes was observed in nuclear and organellar genes that participate in antigenic variation, pathogenesis, DNA/RNA regulation, metabolic and protein quality control processes. Data also suggested association of quadruplexes with SNPs and DNA methylation. Furthermore, analysis of steady state mRNA (RNA-seq) and polysome-associated mRNA (Ribosome profiling) data revealed stage-specific differences in translational efficiency of quadruplex harboring genes. Taken together, our findings hint towards existence of regulatory dynamics associated with quadruplexes that may modulate translational efficiency of quadruplex harboring genes to provide survival advantage to the parasite against host immune response and antimalarial drug pressure.

  1. 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

  2. Plasmodium vivax but Not Plasmodium falciparum Blood-Stage Infection in Humans Is Associated with the Expansion of a CD8+ T Cell Population with Cytotoxic Potential

    PubMed Central

    Burel, Julie G.; Apte, Simon H.; McCarthy, James S.; Doolan, Denise L.

    2016-01-01

    P. vivax and P. falciparum parasites display different tropism for host cells and induce very different clinical symptoms and pathology, suggesting that the immune responses required for protection may differ between these two species. However, no study has qualitatively compared the immune responses to P. falciparum or P. vivax in humans following primary exposure and infection. Here, we show that the two species differ in terms of the cellular immune responses elicited following primary infection. Specifically, P. vivax induced the expansion of a subset of CD8+ T cells expressing the activation marker CD38, whereas P. falciparum induced the expansion of CD38+ CD4+ T cells. The CD38+ CD8+ T cell population that expanded following P. vivax infection displayed greater cytotoxic potential compared to CD38- CD8+ T cells, and compared to CD38+ CD8+ T cells circulating during P. falciparum infection. We hypothesize that P. vivax infection leads to a stronger CD38+ CD8+ T cell activation because of its preferred tropism for MHC-I-expressing reticulocytes that, unlike mature red blood cells, can present antigen directly to CD8+ T cells. This study provides the first line of evidence to suggest an effector role for CD8+ T cells in P. vivax blood-stage immunity. It is also the first report of species-specific differences in the subset of T cells that are expanded following primary Plasmodium infection, suggesting that malaria vaccine development may require optimization according to the target parasite. Trial Registration anzctr.org.au ACTRN12612000814875; anzctr.org.au ACTRN12613000565741; anzctr.org.au ACTRN12613001040752; ClinicalTrials.gov NCT02281344; anzctr.org.au ACTRN12612001096842; anzctr.org.au ACTRN12613001008718 PMID:27930660

  3. Construction of Transgenic Plasmodium berghei as a Model for Evaluation of Blood-Stage Vaccine Candidate of Plasmodium falciparum Chimeric Protein 2.9

    PubMed Central

    Cao, Yi; Zhang, Dongmei; Pan, Weiqing

    2009-01-01

    Background The function of the 19 kDa C-terminal region of the merozoite surface protein 1 (MSP1-19) expressed by Plasmodium has been demonstrated to be conserved across distantly related Plasmodium species. The green fluorescent protein (GFP) is a reporter protein that has been widely used because it can be easily detected in living organisms by fluorescence microscopy and flow cytometry. Methodology and Results In this study, we used gene targeting to generate transgenic P. berghei (Pb) parasites (designated as PfMSP1-19Pb) that express the MSP1-19 of P. falciparum (Pf) and the GFP reporter protein simultaneously. The replacement of the PbMSP1-19 locus by PfMSP1-19 was verified by PCR and Southern analysis. The expression of the chimeric PbfMSP-1 and the GFP was verified by Western blot and fluorescence microscopy, respectively. Moreover, GFP-expressing transgenic parasites in blood stages can be readily differentiated from other blood cells using flow cytometry. A comparion of growth rates between wild-type and the PfMSP1-19Pb transgenic parasite indicated that the replacement of the MSP1-19 region and the expression of the GFP protein were not deleterious to the transgenic parasites. We used this transgenic mouse parasite as a murine model to evaluate the protective efficacy in vivo of specific IgG elicited by a PfCP-2.9 malaria vaccine that contains the PfMSP1-19. The BALB/c mice passively transferred with purified rabbit IgG to the PfCP-2.9 survived a lethal challenge of the PfMSP1-19Pb transgenic murine parasites, but not the wild-type P. berghei whereas the control mice passively transferred with purified IgG obtained from adjuvant only-immunized rabbits were vulnerable to both transgenic and wild-type infections. Conclusions We generated a transgenic P. berghei line that expresses PfMSP1-19 and the GFP reporter gene simultaneously. The availability of this parasite line provides a murine model to evaluate the protective efficacy in vivo of anti-MSP1

  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. Cerebral Malaria.

    PubMed

    Marsden, P D; Bruce-Chwatt, L J

    1975-01-01

    Cerebral malaria is an acute diffuse encephalopathy associated only with Plasmodium falciparum. It is probably a consequence of the rapid proliferation of the parasites in the body of man in relation to red cell invasion, and results in stagnation of blood flow in cerebralcapillaries with thromobotic occlusion of large numbers of cerebral capillaries. The subsequent cerebral pathology is cerebral infarction with haemorrhage and cerebral oedema. The wide prevalence of P. falciparum in highly endemic areas results in daily challenges to patients from several infected mosquitoes. It is thus important to understand the characteristics of P. falciparum, since this is one of the most important protozoan parasites of man and severe infection from it constitutes one of the few real clinical emergencies in tropical medicine. One of the more important aspects of the practice of medicine in the tropics is to establish a good understanding of the pattern of medical practice in that area. This applies to malaria as well as to other diseases. The neophyte might be somewhat surprised to learn, for example that an experienced colleague who lives in a holoendemic malarious area such as West Africa, sees no cerebral malaria. But the explanation is simple when the doctor concerned has a practice which involves treating adults only. Cerebral malaria is rare in adults, because in highly endemic areas, by the age of 1 year most of the infants in a group under study have already experienced their first falciparum infection. By the time they reach adult life, they have a solid immunity against severe falciparum infections. In fact, "clinical malaria" could occur in such a group under only two circumstances: 1) in pregnancy, a patent infection with P. falciparum might develop, probably due to an IgG drain across the placenta to the foetus;2) in an individual who has constantly taken antimalarials and who may have an immunity at such a low level that when antimalarial therapy is interrupted

  6. Infection dynamics of endemic malaria in a wild bird population: parasite species-dependent drivers of spatial and temporal variation in transmission rates.

    PubMed

    Lachish, Shelly; Knowles, Sarah C L; Alves, Ricardo; Wood, Matthew J; Sheldon, Ben C

    2011-11-01

    1. Investigating the ecological context in which host-parasite interactions occur and the roles of biotic and abiotic factors in forcing infection dynamics is essential to understanding disease transmission, spread and maintenance. 2. Despite their prominence as model host-pathogen systems, the relative influence of environmental heterogeneity and host characteristics in influencing the infection dynamics of avian blood parasites has rarely been assessed in the wild, particularly at a within-population scale. 3. We used a novel multievent modelling framework (an extension of multistate mark-recapture modelling) that allows for uncertainty in disease state, to estimate transmission parameters and assess variation in the infection dynamics of avian malaria in a large, longitudinally sampled data set of breeding blue tits infected with two divergent species of Plasmodium parasites. 4. We found striking temporal and spatial heterogeneity in the disease incidence rate and the likelihood of recovery within this single population and demonstrate marked differences in the relative influence of environmental and host factors in forcing the infection dynamics of the two Plasmodium species. 5. Proximity to a permanent water source greatly influenced the transmission rates of P. circumflexum, but not of P. relictum, suggesting that these parasites are transmitted by different vectors. 6. Host characteristics (age/sex) were found to influence infection rates but not recovery rates, and their influence on infection rates was also dependent on parasite species: P. relictum infection rates varied with host age, whilst P. circumflexum infection rates varied with host sex. 7. Our analyses reveal that transmission of endemic avian malaria is a result of complex interactions between biotic and abiotic components that can operate on small spatial scales and demonstrate that knowledge of the drivers of spatial and temporal heterogeneity in disease transmission will be

  7. Malaria and Travelers

    MedlinePlus

    ... CDC’s Malaria Maps are another reference to help locate areas with malaria. Conduct an individualized risk assessment Prevention of malaria involves a balance between ensuring that all people who will be at risk of infection use ...

  8. Plasmodium knowlesi malaria in children.

    PubMed

    Barber, Bridget E; William, Timothy; Jikal, Mohammad; Jilip, Jenarun; Dhararaj, Prabakaran; Menon, Jayaram; Yeo, Tsin W; Anstey, Nicholas M

    2011-05-01

    Plasmodium knowlesi can cause severe malaria in adults; however, descriptions of clinical disease in children are lacking. We reviewed case records of children (age <15 years) with a malaria diagnosis at Kudat District Hospital, serving a largely deforested area of Sabah, Malaysia, during January-November 2009. Sixteen children with PCR-confirmed P. knowlesi monoinfection were compared with 14 children with P. falciparum monoinfection diagnosed by microscopy or PCR. Four children with knowlesi malaria had a hemoglobin level at admission of <10.0 g/dL (minimum lowest level 6.4 g/dL). Minimum level platelet counts were lower in knowlesi than in falciparum malaria (median 76,500/μL vs. 156,000/mL; p = 0.01). Most (81%) children with P. knowlesi malaria received chloroquine and primaquine; median parasite clearance time was 2 days (range 1-5 days). P. knowlesi is the most common cause of childhood malaria in Kudat. Although infection is generally uncomplicated, anemia is common and thrombocytopenia universal. Transmission dynamics in this region require additional investigation.

  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. Dynamical Mapping of Anopheles darlingi Densities in a Residual Malaria Transmission Area of French Guiana by Using Remote Sensing and Meteorological Data

    PubMed Central

    Adde, Antoine; Roux, Emmanuel; Mangeas, Morgan; Dessay, Nadine; Nacher, Mathieu; Dusfour, Isabelle; Girod, Romain; Briolant, Sébastien

    2016-01-01

    Local variation in the density of Anopheles mosquitoes and the risk of exposure to bites are essential to explain the spatial and temporal heterogeneities in the transmission of malaria. Vector distribution is driven by environmental factors. Based on variables derived from satellite imagery and meteorological observations, this study aimed to dynamically model and map the densities of Anopheles darlingi in the municipality of Saint-Georges de l’Oyapock (French Guiana). Longitudinal sampling sessions of An. darlingi densities were conducted between September 2012 and October 2014. Landscape and meteorological data were collected and processed to extract a panel of variables that were potentially related to An. darlingi ecology. Based on these data, a robust methodology was formed to estimate a statistical predictive model of the spatial-temporal variations in the densities of An. darlingi in Saint-Georges de l’Oyapock. The final cross-validated model integrated two landscape variables—dense forest surface and built surface—together with four meteorological variables related to rainfall, evapotranspiration, and the minimal and maximal temperatures. Extrapolation of the model allowed the generation of predictive weekly maps of An. darlingi densities at a resolution of 10-m. Our results supported the use of satellite imagery and meteorological data to predict malaria vector densities. Such fine-scale modeling approach might be a useful tool for health authorities to plan control strategies and social communication in a cost-effective, targeted, and timely manner. PMID:27749938

  11. 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

  12. Cerebral malaria

    PubMed Central

    Newton, C.; Hien, T. T.; White, N.

    2000-01-01

    Cerebral malaria may be the most common non-traumatic encephalopathy in the world. The pathogenesis is heterogenous and the neurological complications are often part of a multisystem dysfunction. The clinical presentation and pathophysiology differs between adults and children. Recent studies have elucidated the molecular mechanisms of pathogenesis and raised possible interventions. Antimalarial drugs, however, remain the only intervention that unequivocally affects outcome, although increasing resistance to the established antimalarial drugs is of grave concern. Artemisinin derivatives have made an impact on treatment, but other drugs may be required. With appropriate antimalarial drugs, the prognosis of cerebral malaria often depends on the management of other complications—for example, renal failure and acidosis. Neurological sequelae are increasingly recognised, but further research on the pathogenesis of coma and neurological damage is required to develop other ancillary treatments.

 PMID:10990500

  13. 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.

  14. Population genetic analysis of large sequence polymorphisms in Plasmodium falciparum blood-stage antigens.

    PubMed

    Ahouidi, Ambroise D; Bei, Amy K; Neafsey, Daniel E; Sarr, Ousmane; Volkman, Sarah; Milner, Dan; Cox-Singh, Janet; Ferreira, Marcelo U; Ndir, Omar; Premji, Zul; Mboup, Souleymane; Duraisingh, Manoj T

    2010-03-01

    Plasmodium falciparum, the causative agent of human malaria, invades host erythrocytes using several proteins on the surface of the invasive merozoite, which have been proposed as potential vaccine candidates. Members of the multi-gene PfRh family are surface antigens that have been shown to play a central role in directing merozoites to alternative erythrocyte receptors for invasion. Recently, we identified a large structural polymorphism, a 0.58Kb deletion, in the C-terminal region of the PfRh2b gene, present at a high frequency in parasite populations from Senegal. We hypothesize that this region is a target of humoral immunity. Here, by analyzing 371 P. falciparum isolates we show that this major allele is present at varying frequencies in different populations within Senegal, Africa, and throughout the world. For allelic dimorphisms in the asexual stage antigens, Msp-2 and EBA-175, we find minimal geographic differentiation among parasite populations from Senegal and other African localities, suggesting extensive gene flow among these populations and/or immune-mediated frequency-dependent balancing selection. In contrast, we observe a higher level of inter-population divergence (as measured by F(st)) for the PfRh2b deletion, similar to that observed for SNPs from the sexual stage Pfs45/48 loci, which is postulated to be under directional selection. We confirm that the region containing the PfRh2b polymorphism is a target of humoral immune responses by demonstrating antibody reactivity of endemic sera. Our analysis of inter-population divergence suggests that in contrast to the large allelic dimorphisms in EBA-175 and Msp-2, the presence or absence of the large PfRh2b deletion may not elicit frequency-dependent immune selection, but may be under positive immune selection, having important implications for the development of these proteins as vaccine candidates.

  15. A novel live-dead staining methodology to study malaria parasite viability

    PubMed Central

    2013-01-01

    Background Malaria is a major health and socio-economical problem in tropical and sub-tropical areas of the world. Several methodologies have been used to assess parasite viability during the adaption of field strains to culture or the assessment of drug potential, but these are in general not able to provide an accurate real-time assessment of whether parasites are alive or dead. Methods Different commercial dyes and kits were assessed for their potential to allow for the real-time detection of whether a blood stage malaria parasite is dead or alive. Results Here, a methodology is presented based on the potential-sensitive mitochondrial probe JC-1, which allows for the real-time visualization of live (red staining) and/or dead (absence of red staining) blood stage parasites in vitro and ex vivo. This method is applicable across malaria parasite species and strains and allows to visualize all parasite blood stages including gametocytes. Further, this methodology has been assessed also for use in drug sensitivity testing. Conclusions The JC-1 staining approach is a versatile methodology that can be used to assess parasite viability during the adaptation of field samples to culture and during drug treatment. It was found to hold promise in the assessment of drugs expected to lead to delayed death phenotypes and it currently being evaluated as a method for the assessment of parasite viability during the adaptation of patient-derived Plasmodium vivax to long-term in vitro culture. PMID:23758788

  16. Malaria parasites and red cell variants: when a house is not a home

    PubMed Central

    Taylor, Steve M.; Fairhurst, Rick M.

    2014-01-01

    Purpose of review Multiple red cell variants are known to confer protection from malaria. Here we review advances in identifying new variants that modulate malaria risk and in defining molecular mechanisms that mediate malaria protection. Recent findings New red cell variants, including an innate variant in the red cell’s major Ca2+ pump and the acquired state of iron deficiency, have been associated with protection from clinical falciparum malaria. The hemoglobin (Hb) mutants HbC and HbS – known to protect carriers from severe falciparum malaria – enhance parasite passage to mosquitoes and may promote malaria transmission. At the molecular level, substantial advances have been made in understanding the impact of HbS and HbC upon the interactions between host microRNAs and Plasmodium falciparum protein translation; remodeling of red cell cytoskeletal components and transport of parasite proteins to the red cell surface; and chronic activation of the human innate immune system which induces tolerance to blood-stage parasites. Several polymorphisms have now been associated with protection from clinical vivax malaria or reduced P. vivax density, including Southeast Asian ovalocytosis and two common forms of glucose-6-phosphate dehydrogenase deficiency. Summary Red cell variants that modulate malaria risk can serve as models to identify clinically relevant mechanisms of pathogenesis, and thus define parasite and host targets for next-generation therapies. PMID:24675047

  17. New cell motility model observed in parasitic cnidarian Sphaerospora molnari (Myxozoa:Myxosporea) blood stages in fish.

    PubMed

    Hartigan, A; Estensoro, I; Vancová, M; Bílý, T; Patra, S; Eszterbauer, E; Holzer, A S

    2016-12-16

    Cellular motility is essential for microscopic parasites, it is used to reach the host, migrate through tissues, or evade host immune reactions. Many cells employ an evolutionary conserved motor protein- actin, to crawl or glide along a substrate. We describe the peculiar movement of Sphaerospora molnari, a myxozoan parasite with proliferating blood stages in its host, common carp. Myxozoa are highly adapted parasitic cnidarians alternately infecting vertebrates and invertebrates. S. molnari blood stages (SMBS) have developed a unique "dancing" behaviour, using the external membrane as a motility effector to rotate and move the cell. SMBS movement is exceptionally fast compared to other myxozoans, non-directional and constant. The movement is based on two cytoplasmic actins that are highly divergent from those of other metazoans. We produced a specific polyclonal actin antibody for the staining and immunolabelling of S. molnari's microfilaments since we found that neither commercial antibodies nor phalloidin recognised the protein or microfilaments. We show the in situ localization of this actin in the parasite and discuss the importance of this motility for evasion from the cellular host immune response in vitro. This new type of motility holds key insights into the evolution of cellular motility and associated proteins.

  18. New cell motility model observed in parasitic cnidarian Sphaerospora molnari (Myxozoa:Myxosporea) blood stages in fish

    PubMed Central

    Hartigan, A.; Estensoro, I.; Vancová, M.; Bílý, T.; Patra, S.; Eszterbauer, E.; Holzer, A. S.

    2016-01-01

    Cellular motility is essential for microscopic parasites, it is used to reach the host, migrate through tissues, or evade host immune reactions. Many cells employ an evolutionary conserved motor protein– actin, to crawl or glide along a substrate. We describe the peculiar movement of Sphaerospora molnari, a myxozoan parasite with proliferating blood stages in its host, common carp. Myxozoa are highly adapted parasitic cnidarians alternately infecting vertebrates and invertebrates. S. molnari blood stages (SMBS) have developed a unique “dancing” behaviour, using the external membrane as a motility effector to rotate and move the cell. SMBS movement is exceptionally fast compared to other myxozoans, non-directional and constant. The movement is based on two cytoplasmic actins that are highly divergent from those of other metazoans. We produced a specific polyclonal actin antibody for the staining and immunolabelling of S. molnari’s microfilaments since we found that neither commercial antibodies nor phalloidin recognised the protein or microfilaments. We show the in situ localization of this actin in the parasite and discuss the importance of this motility for evasion from the cellular host immune response in vitro. This new type of motility holds key insights into the evolution of cellular motility and associated proteins. PMID:27982057

  19. Pre-erythrocytic malaria vaccines: identifying the targets

    PubMed Central

    Duffy, Patrick E; Sahu, Tejram; Akue, Adovi; Milman, Neta; Anderson, Charles

    2013-01-01

    Pre-erythrocytic malaria vaccines target Plasmodium during its sporozoite and liver stages, and can prevent progression to blood-stage disease, which causes a million deaths each year. Whole organism sporozoite vaccines induce sterile immunity in animals and humans and guide subunit vaccine development. A recombinant protein-in-adjuvant pre-erythrocytic vaccine called RTS,S reduces clinical malaria without preventing infection in field studies and additional antigens may be required to achieve sterile immunity. Although few vaccine antigens have progressed to human testing, new insights into parasite biology, expression profiles and immunobiology have offered new targets for intervention. Future advances require human trials of additional antigens, as well as platforms to induce the durable antibody and cellular responses including CD8+ T cells that contribute to sterile protection. PMID:23176657

  20. Vaccines against malaria.

    PubMed

    Ouattara, Amed; Laurens, Matthew B

    2015-03-15

    Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease.

  1. An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials.

    PubMed

    Steel, Ryan Wj; Kappe, Stefan Hi; Sack, Brandon K

    2016-12-01

    Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts.

  2. Signatures of malaria-associated pathology revealed by high-resolution whole-blood transcriptomics in a rodent model of malaria

    PubMed Central

    Lin, Jing-wen; Sodenkamp, Jan; Cunningham, Deirdre; Deroost, Katrien; Tshitenge, Tshibuayi Christine; McLaughlin, Sarah; Lamb, Tracey J.; Spencer-Dene, Bradley; Hosking, Caroline; Ramesar, Jai; Janse, Chris J.; Graham, Christine; O’Garra, Anne; Langhorne, Jean

    2017-01-01

    The influence of parasite genetic factors on immune responses and development of severe pathology of malaria is largely unknown. In this study, we performed genome-wide transcriptomic profiling of mouse whole blood during blood-stage infections of two strains of the rodent malaria parasite Plasmodium chabaudi that differ in virulence. We identified several transcriptomic signatures associated with the virulent infection, including signatures for platelet aggregation, stronger and prolonged anemia and lung inflammation. The first two signatures were detected prior to pathology. The anemia signature indicated deregulation of host erythropoiesis, and the lung inflammation signature was linked to increased neutrophil infiltration, more cell death and greater parasite sequestration in the lungs. This comparative whole-blood transcriptomics profiling of virulent and avirulent malaria shows the validity of this approach to inform severity of the infection and provide insight into pathogenic mechanisms. PMID:28155887

  3. 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

  4. Population dynamics of pest mosquitoes and potential malaria and West Nile virus vectors in relation to climatic factors and human activities in the Camargue, France.

    PubMed

    Ponçon, N; Toty, C; L'ambert, G; le Goff, G; Brengues, C; Schaffner, F; Fontenille, D

    2007-12-01

    The Camargue is an extensive wetland in the southeast of France, which is highly influenced by human activities. Large ponds, marshes and irrigated fields provide abundant potential breeding sites for mosquitoes. mosquitoes, which are important in terms of the nuisance they cause to people and animals, the limitations they impose on tourism and their potential threat to human health. Several of the mosquito species present are potential vectors of malaria and West Nile virus. Therefore, the population dynamics of these species were monitored over an entire breeding season during March-October 2005. Mosquito populations were sampled in two study areas once every 2 weeks, using CDC light traps baited with CO(2). Sixteen species were collected. The majority (98.7%) of the catch were Aedes caspius (Pallas) (Diptera: Culicidae), Culex modestus (Ficalbi), Culex pipiens L. and Anopheles hyrcanus (Pallas). The population dynamics of these species varied considerably in relation to the species' biology, climatic conditions (rainfall, temperature and season), water management, implementation of mosquito control campaigns and landscape use.

  5. [WHO's malaria program Roll Back Malaria].

    PubMed

    Myrvang, B; Godal, T

    2000-05-30

    Malaria is one of the main health problems in the world with 300-500 millions cases yearly and about one million deaths, mainly children in Sub-Saharan Africa. In the 1990s the malaria problem in Africa has increased, although we have methods to control the disease. In 1998 the new secretary general of WHO, Gro Harlem Brundtland, established the Roll Back Malaria programme, with the aim to markedly reduce malaria morbidity and mortality. Governments in malaria-affected countries have to take the lead in Roll Back Malaria. Their health systems must be improved and malaria control integrated into the general health system, and the methods available for prevention and treatment have to be intensified and improved. At the same time, Roll Back Malaria will encourage and promote malaria research which hopefully will result in new medicines, vaccines and other tools which will improve the chances of reducing malaria-related deaths and suffering. Roll Back Malaria is a cabinet project within the WHO, and the organisation has a key role as manager, co-ordinator and monitor of the project. However, it depends for resources on international support and commitment from other UN bodies, the World Bank, governments in the western world, pharmaceutical industry, philanthropists and other sources. At present an optimistic view prevails, and the preliminary aim, to halve the malaria mortality by the year 2010, seems realistic even with the control methods of today. However, if research efforts result in new and better tools to combat the disease, the task will definitely be easier.

  6. Malaria (For Parents)

    MedlinePlus

    ... period for malaria is the time between the mosquito bite and the release of parasites from the ... Health authorities try to prevent malaria by using mosquito-control programs aimed at killing mosquitoes that carry ...

  7. Malaria (For Parents)

    MedlinePlus

    ... it is passed from person to person (from mother to child in "congenital malaria," or through blood ... risk for malaria. Your doctor can give your family anti-malarial drugs to prevent the disease, which ...

  8. Malaria Parasite Liver Infection and Exoerythrocytic Biology.

    PubMed

    Vaughan, Ashley M; Kappe, Stefan H I

    2017-02-27

    In their infection cycle, malaria parasites undergo replication and population expansions within the vertebrate host and the mosquito vector. Host infection initiates with sporozoite invasion of hepatocytes, followed by a dramatic parasite amplification event during liver stage parasite growth and replication within hepatocytes. Each liver stage forms up to 90,000 exoerythrocytic merozoites, which are in turn capable of initiating a blood stage infection. Liver stages not only exploit host hepatocyte resources for nutritional needs but also endeavor to prevent hepatocyte cell death and detection by the host's immune system. Research over the past decade has identified numerous parasite factors that play a critical role during liver infection and has started to delineate a complex web of parasite-host interactions that sustain successful parasite colonization of the mammalian host. Targeting the parasites' obligatory infection of the liver as a gateway to the blood, with drugs and vaccines, constitutes the most effective strategy for malaria eradication, as it would prevent clinical disease and onward transmission of the parasite.

  9. Malaria-associated rubber plantations in Thailand.

    PubMed

    Bhumiratana, Adisak; Sorosjinda-Nunthawarasilp, Prapa; Kaewwaen, Wuthichai; Maneekan, Pannamas; Pimnon, Suntorn

    2013-01-01

    Rubber forestry is intentionally used as a land management strategy. The propagation of rubber plantations in tropic and subtropic regions appears to influence the economical, sociological and ecological aspects of sustainable development as well as human well-being and health. Thailand and other Southeast Asian countries are the world's largest producers of natural rubber products; interestingly, agricultural workers on rubber plantations are at risk for malaria and other vector-borne diseases. The idea of malaria-associated rubber plantations (MRPs) encompasses the complex epidemiological settings that result from interactions among human movements and activities, land cover/land use changes, agri-environmental and climatic conditions and vector population dynamics. This paper discusses apparent issues pertaining to the connections between rubber plantations and the populations at high risk for malaria. The following questions are addressed: (i) What are the current and future consequences of rubber plantations in Thailand and Southeast Asia relative to malaria epidemics or outbreaks of other vector-borne diseases? (ii) To what extent is malaria transmission in Thailand related to the forest versus rubber plantations? and (iii) What are the vulnerabilities of rubber agricultural workers to malaria, and how contagious is malaria in these areas?

  10. The immunological balance between host and parasite in malaria.

    PubMed

    Deroost, Katrien; Pham, Thao-Thy; Opdenakker, Ghislain; Van den Steen, Philippe E

    2016-03-01

    Coevolution of humans and malaria parasites has generated an intricate balance between the immune system of the host and virulence factors of the parasite, equilibrating maximal parasite transmission with limited host damage. Focusing on the blood stage of the disease, we discuss how the balance between anti-parasite immunity versus immunomodulatory and evasion mechanisms of the parasite may result in parasite clearance or chronic infection without major symptoms, whereas imbalances characterized by excessive parasite growth, exaggerated immune reactions or a combination of both cause severe pathology and death, which is detrimental for both parasite and host. A thorough understanding of the immunological balance of malaria and its relation to other physiological balances in the body is of crucial importance for developing effective interventions to reduce malaria-related morbidity and to diminish fatal outcomes due to severe complications. Therefore, we discuss in this review the detailed mechanisms of anti-malarial immunity, parasite virulence factors including immune evasion mechanisms and pathogenesis. Furthermore, we propose a comprehensive classification of malaria complications according to the different types of imbalances.

  11. Novel approaches to identify protective malaria vaccine candidates

    PubMed Central

    Chia, Wan Ni; Goh, Yun Shan; Rénia, Laurent

    2014-01-01

    Efforts to develop vaccines against malaria have been the focus of substantial research activities for decades. Several categories of candidate vaccines are currently being developed for protection against malaria, based on antigens corresponding to the pre-erythrocytic, blood stage, or sexual stages of the parasite. Long lasting sterile protection from Plasmodium falciparum sporozoite challenge has been observed in human following vaccination with whole parasite formulations, clearly demonstrating that a protective immune response targeting predominantly the pre-erythrocytic stages can develop against malaria. However, most of vaccine candidates currently being investigated, which are mostly subunits vaccines, have not been able to induce substantial (>50%) protection thus far. This is due to the fact that the antigens responsible for protection against the different parasite stages are still yet to be known and relevant correlates of protection have remained elusive. For a vaccine to be developed in a timely manner, novel approaches are required. In this article, we review the novel approaches that have been developed to identify the antigens for the development of an effective malaria vaccine. PMID:25452745

  12. Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites

    PubMed Central

    Douglass, Alyse N; Kain, Heather S; Abdullahi, Marian; Arang, Nadia; Austin, Laura S; Mikolajczak, Sebastian A; Billman, Zachary P; Hume, Jen C C; Murphy, Sean C; Kappe, Stefan H I; Kaushansky, Alexis

    2015-01-01

    Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand the repertoire of prophylactic drugs against malaria. Here, we demonstrate that both Bcl-2 inhibitors and P53 agonists dramatically reduce LS burden in a mouse malaria model in vitro and in vivo by altering the activity of key hepatocyte factors on which the parasite relies. Bcl-2 inhibitors act primarily by inducing apoptosis in infected hepatocytes, whereas P53 agonists eliminate parasites in an apoptosis-independent fashion. In combination, Bcl-2 inhibitors and P53 agonists act synergistically to delay, and in some cases completely prevent, the onset of blood stage disease. Both families of drugs are highly effective at doses that do not cause substantial hepatocyte cell death in vitro or liver damage in vivo. P53 agonists and Bcl-2 inhibitors were also effective when administered to humanized mice infected with Plasmodium falciparum. Our data demonstrate that host-based prophylaxis could be developed into an effective intervention strategy that eliminates LS parasites before the onset of clinical disease and thus opens a new avenue to prevent malaria. PMID:25648263

  13. Comparison of modeling methods to determine liver-to-blood inocula and parasite multiplication rates during controlled human malaria infection.

    PubMed

    Douglas, Alexander D; Edwards, Nick J; Duncan, Christopher J A; Thompson, Fiona M; Sheehy, Susanne H; O'Hara, Geraldine A; Anagnostou, Nicholas; Walther, Michael; Webster, Daniel P; Dunachie, Susanna J; Porter, David W; Andrews, Laura; Gilbert, Sarah C; Draper, Simon J; Hill, Adrian V S; Bejon, Philip

    2013-07-15

    Controlled human malaria infection is used to measure efficacy of candidate malaria vaccines before field studies are undertaken. Mathematical modeling using data from quantitative polymerase chain reaction (qPCR) parasitemia monitoring can discriminate between vaccine effects on the parasite's liver and blood stages. Uncertainty regarding the most appropriate modeling method hinders interpretation of such trials. We used qPCR data from 267 Plasmodium falciparum infections to compare linear, sine-wave, and normal-cumulative-density-function models. We find that the parameters estimated by these models are closely correlated, and their predictive accuracy for omitted data points was similar. We propose that future studies include the linear model.

  14. Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling.

    PubMed

    Labbé, Katherine; Miu, Jenny; Yeretssian, Garabet; Serghides, Lena; Tam, Mifong; Finney, Constance A; Erdman, Laura K; Goulet, Marie-Line; Kain, Kevin C; Stevenson, Mary M; Saleh, Maya

    2010-11-01

    Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T(125)C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1(-/-) mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/β, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12(-/-) mice to blood-stage malaria infection.

  15. Malaria. Can WHO roll back malaria?

    PubMed

    Balter, M

    2000-10-20

    In October 1998, World Health Organization Director-General Gro Harlem Brundtland announced Roll Back Malaria, a multiagency crusade that aims to cut malaria mortality in half over the next 10 years. Brundtland might just be the one to pull it off, say numerous public health experts, although some researchers question whether the goal is realistic.

  16. Antibody acquisition models: A new tool for serological surveillance of malaria transmission intensity

    PubMed Central

    Yman, Victor; White, Michael T.; Rono, Josea; Arcà, Bruno; Osier, Faith H.; Troye-Blomberg, Marita; Boström, Stéphanie; Ronca, Raffaele; Rooth, Ingegerd; Färnert, Anna

    2016-01-01

    Serology has become an increasingly important tool for the surveillance of a wide range of infectious diseases. It has been particularly useful to monitor malaria transmission in elimination settings where existing metrics such as parasite prevalence and incidence of clinical cases are less sensitive. Seroconversion rates, based on antibody prevalence to Plasmodium falciparum asexual blood-stage antigens, provide estimates of transmission intensity that correlate with entomological inoculation rates but lack precision in settings where seroprevalence is still high. Here we present a new and widely applicable method, based on cross-sectional data on individual antibody levels. We evaluate its use as a sero-surveillance tool in a Tanzanian setting with declining malaria prevalence. We find that the newly developed mathematical models produce more precise estimates of transmission patterns, are robust in high transmission settings and when sample sizes are small, and provide a powerful tool for serological evaluation of malaria transmission intensity. PMID:26846726

  17. Dynamics of multiple insecticide resistance in the malaria vector Anopheles gambiae in a rice growing area in South-Western Burkina Faso

    PubMed Central

    Dabiré, Kounbobr Roch; Diabaté, Abdoulaye; Djogbenou, Luc; Ouari, Ali; N'Guessan, Raphaël; Ouédraogo, Jean-Bosco; Hougard, Jean-Marc; Chandre, Fabrice; Baldet, Thierry

    2008-01-01

    Background Insecticide resistance of the main malaria vector, Anopheles gambiae, has been reported in south-western Burkina Faso, West Africa. Cross-resistance to DDT and pyrethroids was conferred by alterations at site of action in the sodium channel, the Leu-Phe kdr mutation; resistance to organophosphates and carbamates resulted from a single point mutation in the oxyanion hole of the acetylcholinesterase enzyme designed as ace-1R. Methods An entomological survey was carried out during the rainy season of 2005 at Vallée du Kou, a rice growing area in south-western Burkina Faso. At the Vallée du Kou, both insecticide resistance mechanisms have been previously described in the M and S molecular forms of An. gambiae. This survey aimed i) to update the temporal dynamics and the circumsporozoite infection rate of the two molecular forms M and S of An. gambiae ii) to update the frequency of the Leu-Phe kdr mutation within these forms and finally iii) to investigate the occurrence of the ace-1R mutation. Mosquitoes collected by indoor residual collection and by human landing catches were counted and morphologically identified. Species and molecular forms of An. gambiae, ace-1R and Leu-Phe kdr mutations were determined using PCR techniques. The presence of the circumsporozoite protein of Plasmodium falciparum was determined using ELISA. Results Anopheles gambiae populations were dominated by the M form. However the S form occurred in relative important proportion towards the end of the rainy season with a maximum peak in October at 51%. Sporozoite rates were similar in both forms. The frequency of the Leu-Phe kdr mutation in the S form reached a fixation level while it is still spreading in the M form. Furthermore, the ace-1R mutation prevailed predominately in the S form and has just started spreading in the M form. The two mutations occurred concomitantly both in M and S populations. Conclusion These results showed that the Vallée du Kou, a rice growing area

  18. Synergistic and antagonistic interactions between bednets and vaccines in the control of malaria

    PubMed Central

    Artzy-Randrup, Yael; Dobson, Andrew P.; Pascual, Mercedes

    2015-01-01

    It is extremely likely that the malaria vaccines currently in development will be used in conjunction with treated bednets and other forms of malaria control. The interaction of different intervention methods is at present poorly understood in a disease such as malaria where immunity is more complex than for other pathogens that have been successfully controlled by vaccination. Here we develop a general mathematical model of malaria transmission to examine the interaction between vaccination and bednets. Counterintuitively, we find that the frailty of malaria immunity will potentially cause both synergistic and antagonistic interactions between vaccination and the use of bednets. We explore the conditions that create these tensions, and outline strategies that minimize their detrimental impact. Our analysis specifically considers the three leading vaccine classes currently in development: preerythrocytic (PEV), blood stage (BSV), and transmission blocking (TBV). We find that the combination of BSV with treated bednets can lead to increased morbidity with no added value in terms of elimination; the interaction is clearly antagonistic. In contrast, there is strong synergy between PEV and treated bednets that may facilitate elimination, although transient stages are likely to increase morbidity. The combination of TBV with treated bednets is synergistic, lowering both morbidity and elimination thresholds. Our results suggest that vaccines will not provide a straightforward solution to malaria control, and that future programs need to consider the synergistic and antagonistic interactions between vaccines and treated bednets. PMID:25605894

  19. 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

  20. 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).

  1. 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

  2. Psychosomatics of malaria.

    PubMed

    Houghton, D L

    1980-03-01

    Cerebral malaria with psychosomatic manifestations is one aspect of malaria which may be mistaken for mental illness. However, the psychosomatic aspects of the disease also relate to the biological, psychological and social influences which may determine changes in disease incidence and distribution. The history of the Global Malaria Eradication Campaign and the resurgence of malaria in many countries of the world have influenced attitudes and the professional milieu in which present day malaria control programmes seek to operate. The individual in a malarious area may obstruct malaria control operations by refusing to allow indoor spraying or to take prophylactic medication. Cultural beliefs often described the history of malaria in a community and the way in which the community had come to terms with this disease. Socio-economic development and population movement may disturb this equilibrium and result in a rise in malaria incidence. Behavioural habits may increase malaria risk and the degree to which the community is prepared to become involved in malaria control may influence its experience with the disease.

  3. 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

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

    PubMed

    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.

  5. 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

  6. Vaccines Against Malaria

    PubMed Central

    Ouattara, Amed; Laurens, Matthew B.

    2015-01-01

    Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. PMID:25452593

  7. 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

  8. 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.

  9. Discovering and developing new medicines for malaria control and elimination.

    PubMed

    Wells, Timothy N C

    2013-08-01

    A steady increase in the number of antimalarial drug candidates since 2007 follows a call to eradicate malaria from the World Health Organization (WHO), the Bill and Melinda Gates Foundation and others. Four new fixed dose combination medicines have been approved by stringent authorities or the WHO in as many years. OZ439, a synthetic endoperoxide currently in Phase II, could reduce treatment to a single dose. Significant challenges remain: while drugs to treat patients suffering from malaria are essential, drugs focused on breaking the lifecycle between human and mosquito host are needed. Effective medicines that are easy to take in the field are needed, together with treatments for infants and for women in the first trimester of pregnancy. Research has concentrated on Plasmodium falciparum infection but there is a need for medicines that prevent relapses of P. vivax infection. In addition, the evolution of pathogen resistance against established drugs poses a threat to existing medicines. Direct testing of compounds against whole parasites as well as target approaches has accelerated the process of drug discovery, and identified new classes of compounds. The most advanced of these, spiroindolone, already in clinical development, kills the blood stages of both P. falciparum and P. vivax by a mechanism unrelated to any current antimalarial. The collaborative model of drug discovery between the Medicines for Malaria Venture, pharmaceutical companies and academic institutions has resulted in the construction of a promising pipeline of new classes of compounds, focused on the needs of the patient.

  10. 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.

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

    PubMed Central

    Smith, Leanna; Peronet, Roger; Commere, Pierre-Henri; Apetoh, Lionel

    2016-01-01

    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

  12. In vitro growth-inhibitory activity and malaria risk in a cohort study in mali.

    PubMed

    Crompton, Peter D; Miura, Kazutoyo; Traore, Boubacar; Kayentao, Kassoum; Ongoiba, Aissata; Weiss, Greta; Doumbo, Safiatou; Doumtabe, Didier; Kone, Younoussou; Huang, Chiung-Yu; Doumbo, Ogobara K; Miller, Louis H; Long, Carole A; Pierce, Susan K

    2010-02-01

    Immunity to the asexual blood stage of Plasmodium falciparum is complex and likely involves several effector mechanisms. Antibodies are thought to play a critical role in malaria immunity, and a corresponding in vitro correlate of antibody-mediated immunity has long been sought to facilitate malaria vaccine development. The growth inhibition assay (GIA) measures the capacity of antibodies to limit red blood cell (RBC) invasion and/or growth of P. falciparum in vitro. In humans, naturally acquired and vaccine-induced P. falciparum-specific antibodies have growth-inhibitory activity, but it is unclear if growth-inhibitory activity correlates with protection from clinical disease. In a longitudinal study in Mali, purified IgGs, obtained from plasmas collected before the malaria season from 220 individuals aged 2 to 10 and 18 to 25 years, were assayed for growth-inhibitory activity. Malaria episodes were recorded by passive surveillance over the subsequent 6-month malaria season. Logistic regression showed that greater age (odds ratio [OR], 0.78; 95% confidence interval [95% CI], 0.63 to 0.95; P = 0.02) and growth-inhibitory activity (OR, 0.50; 95% CI, 0.30 to 0.85; P = 0.01) were significantly associated with decreased malaria risk in children. A growth-inhibitory activity level of 40% was determined to be the optimal cutoff for discriminating malaria-immune and susceptible individuals in this cohort, with a sensitivity of 97.0%, but a low specificity of 24.3%, which limited the assay's ability to accurately predict protective immunity and to serve as an in vitro correlate of antibody-mediated immunity. These data suggest that antibodies which block merozoite invasion of RBC and/or inhibit the intra-RBC growth of the parasite contribute to but are not sufficient for the acquisition of malaria immunity.

  13. Transposable element dynamics of the hAT element Herves in the human malaria vector Anopheles gambiae s.s.

    PubMed

    Subramanian, Ramanand A; Arensburger, Peter; Atkinson, Peter W; O'Brochta, David A

    2007-08-01

    Transposable elements are being considered as genetic drive agents for introducing phenotype-altering genes into populations of vectors of human disease. The dynamics of endogenous elements will assist in predicting the behavior of introduced elements. Transposable element display was used to estimate the site-occupancy frequency distribution of Herves in six populations of Anopheles gambiae s.s. The site-occupancy distribution data suggest that the element has been recently active within the sampled populations. All 218 individuals sampled contained at least one copy of Herves with a mean of 3.6 elements per diploid genome. No significant differences in copy number were observed among populations. Nucleotide polymorphism within the element was high (pi = 0.0079 in noncoding sequences and 0.0046 in coding sequences) relative to that observed in some of the more well-studied elements in Drosophila melanogaster. In total, 33 distinct forms of Herves were found on the basis of the sequence of the first 528 bp of the transposase open reading frame. Only two forms were found in all six study populations. Although Herves elements in An. gambiae are quite diverse, 85% of the individuals examined had evidence of complete forms of the element. Evidence was found for the lateral transfer of Herves from an unknown source into the An. gambiae lineage prior to the diversification of the An. gambiae species complex. The characteristics of Herves in An. gambiae are somewhat unlike those of P elements in D. melanogaster.

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

    PubMed

    van Bruggen, Rebekah; Gualtieri, Christian; Iliescu, Alexandra; Louicharoen Cheepsunthorn, Chalisa; Mungkalasut, Punchalee; Trape, Jean-François; Modiano, David; Sirima, Bienvenu Sodiomon; 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.

  15. 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

  16. Rice volatiles lure gravid malaria mosquitoes, Anopheles arabiensis.

    PubMed

    Wondwosen, Betelehem; Birgersson, Göran; Seyoum, Emiru; Tekie, Habte; Torto, Baldwyn; Fillinger, Ulrike; Hill, Sharon R; Ignell, Rickard

    2016-11-30

    Mosquito oviposition site selection is essential for vector population dynamics and malaria epidemiology. Irrigated rice cultivations provide ideal larval habitats for malaria mosquitoes, which has resulted in increased prevalence of the malaria vector, Anopheles arabiensis, in sub-Saharan Africa. The nature and origin of the cues regulating this behaviour are only now being elucidated. We show that gravid Anopheles arabiensis are attracted and oviposit in response to the odour present in the air surrounding rice. Furthermore, we identify a synthetic rice odour blend, using electrophysiological and chemical analyses, which elicits attraction and oviposition in laboratory assays, as well as attraction of free-flying gravid mosquitoes under semi-field conditions. This research highlights the intimate link between malaria vectors and agriculture. The identified volatile cues provide important substrates for the development of novel and cost-effective control measures that target female malaria mosquitoes, irrespective of indoor or outdoor feeding and resting patterns.

  17. Rice volatiles lure gravid malaria mosquitoes, Anopheles arabiensis

    PubMed Central

    Wondwosen, Betelehem; Birgersson, Göran; Seyoum, Emiru; Tekie, Habte; Torto, Baldwyn; Fillinger, Ulrike; Hill, Sharon R.; Ignell, Rickard

    2016-01-01

    Mosquito oviposition site selection is essential for vector population dynamics and malaria epidemiology. Irrigated rice cultivations provide ideal larval habitats for malaria mosquitoes, which has resulted in increased prevalence of the malaria vector, Anopheles arabiensis, in sub-Saharan Africa. The nature and origin of the cues regulating this behaviour are only now being elucidated. We show that gravid Anopheles arabiensis are attracted and oviposit in response to the odour present in the air surrounding rice. Furthermore, we identify a synthetic rice odour blend, using electrophysiological and chemical analyses, which elicits attraction and oviposition in laboratory assays, as well as attraction of free-flying gravid mosquitoes under semi-field conditions. This research highlights the intimate link between malaria vectors and agriculture. The identified volatile cues provide important substrates for the development of novel and cost-effective control measures that target female malaria mosquitoes, irrespective of indoor or outdoor feeding and resting patterns. PMID:27901056

  18. 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

  19. DNA from pre-erythrocytic stage malaria parasites is detectable by PCR in the faeces and blood of hosts.

    PubMed

    Abkallo, Hussein M; Liu, Weimin; Hokama, Sarina; Ferreira, Pedro E; Nakazawa, Shusuke; Maeno, Yoshimasa; Quang, Nguyen T; Kobayashi, Nobuyuki; Kaneko, Osamu; Huffman, Michael A; Kawai, Satoru; Marchand, Ron P; Carter, Richard; Hahn, Beatrice H; Culleton, Richard

    2014-06-01

    Following the bite of an infective mosquito, malaria parasites first invade the liver where they develop and replicate for a number of days before being released into the bloodstream where they invade red blood cells and cause disease. The biology of the liver stages of malaria parasites is relatively poorly understood due to the inaccessibility of the parasites to sampling during this phase of their life cycle. Here we report the detection in blood and faecal samples of malaria parasite DNA throughout their development in the livers of mice and before the parasites begin their growth in the blood circulation. It is shown that parasite DNA derived from pre-erythrocytic stage parasites reaches the faeces via the bile. We then show that different primate malaria species can be detected by PCR in blood and faecal samples from naturally infected captive macaque monkeys. These results demonstrate that pre-erythrocytic parasites can be detected and quantified in experimentally infected animals. Furthermore, these results have important implications for both molecular epidemiology and phylogenetics of malaria parasites. In the former case, individuals who are malaria parasite negative by microscopy, but PCR positive for parasite DNA in their blood, are considered to be "sub-microscopic" blood stage parasite carriers. We now propose that PCR positivity is not necessarily an indicator of the presence of blood stage parasites, as the DNA could derive from pre-erythrocytic parasites. Similarly, in the case of molecular phylogenetics based on DNA sequences alone, we argue that DNA amplified from blood or faeces does not necessarily come from a parasite species that infects the red blood cells of that particular host.

  20. Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria

    PubMed Central

    White, Nicholas J.; Duong, Tran T.; Uthaisin, Chirapong; Nosten, François; Phyo, Aung P.; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chuthasmit, Kittiphum; Cheung, Ming S.; Feng, Yiyan; Li, Ruobing; Magnusson, Baldur; Sultan, Marc; Wieser, Daniela; Xun, Xiaolei; Zhao, Rong; Diagana, Thierry T.; Pertel, Peter; Leong, F. Joel

    2016-01-01

    Background KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. Methods We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). Results Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. Conclusions KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P

  1. [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.

  2. The first field trials of the chemically synthesized malaria vaccine SPf66: safety, immunogenicity and protectivity.

    PubMed

    Amador, R; Moreno, A; Valero, V; Murillo, L; Mora, A L; Rojas, M; Rocha, C; Salcedo, M; Guzman, F; Espejo, F

    1992-01-01

    This paper reports the results of the first field study performed to assess the safety, immunogenicity and protectivity of the synthetic malaria vaccine SPf66 directed against the asexual blood stages of Plasmodium falciparum. Clinical and laboratory tests were performed on all volunteers prior to and after each immunization, demonstrating that no detectable alteration was induced by the immunization process. The vaccines were grouped as high, intermediate or low responders according to their antibody titres directed against the SPf66 molecule. Two of the 185 (1.08%) SPf66-vaccinated and nine of the 214 (4.20%) placebo-vaccinated volunteers developed P. falciparum malaria. The efficacy of the vaccine was calculated as 82.3% against P. falciparum and 60.6% against Plasmodium vivax.

  3. 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

  4. B and T lymphocyte attenuator restricts the protective immune response against experimental malaria.

    PubMed

    Adler, Guido; Steeg, Christiane; Pfeffer, Klaus; Murphy, Theresa L; Murphy, Kenneth M; Langhorne, Jean; Jacobs, Thomas

    2011-11-15

    The immune response against the blood stage of malaria has to be tightly regulated to allow for vigorous antiplasmodial activity while restraining potentially lethal immunopathologic damage to the host like cerebral malaria. Coinhibitory cell surface receptors are important modulators of immune activation. B and T lymphocyte attenuator (BTLA) (CD272) is a coinhibitory receptor expressed by most leukocytes, with the highest expression levels on T and B cells, and is involved in the maintenance of peripheral tolerance by dampening the activation of lymphocytes. The function of BTLA is described in several models of inflammatory disorders and autoimmunity, but its function in infectious diseases is less well characterized. Also, little is known about the influence of BTLA on non-T cells. In this study, we analyzed the function of BTLA during blood-stage malaria infection with the nonlethal Plasmodium yoelii strain 17NL. We show that BTLA knockout mice exhibit strongly reduced parasitemia and clear the infection earlier compared with wild-type mice. This increased resistance was seen before the onset of adaptive immune mechanisms and even in the absence of T and B cells but was more pronounced at later time points when activation of T and B cells was observed. We demonstrate that BTLA regulates production of proinflammatory cytokines in a T cell-intrinsic way and B cell intrinsically regulates the production of P. yoelii 17NL-specific Abs. These results indicate that the coinhibitory receptor BTLA plays a critical role during experimental malaria and attenuates the innate as well as the subsequent adaptive immune response.

  5. MALARIA RESEARCH PROGRAM.

    DTIC Science & Technology

    Analytical clinical summaries are presented on the following: Summary and analysis of therapeutic effect of new drugs in human volunteers with...Falciparum Malaria; Summary and analysis of therapeutic effect of new drugs in human volunteers with Vivax Malaria; Potentiation by drug combination...Problems of resistance for both old and new drugs ; Analysis of P. berghei infections; Studies on mechanisms of drug action; Cumulative summary of all new drug trials.

  6. Malaria in pregnancy.

    PubMed

    Alvarez, Jesus R; Al-Khan, Abdulla; Apuzzio, Joseph J

    2005-12-01

    Recently, there has been a resurgence of malaria in densely populated areas of the United States secondary to human migration from endemic areas where factors such as cessation of vector control, vector resistance to insecticides, disease resistance to drugs, environmental changes, political instability, and indifference, have played a role for malaria becoming an overwhelming infection of these tropical underdeveloped countries. It is important for health care providers of gravida to be alert of the disease and its effects on pregnancy.

  7. 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.

  8. 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

  9. Epidemiological risk stratification of malaria in the Americas.

    PubMed

    Castillo-Salgado, C

    1992-01-01

    During the last years, malaria had a significant increase in Latin America, emerging again as one critical health problem in the Region of the Americas. More than 1.04 million new cases were reported in 1990. This resurgence of malaria needed a comprehensive strategy for its prevention and control. National malaria control programs recognized the epidemiological stratification of malaria as a valuable method to assist them in the recognition of local variations and factors that specifically contribute to the level and intensity of transmission in critical malarious areas. Also it serves as a useful instrument for the selection of needed malaria prevention and control activities. The principal feature of this approach is to provide a dynamic and ongoing process for assessing the epidemiological importance of different risk factors (socio-economic, ecological, organization of health services) in malaria transmission. Health interventions are based on this assessment and are aimed directly at the reduction or elimination of the identified risk factors operating at the local level. Intersectorial co-participation and the integration of malaria programs in local health services are also important aspects of this public health approach.

  10. 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.

  11. 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

  12. [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.

  13. Standardization in generating and reporting genetically modified rodent malaria parasites: the RMgmDB database.

    PubMed

    Khan, Shahid M; Kroeze, Hans; Franke-Fayard, Blandine; Janse, Chris J

    2013-01-01

    Genetically modified Plasmodium parasites are central gene function reagents in malaria research. The Rodent Malaria genetically modified DataBase (RMgmDB) ( www.pberghei.eu ) is a manually curated Web - based repository that contains information on genetically modified rodent malaria parasites. It provides easy and rapid access to information on the genotype and phenotype of genetically modified mutant and reporter parasites. Here, we provide guidelines for generating and describing rodent malaria parasite mutants. Standardization in describing mutant genotypes and phenotypes is important not only to enhance publication quality but also to facilitate cross-linking and mining data from multiple sources, and should permit information derived from mutant parasites to be used in integrative system biology approaches. We also provide guidelines on how to submit information to RMgmDB on non-published mutants, mutants that do not exhibit a clear phenotype, as well as negative attempts to disrupt/mutate genes. Such information helps to prevent unnecessary duplication of experiments in different laboratories, and can provide indirect evidence that these genes are essential for blood-stage development.

  14. Gut microbes influence fitness and malaria transmission potential of Asian malaria vector Anopheles stephensi.

    PubMed

    Sharma, Anil; Dhayal, Devender; Singh, O P; Adak, T; Bhatnagar, Raj K

    2013-10-01

    The midgut of parasite transmitting vector, Anopheles stephensi is a physiologically dynamic ecological niche of resident microbes. The gut resident microbes of anisomorphic and physiologically variable male and female A. stephensi mosquitoes were different (Rani et al., 2009). To understand the possible interaction of gut microbes and mosquito host, we examined the contribution of the microbe community on the fitness of the adult mosquitoes and their ability to permit development of the malaria parasite. A. stephensi mosquitoes were fed with antibiotic to sterilize their gut to study longevity, blood meal digestion, egg laying and maturation capacity, and consequently ability to support malaria parasite development. The sterilization of gut imparted reduction in longevity by a median of 5 days in male and 2 days in female mosquitoes. Similarly, the sterilization also diminished the reproductive potential probably due to increased rate of the resorption of follicles in ovaries coupled with abated blood meal digestion in gut-sterilized females. Additionally, gut sterilization also led to increased susceptibility to oocyst development upon feeding on malaria infected blood. The susceptibility to malaria parasite introduced upon gut sterilization of A. stephensi was restored completely upon re-colonization of gut by native microbes. The information provided in the study provides insights into the role of the gut-resident microbial community in various life events of the mosquito that may be used to develop alternate malaria control strategies, such as paratransgenesis.

  15. 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

  16. A central role for free heme in the pathogenesis of severe malaria: the missing link?

    PubMed

    Ferreira, Ana; Balla, József; Jeney, Viktória; Balla, György; Soares, Miguel P

    2008-10-01

    Malaria, the disease caused by Plasmodium infection, is endemic to poverty in so-called underdeveloped countries. Plasmodium falciparum, the main infectious Plasmodium species in sub-Saharan countries, can trigger the development of severe malaria, including cerebral malaria, a neurological syndrome that claims the lives of more than one million children (<5 years old) per year. Attempts to eradicate Plasmodium infection, and in particular its lethal outcomes, have so far been unsuccessful. Using well-established rodent models of malaria infection, we found that survival of a Plasmodium-infected host is strictly dependent on the host's ability to up-regulate the expression of heme oxygenase-1 (HO-1 encoded by the gene Hmox1). HO-1 is a stress-responsive enzyme that catabolizes free heme into biliverdin, via a reaction that releases Fe and generates the gas carbon monoxide (CO). Generation of CO through heme catabolism by HO-1 prevents the onset of cerebral malaria. The protective effect of CO is mediated via its binding to cell-free hemoglobin (Hb) released from infected red blood cells during the blood stage of Plasmodium infection. Binding of CO to cell-free Hb prevents heme release and thus generation of free heme, which we found to play a central role in the pathogenesis of cerebral malaria. We will address hereby how defense mechanisms that prevent the deleterious effects of free heme, including the expression of HO-1, impact on the pathologic outcome of Plasmodium infection and how these may be used therapeutically to suppress its lethal outcomes.

  17. 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

    2014-03-04

    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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. Malaria: Biology and Disease.

    PubMed

    Cowman, Alan F; Healer, Julie; Marapana, Danushka; Marsh, Kevin

    2016-10-20

    Malaria has been a major global health problem of humans through history and is a leading cause of death and disease across many tropical and subtropical countries. Over the last fifteen years renewed efforts at control have reduced the prevalence of malaria by over half, raising the prospect that elimination and perhaps eradication may be a long-term possibility. Achievement of this goal requires the development of new tools including novel antimalarial drugs and more efficacious vaccines as well as an increased understanding of the disease and biology of the parasite. This has catalyzed a major effort resulting in development and regulatory approval of the first vaccine against malaria (RTS,S/AS01) as well as identification of novel drug targets and antimalarial compounds, some of which are in human clinical trials.

  3. Imported malaria in Kuwait.

    PubMed

    Hira, P R; Behbehani, K; Al-Kandari, S

    1985-01-01

    The number of imported malaria cases in Kuwait rose from 87 in 1980 to 504 in 1983, an increase of 579%. The continued resurgence of malaria in endemic zones, improved diagnostic techniques and a heightened awareness of imported malaria have contributed to the increase in the number of microscopically proved cases. Thick blood films fixed in acetone and stained in Giemsa proved a rapid method of diagnosis; species identification on the basis of a thin film on the same slide was performed with ease. Malaria was acquired in 38 countries. Most patients were young male adults. Most of the cases were due to Plasmodium vivax originating from India, although an increasing number of P. falciparum cases are also now being diagnosed from there. P. falciparum infections were evenly distributed throughout the year and most cases presented within 14 days of their arrival in the country. The highest number of P. vivax cases were diagnosed between May and October, when heat stress might have been a factor in precipitating a clinical attack of an infection previously acquired in the endemic zone. Attention is drawn to the importance of delayed attacks of P. vivax and, in semi-immunes, of P. falciparum. The time interval involved in establishing a history of "recent" travel in clinically suspected cases of malaria needs to be more clearly defined in each geographical area. Cases of induced malaria due to transfusion, accidental and congenital infections were identified. The fatality rate due to P. falciparum infections was low. In terms of the risk of renewed transmission, Kuwait may be considered a vulnerable area.

  4. Metabolomics and malaria biology

    PubMed Central

    Lakshmanan, Viswanathan; Rhee, Kyu Y.; Daily, Johanna P.

    2010-01-01

    Metabolomics has ushered in a novel and multi-disciplinary realm in biological research. It has provided researchers with a platform to combine powerful biochemical, statistical, computational, and bioinformatics techniques to delve into the mysteries of biology and disease. The application of metabolomics to study malaria parasites represents a major advance in our approach towards gaining a more comprehensive perspective on parasite biology and disease etiology. This review attempts to highlight some of the important aspects of the field of metabolomics, and its ongoing and potential future applications to malaria research. PMID:20970461

  5. 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.

  6. A co-infection model of malaria and cholera diseases with optimal control.

    PubMed

    Okosun, K O; Makinde, O D

    2014-12-01

    In this paper we formulate a mathematical model for malaria-cholera co-infection in order to investigate their synergistic relationship in the presence of treatments. We first analyze the single infection steady states, calculate the basic reproduction number and then investigate the existence and stability of equilibria. We then analyze the co-infection model, which is found to exhibit backward bifurcation. The impact of malaria and its treatment on the dynamics of cholera is further investigated. Secondly, we incorporate time dependent controls, using Pontryagin's Maximum Principle to derive necessary conditions for the optimal control of the disease. We found that malaria infection may be associated with an increased risk of cholera but however, cholera infection is not associated with an increased risk for malaria. Therefore, to effectively control malaria, the malaria intervention strategies by policy makers must at the same time also include cholera control.

  7. Predicting Antidisease Immunity Using Proteome Arrays and Sera from Children Naturally Exposed to Malaria*

    PubMed Central

    Finney, Olivia C.; Danziger, Samuel A.; Molina, Douglas M.; Vignali, Marissa; Takagi, Aki; Ji, Ming; Stanisic, Danielle I.; Siba, Peter M.; Liang, Xiawu; Aitchison, John D.; Mueller, Ivo; Gardner, Malcolm J.; Wang, Ruobing

    2014-01-01

    Malaria remains one of the most prevalent and lethal human infectious diseases worldwide. A comprehensive characterization of antibody responses to blood stage malaria is essential to support the development of future vaccines, sero-diagnostic tests, and sero-surveillance methods. We constructed a proteome array containing 4441 recombinant proteins expressed by the blood stages of the two most common human malaria parasites, P. falciparum (Pf) and P. vivax (Pv), and used this array to screen sera of Papua New Guinea children infected with Pf, Pv, or both (Pf/Pv) that were either symptomatic (febrile), or asymptomatic but had parasitemia detectable via microscopy or PCR. We hypothesized that asymptomatic children would develop antigen-specific antibody profiles associated with antidisease immunity, as compared with symptomatic children. The sera from these children recognized hundreds of the arrayed recombinant Pf and Pv proteins. In general, responses in asymptomatic children were highest in those with high parasitemia, suggesting that antibody levels are associated with parasite burden. In contrast, symptomatic children carried fewer antibodies than asymptomatic children with infections detectable by microscopy, particularly in Pv and Pf/Pv groups, suggesting that antibody production may be impaired during symptomatic infections. We used machine-learning algorithms to investigate the relationship between antibody responses and symptoms, and we identified antibody responses to sets of Plasmodium proteins that could predict clinical status of the donors. Several of these antibody responses were identified by multiple comparisons, including those against members of the serine enriched repeat antigen family and merozoite protein 4. Interestingly, both P. falciparum serine enriched repeat antigen-5 and merozoite protein 4 have been previously investigated for use in vaccines. This machine learning approach, never previously applied to proteome arrays, can be used to

  8. Predicting antidisease immunity using proteome arrays and sera from children naturally exposed to malaria.

    PubMed

    Finney, Olivia C; Danziger, Samuel A; Molina, Douglas M; Vignali, Marissa; Takagi, Aki; Ji, Ming; Stanisic, Danielle I; Siba, Peter M; Liang, Xiawu; Aitchison, John D; Mueller, Ivo; Gardner, Malcolm J; Wang, Ruobing

    2014-10-01

    Malaria remains one of the most prevalent and lethal human infectious diseases worldwide. A comprehensive characterization of antibody responses to blood stage malaria is essential to support the development of future vaccines, sero-diagnostic tests, and sero-surveillance methods. We constructed a proteome array containing 4441 recombinant proteins expressed by the blood stages of the two most common human malaria parasites, P. falciparum (Pf) and P. vivax (Pv), and used this array to screen sera of Papua New Guinea children infected with Pf, Pv, or both (Pf/Pv) that were either symptomatic (febrile), or asymptomatic but had parasitemia detectable via microscopy or PCR. We hypothesized that asymptomatic children would develop antigen-specific antibody profiles associated with antidisease immunity, as compared with symptomatic children. The sera from these children recognized hundreds of the arrayed recombinant Pf and Pv proteins. In general, responses in asymptomatic children were highest in those with high parasitemia, suggesting that antibody levels are associated with parasite burden. In contrast, symptomatic children carried fewer antibodies than asymptomatic children with infections detectable by microscopy, particularly in Pv and Pf/Pv groups, suggesting that antibody production may be impaired during symptomatic infections. We used machine-learning algorithms to investigate the relationship between antibody responses and symptoms, and we identified antibody responses to sets of Plasmodium proteins that could predict clinical status of the donors. Several of these antibody responses were identified by multiple comparisons, including those against members of the serine enriched repeat antigen family and merozoite protein 4. Interestingly, both P. falciparum serine enriched repeat antigen-5 and merozoite protein 4 have been previously investigated for use in vaccines. This machine learning approach, never previously applied to proteome arrays, can be used to

  9. 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

  10. Clearance of Asymptomatic P. falciparum Infections Interacts with the Number of Clones to Predict the Risk of Subsequent Malaria in Kenyan Children

    PubMed Central

    Liljander, Anne; Bejon, Philip; Mwacharo, Jedidah; Kai, Oscar; Ogada, Edna; Peshu, Norbert; Marsh, Kevin; Färnert, Anna

    2011-01-01

    Background Protective immunity to malaria is acquired after repeated infections in endemic areas. Asymptomatic multiclonal P. falciparum infections are common and may predict host protection. Here, we have investigated the effect of clearing asymptomatic infections on the risk of clinical malaria. Methods Malaria episodes were continuously monitored in 405 children (1–6 years) in an area of moderate transmission, coastal Kenya. Blood samples collected on four occasions were assessed by genotyping the polymorphic P. falciparum merozoite surface protein 2 using fluorescent PCR and capillary electrophoresis. Following the second survey, asymptomatic infections were cleared with a full course of dihydroartemisinin. Results Children who were parasite negative by PCR had a lower risk of subsequent malaria regardless of whether treatment had been given. Children with ≥2 clones had a reduced risk of febrile malaria compared with 1 clone after clearance of asymptomatic infections, but not if asymptomatic infections were not cleared. Multiclonal infection was associated with an increased risk of re-infection after drug treatment. However, among the children who were re-infected, multiclonal infections were associated with a shift from clinical malaria to asymptomatic parasitaemia. Conclusion The number of clones was associated with exposure as well as blood stage immunity. These effects were distinguished by clearing asymptomatic infection with anti-malarials. Exposure to multiple P. falciparum infections is associated with protective immunity, but there appears to be an additional effect in untreated multiclonal infections that offsets this protective effect. PMID:21383984

  11. Nanomedicine against malaria.

    PubMed

    Urbán, Patricia; Fernàndez-Busquets, Xavier

    2014-01-01

    Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. Different types of encapsulating structure, targeting molecule, and antimalarial compound will be discussed for the assembly of Trojan horse nanocapsules capable of targeting with complete specificity diseased cells and of delivering inside them their antimalarial cargo with the objective of eliminating the parasite with a single dose. Nanotechnology can also be applied to the discovery of new antimalarials through single-molecule manipulation approaches for the identification of novel drugs targeting essential molecular components of the parasite. Finally, methods for the diagnosis of malaria can benefit from nanotools applied to the design of microfluidic-based devices for the accurate identification of the parasite's strain, its precise infective load, and the relative content of the different stages of its life cycle, whose knowledge is essential for the administration of adequate therapies. The benefits and drawbacks of these nanosystems will be considered in different possible scenarios, including cost-related issues that might be hampering the development of nanotechnology-based medicines against malaria with the dubious argument that they are too expensive to be used in developing areas.

  12. 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 ...

  13. Diagnosis and Treatment of Plasmodium vivax Malaria

    PubMed Central

    Baird, J. Kevin; Valecha, Neena; Duparc, Stephan; White, Nicholas J.; Price, Ric N.

    2016-01-01

    The diagnosis and treatment of Plasmodium vivax malaria differs from that of Plasmodium falciparum malaria in fundamentally important ways. This article reviews the guiding principles, practices, and evidence underpinning the diagnosis and treatment of P. vivax malaria. PMID:27708191

  14. 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.

  15. 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

    2016-03-31

    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.

  16. Disrupting Mosquito Reproduction and Parasite Development for Malaria Control

    PubMed Central

    Gabrieli, Paolo; Buckee, Caroline O.; Catteruccia, Flaminia

    2016-01-01

    The control of mosquito populations with insecticide treated bed nets and indoor residual sprays remains the cornerstone of malaria reduction and elimination programs. In light of widespread insecticide resistance in mosquitoes, however, alternative strategies for reducing transmission by the mosquito vector are urgently needed, including the identification of safe compounds that affect vectorial capacity via mechanisms that differ from fast-acting insecticides. Here, we show that compounds targeting steroid hormone signaling disrupt multiple biological processes that are key to the ability of mosquitoes to transmit malaria. When an agonist of the steroid hormone 20-hydroxyecdysone (20E) is applied to Anopheles gambiae females, which are the dominant malaria mosquito vector in Sub Saharan Africa, it substantially shortens lifespan, prevents insemination and egg production, and significantly blocks Plasmodium falciparum development, three components that are crucial to malaria transmission. Modeling the impact of these effects on Anopheles population dynamics and Plasmodium transmission predicts that disrupting steroid hormone signaling using 20E agonists would affect malaria transmission to a similar extent as insecticides. Manipulating 20E pathways therefore provides a powerful new approach to tackle malaria transmission by the mosquito vector, particularly in areas affected by the spread of insecticide resistance. PMID:27977810

  17. Model stimulations to estimate malaria risk under climate change.

    PubMed

    Jetten, T H; Martens, W J; Takken, W

    1996-05-01

    The current geographic range of malaria is much smaller than its potential range. In many regions there exists a phenomena characterized as "Anophelism without malaria." The vectors are present but malaria transmission does not occur. Vectorial capacity often has been used as a parameter to estimate the susceptibility of an area to malaria. Model computations with global climatological data show that a dynamic concept of vectorial capacity can be used as a comparative risk indicator to predict the current extent and distribution of malarious regions in the world. A sensitivity analysis done in 3 distinct geographic areas shows that the areas of largest change of epidemic potential caused by a temperature increase are those where mosquitoes already occur but where development of the parasite is limited by temperature. Computations with the model presented here predict, with different climate scenarios, an increased malaria risk in areas bordering malaria endemic regions and at higher altitudes within malarious regions under a temperature increase of 2-4 degrees C.

  18. Role of geographic information system in malaria control.

    PubMed

    Sharma, V P; Srivastava, A

    1997-08-01

    In this paper we provide an account of our experience in the application of remote sensing (RS) and geographic information system (GIS) in understanding malaria transmission dynamics at the local level. Two studies have been briefly reviewed. One is the application of RS on the mosquito production in the Sanjay lake and surrounding areas in Delhi. Studies are demonstrated that remote sensing data were useful in assessing relative mosquito abundance from large water bodies. The second study was carried out in Nadiad taluka, Kheda district, Gujarat on the application of RS and GIS in a village-wise analysis of receptivity and vulnerability to malaria. For this study, remote sensed data and topo sheets of 1:50,000 and 1:125,000 were used in preparing thematic maps. Digitised overlaid maps were subjected to computer analysis using ARC/INFO 3.1 software. Malaria annual parasite incidence (API) showed relationship with water table followed by soil type, irrigation and water quality, other parameters also contributed to malaria receptivity but less significantly. Based on GIS analysis location specific malaria control strategy was suggested to achieve cost effective control of malaria on a sustainable basis.

  19. Diagnostic approaches to malaria in Zambia, 2009-2014.

    PubMed

    Mukonka, Victor M; Chanda, Emmanuel; Kamuliwo, Mulakwa; Elbadry, Maha A; Wamulume, Pauline K; Mwanza-Ingwe, Mercy; Lubinda, Jailos; Laytner, Lindsey A; Zhang, Wenyi; Mushinge, Gabriel; Haque, Ubydul

    2015-06-03

    Malaria is an important health burden in Zambia with proper diagnosis remaining as one of the biggest challenges. The need for reliable diagnostics is being addressed through the introduction of rapid diagnostic tests (RDTs). However, without sufficient laboratory amenities in many parts of the country, diagnosis often still relies on non-specific, clinical symptoms. In this study, geographical information systems were used to both visualize and analyze the spatial distribution and the risk factors related to the diagnosis of malaria. The monthly reported, district-level number of malaria cases from January 2009 to December 2014 were collected from the National Malaria Control Center (NMCC). Spatial statistics were used to reveal cluster tendencies that were subsequently linked to possible risk factors, using a non-spatial regression model. Significant, spatio-temporal clusters of malaria were spotted while the introduction of RDTs made the number of clinically diagnosed malaria cases decrease by 33% from 2009 to 2014. The limited access to road network(s) was found to be associated with higher levels of malaria, which can be traced by the expansion of health promotion interventions by the NMCC, indicating enhanced diagnostic capability. The capacity of health facilities has been strengthened with the increased availability of proper diagnostic tools and through retraining of community health workers. To further enhance spatial decision support systems, a multifaceted approach is required to ensure mobilization and availability of human, infrastructural and technological resources. Surveillance based on standardized geospatial or other analytical methods should be used by program managers to design, target, monitor and assess the spatio-temporal dynamics of malaria diagnostic resources country-wide.

  20. Plasmodium vivax Malaria in Cambodia

    PubMed Central

    Siv, Sovannaroth; Roca-Feltrer, Arantxa; Vinjamuri, Seshu Babu; Bouth, Denis Mey; Lek, Dysoley; Rashid, Mohammad Abdur; By, Ngau Peng; Popovici, Jean; Huy, Rekol; Menard, Didier

    2016-01-01

    The Cambodian National Strategic Plan for Elimination of Malaria aims to move step by step toward elimination of malaria across Cambodia with an initial focus on Plasmodium falciparum malaria before achieving elimination of all forms of malaria, including Plasmodium vivax in 2025. The emergence of artemisinin-resistant P. falciparum in western Cambodia over the last decade has drawn global attention to support the ultimate goal of P. falciparum elimination, whereas the control of P. vivax lags much behind, making the 2025 target gradually less achievable unless greater attention is given to P. vivax elimination in the country. The following review presents in detail the past and current situation regarding P. vivax malaria, activities of the National Malaria Control Program, and interventional measures applied. Constraints and obstacles that can jeopardize our efforts to eliminate this parasite species are discussed. PMID:27708187

  1. Rapid diagnostic tests for malaria.

    PubMed

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

    2015-12-01

    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.

  2. 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

  3. Malaria in Pregnancy

    PubMed Central

    Takem, Ebako Ndip; D’Alessandro, Umberto

    2013-01-01

    Pregnant women have a higher risk of malaria compared to non-pregnant women. This review provides an update on knowledge acquired since 2000 on P. falciparum and P.vivax infections in pregnancy. Maternal risk factors for malaria in pregnancy (MiP) include low maternal age, low parity, and low gestational age. The main effects of MIP include maternal anaemia, low birth weight (LBW), preterm delivery and increased infant and maternal mortality. P. falciparum infected erythrocytes sequester in the placenta by expressing surface antigens, mainly variant surface antigen (VAR2CSA), that bind to specific receptors, mainly chondroitin sulphate A. In stable transmission settings, the higher malaria risk in primigravidae can be explained by the non-recognition of these surface antigens by the immune system. Recently, placental sequestration has been described also for P.vivax infections. The mechanism of preterm delivery and intrauterine growth retardation is not completely understood, but fever (preterm delivery), anaemia, and high cytokines levels have been implicated. Clinical suspicion of MiP should be confirmed by parasitological diagnosis. The sensitivity of microscopy, with placenta histology as the gold standard, is 60% and 45% for peripheral and placental falciparum infections in African women, respectively. Compared to microscopy, RDTs have a lower sensitivity though when the quality of microscopy is low RDTs may be more reliable. Insecticide treated nets (ITN) and intermittent preventive treatment in pregnancy (IPTp) are recommended for the prevention of MiP in stable transmission settings. ITNs have been shown to reduce malaria infection and adverse pregnancy outcomes by 28–47%. Although resistance is a concern, SP has been shown to be equivalent to MQ and AQ for IPTp. For the treatment of uncomplicated malaria during the first trimester, quinine plus clindamycin for 7 days is the first line treatment and artesunate plus clindamycin for 7 days is indicated if

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

    PubMed Central

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

    2015-01-01

    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

  5. 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

  6. 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.

  7. 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

  8. Development of the Regional Malaria Training Centre in Bandar-e Abbas, Islamic Republic of Iran.

    PubMed

    Vatandoost, H; Mesdaghinia, A R; Zamani, G; Madjdzadeh, R; Holakouie, K; Sadrizadeh, B; Atta, H; Beales, P F

    2004-01-01

    The resurgence of malaria has highlighted the need for training health professionals in malaria control planning. The course described here was organized jointly by the World Health Organization, the Ministry of Health and Medical Education and the School of Public Health in Iran. The first course was held in 1997 and the fifth WHO-approved course is now in progress. The course focuses on dynamic, interactive, practical and problem-solving learning methods. It provides the participants with the knowledge, skills, competence and confidence to be able to analyse the malaria problem. The course fulfils the requirements of the Roll Back Malaria campaign. In the 8-week training period subjects such as basic bio-statistics and epidemiology, microcomputing, malaria parasitology, malaria entomology, vector control, case management, epidemiological approach to malaria control, field work and planning for malaria control are taught. Each participant is evaluated in each subject. A total of 71 participants from 17 countries in the WHO African and Eastern Mediterranean Regions, mainly those with a malaria problem, have graduated.

  9. 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

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

    PubMed

    MacLeod, D A; Morse, A P

    2014-12-02

    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.

  11. 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

  12. Chemical attenuation of Plasmodium in the liver modulates severe malaria disease progression.

    PubMed

    Lewis, Matthew D; Behrends, Jochen; Sá E Cunha, Cláudia; Mendes, António M; Lasitschka, Felix; Sattler, Julia M; Heiss, Kirsten; Kooij, Taco W A; Prudêncio, Miguel; Bringmann, Gerhard; Frischknecht, Friedrich; Mueller, Ann-Kristin

    2015-05-15

    Cerebral malaria is one of the most severe complications of malaria disease, attributed to a complicated series of immune reactions in the host. The syndrome is marked by inflammatory immune responses, margination of leukocytes, and parasitized erythrocytes in cerebral vessels leading to breakdown of the blood-brain barrier. We show that chemical attenuation of the parasite at the very early, clinically silent liver stage suppresses parasite development, delays the time until parasites establish blood-stage infection, and provokes an altered host immune response, modifying immunopathogenesis and protecting from cerebral disease. The early response is proinflammatory and cell mediated, with increased T cell activation in the liver and spleen, and greater numbers of effector T cells, cytokine-secreting T cells, and proliferating, proinflammatory cytokine-producing T cells. Dendritic cell numbers, T cell activation, and infiltration of CD8(+) T cells to the brain are decreased later in infection, possibly mediated by the anti-inflammatory cytokine IL-10. Strikingly, protection can be transferred to naive animals by adoptive transfer of lymphocytes from the spleen at very early times of infection. Our data suggest that a subpopulation belonging to CD8(+) T cells as early as day 2 postinfection is responsible for protection. These data indicate that liver stage-directed early immune responses can moderate the overall downstream host immune response and modulate severe malaria outcome.

  13. 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.

  14. [Prophylaxis of malaria].

    PubMed

    Gentilini, M; Caumes, E; Danis, M

    1992-01-01

    The prevention of malaria is based on chemoprophylaxis and protection against the vector. Nocturnal mosquito bites can be avoided by individual and collective measures, while chemoprophylaxis involves the use of various agents according to the place and duration of stay. Three endemic zones can be defined on the basis of chemoresistance. Chloroquine, proguanil and mefloquine are the three drugs used in this setting, the latter being contraindicated for pregnant women and children. Travellers making long stays in areas of low-level chemoresistance and short stays in areas of high-level resistance and for whom mefloquine is contraindicated are advised to take antimalarial drugs at the first signs of potentially malarial fever when medical care is unavailable. Quinine, halofantrine and mefloquine are used for the curative treatment of malaria in areas of chloroquine resistance.

  15. Seroprevalence of Antibodies against Plasmodium falciparum Sporozoite Antigens as Predictive Disease Transmission Markers in an Area of Ghana with Seasonal Malaria Transmission

    PubMed Central

    Bosomprah, Samuel; Kyei-Baafour, Eric; Dickson, Emmanuel K.; Tornyigah, Bernard; Angov, Evelina; Dutta, Sheetij; Dodoo, Daniel; Sedegah, Martha; Koram, Kwadwo A.

    2016-01-01

    Introduction As an increasing number of malaria-endemic countries approach the disease elimination phase, sustenance of control efforts and effective monitoring are necessary to ensure success. Mathematical models that estimate anti-parasite antibody seroconversion rates are gaining relevance as more sensitive transmission intensity estimation tools. Models however estimate yearly seroconversion and seroreversion rates and usually predict long term changes in transmission, occurring years before the time of sampling. Another challenge is the identification of appropriate antigen targets since specific antibody levels must directly reflect changes in transmission patterns. We therefore investigated the potential of antibodies to sporozoite and blood stage antigens for detecting short term differences in malaria transmission in two communities in Northern Ghana with marked, seasonal transmission. Methods Cross-sectional surveys were conducted during the rainy and dry seasons in two communities, one in close proximity to an irrigation dam and the other at least 20 Km away from the dam. Antibodies against the sporozoite-specific antigens circumsporozoite protein (CSP) and Cell traversal for ookinetes and sporozoites (CelTOS) and the classical blood stage antigen apical membrane antigen 1 (AMA1) were measured by indirect ELISA. Antibody levels and seroprevalence were compared between surveys and between study communities. Antibody seroprevalence data were fitted to a modified reversible catalytic model to estimate the seroconversion and seroreversion rates. Results Changes in sporozoite-specific antibody levels and seroprevalence directly reflected differences in parasite prevalence between the rainy and dry seasons and hence the extent of malaria transmission. Seroconversion rate estimates from modelled seroprevalence data did not however support the above observation. Conclusions The data confirms the potential utility of sporozoite-specific antigens as useful markers

  16. 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

  17. [Malaria in hominids].

    PubMed

    Snounou, Georges; Escalante, Ananias; Kasenene, John; Rénia, Laurent; Grüner, Anne-Charlotte; Krief, Sabrina

    2011-11-01

    Malaria parasites (Plasmodium spp) that infect great apes are very poorly documented Malaria was first described in gorillas, chimpanzees and orangutans in the early 20th century, but most studies were confined to a handful of chimpanzees in the 1930-1950s and a few orangutans in the 1970s. The three Plasmodium species described in African great apes were very similar to those infecting humans. The most extensively studied was P reichenowi, because of its close phylogenetic relation to P. falciparum, the predominant parasite in Africa and the most dangerous for humans. In the last three years, independent molecular studies of various chimpanzee and gorilla populations have revealed an unexpected diversity in the Plasmodium species they harbor, which are also phylogenetically close to P falciparum. In addition, cases of non human primate infection by human malaria parasites have been observed. These observations shed fresh light on the origin and evolutionary history of P. falciparum and provide a unique opportunity to probe the biological specificities of this major human parasite.

  18. Malaria parasite clearance.

    PubMed

    White, Nicholas J

    2017-02-23

    Following anti-malarial drug treatment asexual malaria parasite killing and clearance appear to be first order processes. Damaged malaria parasites in circulating erythrocytes are removed from the circulation mainly by the spleen. Splenic clearance functions increase markedly in acute malaria. Either the entire infected erythrocytes are removed because of their reduced deformability or increased antibody binding or, for the artemisinins which act on young ring stage parasites, splenic pitting of drug-damaged parasites is an important mechanism of clearance. The once-infected erythrocytes returned to the circulation have shortened survival. This contributes to post-artesunate haemolysis that may follow recovery in non-immune hyperparasitaemic patients. As the parasites mature Plasmodium vivax-infected erythrocytes become more deformable, whereas Plasmodium falciparum-infected erythrocytes become less deformable, but they escape splenic filtration by sequestering in venules and capillaries. Sequestered parasites are killed in situ by anti-malarial drugs and then disintegrate to be cleared by phagocytic leukocytes. After treatment with artemisinin derivatives some asexual parasites become temporarily dormant within their infected erythrocytes, and these may regrow after anti-malarial drug concentrations decline. Artemisinin resistance in P. falciparum reflects reduced ring stage susceptibility and manifests as slow parasite clearance. This is best assessed from the slope of the log-linear phase of parasitaemia reduction and is commonly measured as a parasite clearance half-life. Pharmacokinetic-pharmacodynamic modelling of anti-malarial drug effects on parasite clearance has proved useful in predicting therapeutic responses and in dose-optimization.

  19. 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.

  20. Immunity to malaria in an era of declining malaria transmission.

    PubMed

    Fowkes, Freya J I; Boeuf, Philippe; Beeson, James G

    2016-02-01

    With increasing malaria control and goals of malaria elimination, many endemic areas are transitioning from high-to-low-to-no malaria transmission. Reductions in transmission will impact on the development of naturally acquired immunity to malaria, which develops after repeated exposure to Plasmodium spp. However, it is currently unclear how declining transmission and malaria exposure will affect the development and maintenance of naturally acquired immunity. Here we review the key processes which underpin this knowledge; the amount of Plasmodium spp. exposure required to generate effective immune responses, the longevity of antibody responses and the ability to mount an effective response upon re-exposure through memory responses. Lastly we identify research priorities which will increase our understanding of how changing transmission will impact on malarial immunity.

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. Identification of an Immunogenic Mimic of a Conserved Epitope on the Plasmodium falciparum Blood Stage Antigen AMA1 Using Virus-Like Particle (VLP) Peptide Display

    PubMed Central

    Crossey, Erin; Frietze, Kathryn; Narum, David L.; Peabody, David S.; Chackerian, Bryce

    2015-01-01

    We have developed a peptide display platform based on VLPs of the RNA bacteriophage MS2 that combines the high immunogenicity of VLP display with affinity selection capabilities. Random peptides can be displayed on the VLP surface by genetically inserting sequences into a surface-exposed loop of the viral coat protein. VLP-displayed peptides can then be isolated by selection using antibodies, and the VLP selectants can then be used directly as immunogens. Here, we investigated the ability of this platform to identify mimotopes of a highly conserved conformational epitope present on the Plasmodium falciparum blood-stage protein AMA1. Using 4G2, a monoclonal antibody that binds to this epitope and is a potent inhibitor of erythrocyte invasion, we screened three different VLP-peptide libraries and identified specific VLPs that bound strongly to the selecting mAb. We then tested the ability of a handful of selected VLPs to elicit anti-AMA1 antibody responses in mice. Most of the selected VLPs failed to reliably elicit AMA1 specific antibodies. However, one VLP consistently induced antibodies that cross-reacted with AMA1. Surprisingly, this VLP bound to 4G2 more weakly than the other selectants we identified. Taken together, these data demonstrate that VLP-peptide display can identify immunogenic mimics of a complex conformational epitope and illustrate the promise and challenges of this approach. PMID:26147502

  9. 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

  10. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs.

    PubMed

    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

    2015-05-20

    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 developing next-generation 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 (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative 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 Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is 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.

  11. Immune activation and induction of memory: lessons learned from controlled human malaria infection with Plasmodium falciparum.

    PubMed

    Scholzen, Anja; Sauerwein, Robert W

    2016-02-01

    Controlled human malaria infections (CHMIs) are a powerful tool to assess the efficacy of drugs and/or vaccine candidates, but also to study anti-malarial immune responses at well-defined time points after infection. In this review, we discuss the insights that CHMI trials have provided into early immune activation and regulation during acute infection, and the capacity to induce and maintain immunological memory. Importantly, these studies show that a single infection is sufficient to induce long-lasting parasite-specific T- and B-cell memory responses, and suggest that blood-stage induced regulatory responses can limit inflammation both in ongoing and potentially future infections. As future perspective of investigation in CHMIs, we discuss the role of innate cell subsets, the interplay between innate and adaptive immune activation and the potential modulation of these responses after natural pre-exposure.

  12. The effect of dams and seasons on malaria incidence and anopheles abundance in Ethiopia

    PubMed Central

    2013-01-01

    Background Reservoirs created by damming rivers are often believed to increase malaria incidence risk and/or stretch the period of malaria transmission. In this paper, we report the effects of a mega hydropower dam on P. falciparum malaria incidence in Ethiopia. Methods A longitudinal cohort study was conducted over a period of 2 years to determine Plasmodium falciparum malaria incidence among children less than 10 years of age living near a mega hydropower dam in Ethiopia. A total of 2080 children from 16 villages located at different distances from a hydropower dam were followed up from 2008 to 2010 using active detection of cases based on weekly house to house visits. Of this cohort of children, 951 (48.09%) were females and 1059 (51.91%) were males, with a median age of 5 years. Malaria vectors were simultaneously surveyed in all the 16 study villages. Frailty models were used to explore associations between time-to-malaria and potential risk factors, whereas, mixed-effects Poisson regression models were used to assess the effect of different covariates on anopheline abundance. Results Overall, 548 (26.86%) children experienced at least one clinical malaria episode during the follow up period with mean incidence rate of 14.26 cases/1000 child-months at risk (95% CI: 12.16 - 16.36). P. falciparum malaria incidence showed no statistically significant association with distance from the dam reservoir (p = 0.32). However, P. falciparum incidence varied significantly between seasons (p < 0.01). The malaria vector, Anopheles arabiensis, was however more abundant in villages nearer to the dam reservoir. Conclusions P. falciparum malaria incidence dynamics were more influenced by seasonal drivers than by the dam reservoir itself. The findings could have implications in timing optimal malaria control interventions and in developing an early warning system in Ethiopia. PMID:23566411

  13. 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

  14. 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.

  15. Seasonally dependent relationships between indicators of malaria transmission and disease provided by mathematical model simulations.

    PubMed

    Stuckey, Erin M; Smith, Thomas; Chitnis, Nakul

    2014-09-01

    Evaluating the effectiveness of malaria control interventions on the basis of their impact on transmission as well as impact on morbidity and mortality is becoming increasingly important as countries consider pre-elimination and elimination as well as disease control. Data on prevalence and transmission are traditionally obtained through resource-intensive epidemiological and entomological surveys that become difficult as transmission decreases. This work employs mathematical modeling to examine the relationships between malaria indicators allowing more easily measured data, such as routine health systems data on case incidence, to be translated into measures of transmission and other malaria indicators. Simulations of scenarios with different levels of malaria transmission, patterns of seasonality and access to treatment were run with an ensemble of models of malaria epidemiology and within-host dynamics, as part of the OpenMalaria modeling platform. For a given seasonality profile, regression analysis mapped simulation results of malaria indicators, such as annual average entomological inoculation rate, prevalence, incidence of uncomplicated and severe episodes, and mortality, to an expected range of values of any of the other indicators. Results were validated by comparing simulated relationships between indicators with previously published data on these same indicators as observed in malaria endemic areas. These results allow for direct comparisons of malaria transmission intensity estimates made using data collected with different methods on different indicators. They also address key concerns with traditional methods of quantifying transmission in areas of differing transmission intensity and sparse data. Although seasonality of transmission is often ignored in data compilations, the models suggest it can be critically important in determining the relationship between transmission and disease. Application of these models could help public health officials

  16. 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.

  17. Immunopathological effects of malaria pigment or hemozoin and other crystals.

    PubMed

    Tyberghein, Ariane; Deroost, Katrien; Schwarzer, Evelin; Arese, Paolo; Van den Steen, Philippe E

    2014-01-01

    Blood-stage malaria parasites produce insoluble hemozoin (Hz) crystals that are released in the blood circulation upon schizont rupture. In general, endogenous crystal formation or inhalation of crystalline materials is often associated with pathology. As the immune system responds differently to crystalline particles than to soluble molecules, in this review, the properties, immunological recognition, and pathogenic responses of Hz are discussed, and compared with two other major pathogenic crystals, monosodium urate (MSU) and asbestos. Because of the size and shape of MSU crystals and asbestos fibers, phagolysosomal formation is inefficient and often results in leakage of lysosomal content in the cell cytoplasm and/or in the extracellular environment with subsequent cell damage and cell death. Phagolysosomal formation after Hz ingestion is normal, but Hz remains stored inside these cells for months or even longer without any detectable degradation. Nonetheless, the different types of crystals are recognized by similar immune receptors, involving Toll-like receptors, the inflammasome, antibodies, and/or complement factors, and through similar signaling cascades, they activate both proinflammatory and anti-inflammatory immune responses that contribute to inflammation-associated pathology.

  18. Chemotherapy of Rodent Malaria.

    DTIC Science & Technology

    1985-07-01

    15 ML W_____ 1 .5 1.25 1-4 1. j . .. .... AD CHEMOTHERAPY OF RODENT MALARIA /I ’ IFINAL REPORT 00 WALLACE PETERS MD DSc I!JULY 1985 Supported by US...Table 15 and detailed report sheets are appended as Tables 16 through 21. 3.1.1 WR 251855 AA This lepidine, an analogue of primaquine, is very active...in our 15 preliminary test. The remaining three compounds also exhibited toxicity in varying degrees at this dose and, consequently, even the low level

  19. [Malaria--chemoprophylaxis 2001].

    PubMed

    Hatz, F R; Beck, B; Blum, J; Funk, M; Furrer, H; Genton, B; Holzer, B; Loutan, L; Markwalder, K; Raeber, P A; Schlagenhauf, P; Siegl, G; Steffen, R; Stürchler, D; Wyss, R

    2001-06-01

    An estimated 20,000 to 30,000 cases of imported malaria are annually diagnosed in industrialised countries. Some 700 of them concern Swiss travellers and foreign guests. Exposure prophylaxis and chemoprophylaxis for high risk destinations lower the risk of malarial disease. The latter is defined as regular intake of antimalarial drugs in subtherapeutic dosage in order to suppress the development of clinical disease. Drugs are usually taken from one week before travel until four weeks after return from an endemic area. Mefloquine, doxycycline, chloroquine plus proguanil, and presumably soon also atovaquone plus proguanil are available in Switzerland for chemoprophylaxis.

  20. [Fake malaria drugs].

    PubMed

    Bygbjerg, Ib Christian

    2009-03-02

    The literature on fake medicaments is sparse, even if approximately 15% of all medicaments are fake, a figure that for antimalarials in particular reaches 50% in parts of Africa and Asia. Sub-standard and fake medicines deplete the public's confidence in health systems, health professionals and in the pharmaceutical industry - and increase the risk that resistance develops. For a traveller coming from a rich Western country, choosing to buy e.g. preventive antimalarials over the internet or in poor malaria-endemic areas, the consequences may be fatal. International trade-, control- and police-collaboration is needed to manage the problem, as is the fight against poverty and poor governance.

  1. 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.

  2. 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

  3. Placental hypoxia during placental malaria

    PubMed Central

    Boeuf, Philippe; Tan, Aimee; Romagosa, Cleofe; Radford, Jane; Mwapasa, Victor; Molyneux, Malcolm E.; Meshnick, Steven R.; Hunt, Nicholas H.; Rogerson, Stephen J.

    2009-01-01

    Background Placental malaria causes fetal growth retardation (FGR), which has been linked epidemiologically to placental monocyte infiltrates. We investigated whether parasite or monocyte infiltrates were associated with placental hypoxia, as a potential mechanism underlying malarial FGR. Methods We studied the hypoxia markers hypoxia inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), placental growth factor, VEGF receptor 1 and its soluble form and VEGF receptor 2. We used real time PCR (in 59 women) to examine gene transcription, immunohistochemistry (in 30 women) to describe protein expression and laser capture microdissection (in 23 women) to examine syncytiotrophoblast-specific changes in gene expression. We compared gene and protein expression in relation to malaria infection, monocytes infiltrates and birth weight. Results we could not associate any hallmark of placental malaria with a transcription, expression or tissue distribution profile characteristic of a response to hypoxia but found higher HIF-1α (P=.0005) and lower VEGF levels (P=.0026) in the syncytiotrophoblast of malaria cases versus asymptomatic controls. Conclusion our data are inconsistent with a role for placental hypoxia in the pathogenesis of malaria-associated FGR. The laser capture microdissection study was small, but suggests that malaria affects syncytiotrophoblast gene transcription, and proposes novel potential mechanisms for placental malaria-associated FGR. PMID:18279052

  4. A rapid dipstick antigen capture assay for the diagnosis of falciparum malaria. WHO Informal Consultation on Recent Advances in Diagnostic Techniques and Vaccines for Malaria.

    PubMed Central

    1996-01-01

    Recent advances in the diagnosis of Plasmodium falciparum infections have made it possible to consider supplementing light microscopy with a standardized dipstick antigen capture assay based on the detection of a parasite-specific protein, which is secreted by the asexual blood stages and immature gametocytes but not by the other stages. Field trials indicate that this dipstick assay provides consistently reproducible results, with a threshold of detection of P. falciparum parasitaemia similar to that obtained by high quality routine malaria microscopy and a specificity and sensitivity of around 90% compared with standard thick blood film microscopy. The stability, reproducibility, and ease of use of the assay clearly indicate that it has potential for application in the management of malaria, particularly at the peripheral health care level, provided its accuracy can be assured and that it can be made affordable. Consideration should be given to its wider use where operational requirements and resources so justify, and where decisions are based on adequate evaluation of the existing health delivery systems. PMID:8653815

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. Malaria: new vaccines for old?

    PubMed

    Waters, Andrew

    2006-02-24

    Detailed analyses of the 5500 genes revealed by the complete Plasmodium genome sequence are yielding new candidate parasite antigens and strategies that may contribute to a successful vaccine against malaria in the coming decade.

  11. 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

    2014-01-02

    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.

  12. 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

  13. The March Toward Malaria Vaccines

    PubMed Central

    Hoffman, Stephen L.; Vekemans, Johan; Richie, Thomas L.; Duffy, Patrick E.

    2016-01-01

    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

  14. 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

  15. 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

  16. Variant Exported Blood-Stage Proteins Encoded by Plasmodium Multigene Families Are Expressed in Liver Stages Where They Are Exported into the Parasitophorous Vacuole

    PubMed Central

    Paraskevi Bechtsi, Dafni; Braks, Joanna A. M.; Annoura, Takeshi; Fonager, Jannik; Spaccapelo, Roberta; Ramesar, Jai; Chevalley-Maurel, Séverine; Klop, Onny; Tanke, Hans J.; Kocken, Clemens H. M.; Pasini, Erica M.; Khan, Shahid M.; Böhme, Ulrike; van Ooij, Christiaan; Otto, Thomas D.; Janse, Chris J.; Franke-Fayard, Blandine

    2016-01-01

    Many variant proteins encoded by Plasmodium-specific multigene families are exported into red blood cells (RBC). P. falciparum-specific variant proteins encoded by the var, stevor and rifin multigene families are exported onto the surface of infected red blood cells (iRBC) and mediate interactions between iRBC and host cells resulting in tissue sequestration and rosetting. However, the precise function of most other Plasmodium multigene families encoding exported proteins is unknown. To understand the role of RBC-exported proteins of rodent malaria parasites (RMP) we analysed the expression and cellular location by fluorescent-tagging of members of the pir, fam-a and fam-b multigene families. Furthermore, we performed phylogenetic analyses of the fam-a and fam-b multigene families, which indicate that both families have a history of functional differentiation unique to RMP. We demonstrate for all three families that expression of family members in iRBC is not mutually exclusive. Most tagged proteins were transported into the iRBC cytoplasm but not onto the iRBC plasma membrane, indicating that they are unlikely to play a direct role in iRBC-host cell interactions. Unexpectedly, most family members are also expressed during the liver stage, where they are transported into the parasitophorous vacuole. This suggests that these protein families promote parasite development in both the liver and blood, either by supporting parasite development within hepatocytes and erythrocytes and/or by manipulating the host immune response. Indeed, in the case of Fam-A, which have a steroidogenic acute regulatory-related lipid transfer (START) domain, we found that several family members can transfer phosphatidylcholine in vitro. These observations indicate that these proteins may transport (host) phosphatidylcholine for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites. PMID:27851824

  17. Microsatellite analysis of malaria parasites.

    PubMed

    Orjuela-Sánchez, Pamela; Brandi, Michelle C; Ferreira, Marcelo U

    2013-01-01

    Microsatellites have been increasingly used to investigate the population structure of malaria parasites, to map genetic loci contributing to phenotypes such as drug resistance and virulence in laboratory crosses and genome-wide association studies and to distinguish between treatment failures and new infections in clinical trials. Here, we provide optimized protocols for genotyping highly polymorphic microsatellites sampled from across the genomes of the human malaria parasites Plasmodium falciparum and P. vivax that have been extensively used in research laboratories worldwide.

  18. Blood Coagulation, Inflammation and Malaria

    PubMed Central

    Francischetti, Ivo M. B.; Seydel, Karl B.; Monteiro, Robson Q.

    2010-01-01

    I. ABSTRACT Malaria remains a highly prevalent disease in more than 90 countries and accounts for at least 1 million deaths every year. Plasmodium falciparum infection is often associated with a procoagulant tonus characterized by thrombocytopenia and activation of the coagulation cascade and fibrinolytic system; however, bleeding and hemorrhage are uncommon events, suggesting that a compensated state of blood coagulation activation occurs in malaria. This article i) reviews the literature related to blood coagulation and malaria in a historic perspective, ii) describes basic mechanisms of coagulation, anticoagulation, and fibrinolysis, iii) explains the laboratory changes in acute and compensated disseminated intravascular coagulation (DIC), iv) discusses the implications of tissue factor (TF) expression in the endothelium of P. falciparum-infected patients, and v) emphasizes the pro-coagulant role of parasitized erythrocytes (pRBC) and activated platelets in the pathogenesis of malaria. This article also presents the ‘Tissue Factor Model’ (TFM) for malaria pathogenesis, which places TF as the interface between sequestration, endothelial cell activation, blood coagulation disorder and inflammation often associated with the disease. The relevance of the coagulation-inflammation cycle for the multiorgan dysfunction and coma is discussed in the context of malaria pathogenesis. PMID:18260002

  19. [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.

  20. 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.

  1. Pulmonary pathology in pediatric cerebral malaria.

    PubMed

    Milner, Danny; Factor, Rachel; Whitten, Rich; Carr, Richard A; Kamiza, Steve; Pinkus, Geraldine; Molyneux, Malcolm; Taylor, Terrie

    2013-12-01

    Respiratory signs are common in African children where malaria is highly endemic, and thus, parsing the role of pulmonary pathology in illness is challenging. We examined the lungs of 100 children from an autopsy series in Blantyre, Malawi, many of whom death was attributed to Plasmodium falciparum malaria. Our aim was to describe the pathologic manifestations of fatal malaria; to understand the role of parasites, pigment, and macrophages; and to catalog comorbidities. From available patients, which included 55 patients with cerebral malaria and 45 controls, we obtained 4 cores of lung tissue for immunohistochemistry and morphological evaluation. We found that, in patients with cerebral malaria, large numbers of malaria parasites were present in pulmonary alveolar capillaries, together with extensive deposits of malaria pigment (hemozoin). The number of pulmonary macrophages in this vascular bed did not differ between patients with cerebral malaria, noncerebral malaria, and nonmalarial diagnoses. Comorbidities found in some cerebral malaria patients included pneumonia, pulmonary edema, hemorrhage, and systemic activation of coagulation. We conclude that the respiratory distress seen in patients with cerebral malaria does not appear to be anatomic in origin but that increasing malaria pigment is strongly associated with cerebral malaria at autopsy.

  2. The position of mefloquine as a 21st century malaria chemoprophylaxis

    PubMed Central

    2010-01-01

    Background Malaria chemoprophylaxis prevents the occurrence of the symptoms of malaria. Travellers to high-risk Plasmodium falciparum endemic areas need an effective chemoprophylaxis. Methods A literature search to update the status of mefloquine as a malaria chemoprophylaxis. Results Except for clearly defined regions with multi-drug resistance, mefloquine is effective against the blood stages of all human malaria species, including the recently recognized fifth species, Plasmodium knowlesi. New data were found in the literature on the tolerability of mefloquine and the use of this medication by groups at high risk of malaria. Discussion Use of mefloquine for pregnant women in the second and third trimester is sanctioned by the WHO and some authorities (CDC) allow the use of mefloquine even in the first trimester. Inadvertent pregnancy while using mefloquine is not considered grounds for pregnancy termination. Mefloquine chemoprophylaxis is allowed during breast-feeding. Studies show that mefloquine is a good option for other high-risk groups, such as long-term travellers, VFR travellers and families with small children. Despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare. A recent US evaluation of serious events (hospitalization data) found no association between mefloquine prescriptions and serious adverse events across a wide range of outcomes including mental disorders and diseases of the nervous system. As part of an in-depth analysis of mefloquine tolerability, a potential trend for increased propensity for neuropsychiatric adverse events in women was identified in a number of published clinical studies. This trend is corroborated by several cohort studies that identified female sex and low body weight as risk factors. Conclusion The choice of anti-malarial drug should be an evidence-based decision that considers the profile of the individual traveller and the risk of malaria. Mefloquine

  3. [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

  4. 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

  5. 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.

  6. Genetic Characterization of Plasmodium Putative Pantothenate Kinase Genes Reveals Their Essential Role in Malaria Parasite Transmission to the Mosquito.

    PubMed

    Hart, Robert J; Cornillot, Emmanuel; Abraham, Amanah; Molina, Emily; Nation, Catherine S; Ben Mamoun, Choukri; Aly, Ahmed S I

    2016-09-20

    The metabolic machinery for the biosynthesis of Coenzyme A (CoA) from exogenous pantothenic acid (Vitamin B5) has long been considered as an excellent target for the development of selective antimicrobials. Earlier studies in the human malaria parasite Plasmodium falciparum have shown that pantothenate analogs interfere with pantothenate phosphorylation and block asexual blood stage development. Although two eukaryotic-type putative pantothenate kinase genes (PanK1 and PanK2) have been identified in all malaria parasite species, their role in the development of Plasmodium life cycle stages remains unknown. Here we report on the genetic characterization of PanK1 and PanK2 in P. yoelii. We show that P. yoelii parasites lacking either PanK1 or PanK2 undergo normal asexual stages development and sexual stages differentiation, however they are severely deficient in ookinete, oocyst and sporozoite formation inside the mosquito vector. Quantitative transcriptional analyses in wild-type and knockout parasites demonstrate an important role for these genes in the regulation of expression of other CoA biosynthesis genes. Together, our data provide the first genetic evidence for the importance of the early steps of pantothenate utilization in the regulation of CoA biosynthesis and malaria parasite transmission to Anopheles mosquitoes.

  7. Genetic analysis in mice identifies cysteamine as a novel partner for artemisinin in the treatment of malaria.

    PubMed

    Min-Oo, Gundula; Gros, Philippe

    2011-08-01

    Malaria continues to be a serious threat to global health. The malaria problem is compounded by the absence of an efficacious vaccine and widespread drug resistance in the Plasmodium malarial parasite. The host factors and parasite virulence determinants that regulate early response to infection and subsequent onset of protective immunity are poorly understood. The molecular characterization of this early host:pathogen interface may identify novel targets for prophylactic or therapeutic intervention. Genetic analyses in mouse model of malaria show that inactivation of the enzyme pantetheinase (Char9 locus) causes susceptibility to blood-stage infection. The pantetheinase product cysteamine is an inexpensive and non-toxic aminothiol that is approved for lifelong clinical management of nephropathic cystinosis. In mouse models of infection, cysteamine not only displays anti-malarial activity of its own, but also dramatically potentiates the anti-malarial activity of artemisinin, at doses currently used for the clinical management of cystinosis. Therefore, the inclusion of cysteamine in current artemisinin combination therapies may significantly increase efficacy and may also prove effective against emerging artemisinin-resistant human Plasmodium parasite.

  8. Genetic Characterization of Plasmodium Putative Pantothenate Kinase Genes Reveals Their Essential Role in Malaria Parasite Transmission to the Mosquito

    PubMed Central

    Hart, Robert J.; Cornillot, Emmanuel; Abraham, Amanah; Molina, Emily; Nation, Catherine S.; Ben Mamoun, Choukri; Aly, Ahmed S. I.

    2016-01-01

    The metabolic machinery for the biosynthesis of Coenzyme A (CoA) from exogenous pantothenic acid (Vitamin B5) has long been considered as an excellent target for the development of selective antimicrobials. Earlier studies in the human malaria parasite Plasmodium falciparum have shown that pantothenate analogs interfere with pantothenate phosphorylation and block asexual blood stage development. Although two eukaryotic-type putative pantothenate kinase genes (PanK1 and PanK2) have been identified in all malaria parasite species, their role in the development of Plasmodium life cycle stages remains unknown. Here we report on the genetic characterization of PanK1 and PanK2 in P. yoelii. We show that P. yoelii parasites lacking either PanK1 or PanK2 undergo normal asexual stages development and sexual stages differentiation, however they are severely deficient in ookinete, oocyst and sporozoite formation inside the mosquito vector. Quantitative transcriptional analyses in wild-type and knockout parasites demonstrate an important role for these genes in the regulation of expression of other CoA biosynthesis genes. Together, our data provide the first genetic evidence for the importance of the early steps of pantothenate utilization in the regulation of CoA biosynthesis and malaria parasite transmission to Anopheles mosquitoes. PMID:27644319

  9. 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

  10. 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

    2015-12-29

    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.

  11. Malaria, photomicrograph of cellular parasites (image)

    MedlinePlus

    Malaria is a disease caused by parasites. This picture shows dark orange-stained malaria parasites inside red blood cells (a) and outside the cells (b). Note the large cells that look like targets; ...

  12. Malaria, microscopic view of cellular parasites (image)

    MedlinePlus

    Malaria is a disease caused by parasites that are carried by mosquitoes. Once in the bloodstream, the parasite inhabits the red blood cell (RBC). This picture shows purple-stained malaria parasites inside red blood cells.

  13. 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

  14. 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

  15. The influence of host genetics on erythrocytes and malaria infection: is there therapeutic potential?

    PubMed

    Lelliott, Patrick M; McMorran, Brendan J; Foote, Simon J; Burgio, Gaetan

    2015-07-29

    As parasites, Plasmodium species depend upon their host for survival. During the blood stage of their life-cycle parasites invade and reside within erythrocytes, commandeering host proteins and resources towards their own ends, and dramatically transforming the host cell. Parasites aptly avoid immune detection by minimizing the exposure of parasite proteins and removing themselves from circulation through cytoadherence. Erythrocytic disorders brought on by host genetic mutations can interfere with one or more of these processes, thereby providing a measure of protection against malaria to the host. This review summarizes recent findings regarding the mechanistic aspects of this protection, as mediated through the parasites interaction with abnormal erythrocytes. These novel findings include the reliance of the parasite on the host enzyme ferrochelatase, and the discovery of basigin and CD55 as obligate erythrocyte receptors for parasite invasion. The elucidation of these naturally occurring malaria resistance mechanisms is increasing the understanding of the host-parasite interaction, and as discussed below, is providing new insights into the development of therapies to prevent this disease.

  16. Type I IFN signaling in CD8– DCs impairs Th1-dependent malaria immunity

    PubMed Central

    Haque, Ashraful; Best, Shannon E.; Montes de Oca, Marcela; James, Kylie R.; Ammerdorffer, Anne; Edwards, Chelsea L.; de Labastida Rivera, Fabian; Amante, Fiona H.; Bunn, Patrick T.; Sheel, Meru; Sebina, Ismail; Koyama, Motoko; Varelias, Antiopi; Hertzog, Paul J.; Kalinke, Ulrich; Gun, Sin Yee; Rénia, Laurent; Ruedl, Christiane; MacDonald, Kelli P.A.; Hill, Geoffrey R.; Engwerda, Christian R.

    2014-01-01

    Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ–producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8– cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8– splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN–inducing pathogens. PMID:24789914

  17. The utility of Plasmodium berghei as a rodent model for anti-merozoite malaria vaccine assessment.

    PubMed

    Goodman, Anna L; Forbes, Emily K; Williams, Andrew R; Douglas, Alexander D; de Cassan, Simone C; Bauza, Karolis; Biswas, Sumi; Dicks, Matthew D J; Llewellyn, David; Moore, Anne C; Janse, Chris J; Franke-Fayard, Blandine M; Gilbert, Sarah C; Hill, Adrian V S; Pleass, Richard J; Draper, Simon J

    2013-01-01

    Rodent malaria species Plasmodium yoelii and P. chabaudi have been widely used to validate vaccine approaches targeting blood-stage merozoite antigens. However, increasing data suggest the P. berghei rodent malaria may be able to circumvent vaccine-induced anti-merozoite responses. Here we confirm a failure to protect against P. berghei, despite successful antibody induction against leading merozoite antigens using protein-in-adjuvant or viral vectored vaccine delivery. No subunit vaccine approach showed efficacy in mice following immunization and challenge with the wild-type P. berghei strains ANKA or NK65, or against a chimeric parasite line encoding a merozoite antigen from P. falciparum. Protection was not improved in knockout mice lacking the inhibitory Fc receptor CD32b, nor against a Δsmac P. berghei parasite line with a non-sequestering phenotype. An improved understanding of the mechanisms responsible for protection, or failure of protection, against P. berghei merozoites could guide the development of an efficacious vaccine against P. falciparum.

  18. Quantitation of malaria parasite-erythrocyte cell-cell interactions using optical tweezers.

    PubMed

    Crick, Alex J; Theron, Michel; Tiffert, Teresa; Lew, Virgilio L; Cicuta, Pietro; Rayner, Julian C

    2014-08-19

    Erythrocyte invasion by Plasmodium falciparum merozoites is an essential step for parasite survival and hence the pathogenesis of malaria. Invasion has been studied intensively, but our cellular understanding has been limited by the fact that it occurs very rapidly: invasion is generally complete within 1 min, and shortly thereafter the merozoites, at least in in vitro culture, lose their invasive capacity. The rapid nature of the process, and hence the narrow time window in which measurements can be taken, have limited the tools available to quantitate invasion. Here we employ optical tweezers to study individual invasion events for what we believe is the first time, showing that newly released P. falciparum merozoites, delivered via optical tweezers to a target erythrocyte, retain their ability to invade. Even spent merozoites, which had lost the ability to invade, retain the ability to adhere to erythrocytes, and furthermore can still induce transient local membrane deformations in the erythrocyte membrane. We use this technology to measure the strength of the adhesive force between merozoites and erythrocytes, and to probe the cellular mode of action of known invasion inhibitory treatments. These data add to our understanding of the erythrocyte-merozoite interactions that occur during invasion, and demonstrate the power of optical tweezers technologies in unraveling the blood-stage biology of malaria.

  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. 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.

  1. 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

  2. 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

  3. High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission.

    PubMed

    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

    2016-01-13

    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.

  4. 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

  5. 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.

  6. 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

  7. Rationalizing historical successes of malaria control in Africa in terms of mosquito resource availability management.

    PubMed

    Killeen, Gerry F; Seyoum, Aklilu; Knols, Bart G J

    2004-08-01

    Environmental management of mosquito resources is a promising approach with which to control malaria, but it has seen little application in Africa for more than half a century. Here we present a kinetic model of mosquito foraging for aquatic habitats and vertebrate hosts that allows estimation of malaria transmission intensity by defining the availability of these resources as the rate at which individual mosquitoes encounter and use them. The model captures historically observed responses of malaria transmission to environmental change, highlights important gaps in current understanding of vector ecology, and suggests convenient solutions. Resource availability is an intuitive concept that provides an adaptable framework for models of mosquito population dynamics, gene flow, and pathogen transmission that can be conveniently parameterized with direct field measurements. Furthermore, the model presented predicts that drastic reductions of malaria transmission are possible with environmental management and elucidates an ecologic basis for previous successes of integrated malaria control in Africa before the advent of DDT or chloroquine. Environmental management for malaria control requires specialist skills that are currently lacking in sub-Saharan Africa where they are needed most. Infrastructure and human capacity building in clinical, public health, and environmental disciplines should therefore be prioritized so that growing financial support for tackling malaria can be translated into truly integrated control programs.

  8. Conflict in Neighboring Countries, a Great Risk for Malaria Elimination in Southwestern Iran: Narrative Review Article

    PubMed Central

    MOLAEE ZADEH, Maryam; SHAHANDEH, Khandan; BIGDELI, Shahla; BASSERI, Hamid Reza

    2014-01-01

    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

  9. 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.

  10. [Lagoonal and coastal malaria at Cotonou: entomological findings].

    PubMed

    Akogbéto, M

    2000-01-01

    Nowadays, malaria control is planned according to the epidemiological context. Various aspects of malaria have been described in sub-Saharan Africa. We report here entomological data from the coastal area of Benin, West Africa, which has many lakes and lagoons. We carried out a longitudinal study in which we investigated the dynamics of populations of malaria vectors in various zones, the frequency of inoculation in these zones, the infestation rate of the Anopheles gambiae mosquitoes collected, the effect of urbanization on malaria transmission, the effects of inundation and of salinity at mosquito breeding sites. A total of 3, 342 identifications were made on a chromosomal basis. Two species of the Anopheles gambiae complex were detected in the coastal and lagoon areas of Benin: An. melas and An. gambiae ss. The density of the populations of these species was highly dependent on the level of urbanization. In traditional villages on the lagoons (such as Agbalilamè, Djegbadji and Kétonou), the density of An. melas (86. 2%) was much higher than that in more urbanized areas (such as Ladji and Abomey-Calavi) (4.9%). We checked for chromosome polymorphism. We detected a 2Rn1 inversion in An. melas, similar to the 2Rn inversion found in mosquitoes in Gambia and Guinea-Bissau. The frequency of the n1 inversion and the density of An. melas populations were correlated and both seemed to depend on a single factor, salinity. The epidemiological situation with respect to malaria was very heterogeneous in the lagoon area of Benin. In the city of Cotonou, transmission was seasonal, sporozoite indices and the frequency of inoculation were high, in contrast to what would normally be expected in an urban area. In communities built on the beach, the level of transmission was markedly lower: about 5 infected bites per person per year versus 29 infected bites per person in the center of the city. In the traditional fishing villages, a paradoxical situation was observed in which the

  11. Taking a Bite out of Malaria: Controlled Human Malaria Infection by Needle and Syringe

    DTIC Science & Technology

    2013-01-01

    2013 2. REPORT TYPE 3. DATES COVERED 00-00-2013 to 00-00-2013 4. TITLE AND SUBTITLE Taking a Bite out of Malaria : Controlled Human Malaria ...American Society of Tropical Medicine and Hygiene Editorial Taking a Bite out of Malaria : Controlled Human Malaria Infection by Needle and Syringe Judith E...organism malaria vaccine, regardless of whether the parasite is attenuated by radiation, genetic modification, or concurrent chemoprophy- laxis. The whole

  12. 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

  13. The economic and social burden of malaria.

    PubMed

    Sachs, Jeffrey; Malaney, Pia

    2002-02-07

    Where malaria prospers most, human societies have prospered least. The global distribution of per-capita gross domestic product shows a striking correlation between malaria and poverty, and malaria-endemic countries also have lower rates of economic growth. There are multiple channels by which malaria impedes development, including effects on fertility, population growth, saving and investment, worker productivity, absenteeism, premature mortality and medical costs.

  14. 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

  15. New guidelines on malaria prevention: A summary.

    PubMed

    Swales, Claire A; Chiodini, Peter L; Bannister, Barbara A

    2007-02-01

    Travellers to many tropical areas remain at risk of contracting malaria. Resistance of malaria parasites to a number of drugs continues to increase in degree and distribution, so that some older, trusted prophylactic drugs, such as chloroquine, are no longer useful in some parts of the world. Despite the introduction of new drugs and the reduction of malaria risk in some areas, such as parts of India, the number of people travelling continues to increase and malaria reports in the UK are not decreasing. New updated prevention guidelines from the Health Protection Agency Advisory Committee on Malaria Prevention (ACMP) in UK travellers (Chiodini P, Hill D, Lalloo D, Lea G, Walker E, Whitty C, et al. Guidelines for malaria prevention in travellers from the United Kingdom. London: Health Protection Agency; January 2007. Available from: http://www.hpa.org.uk/infections/topics_az/malaria/default.htm) aim to raise awareness of the risks of malaria and help UK travel health advisors in giving malaria prevention advice to all those who need it. Together with the ACMP malaria treatment guidelines it is hoped that the risk of illness and death from malaria in UK travellers can be reduced. This article summarises the new ACMP malaria prevention guidelines.

  16. Malaria transmission rates estimated from serological data.

    PubMed Central

    Burattini, M. N.; Massad, E.; Coutinho, F. A.

    1993-01-01

    A mathematical model was used to estimate malaria transmission rates based on serological data. The model is minimally stochastic and assumes an age-dependent force of infection for malaria. The transmission rates estimated were applied to a simple compartmental model in order to mimic the malaria transmission. The model has shown a good retrieving capacity for serological and parasite prevalence data. PMID:8270011

  17. 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.

  18. Vector control after malaria eradication

    PubMed Central

    Micks, D. W.

    1963-01-01

    In considerable areas now in or near the consolidation phase of malaria eradication, other vector-borne diseases present serious public health problems, even though not susceptible to control on the same world-wide scale as malaria. Several of these areas are already making plans for converting their malaria eradication services to vector control services. While it is possible to use essentially the same personnel and equipment, the methods must be adapted to the biology and habits of the vector. For a smooth and rapid transition, considerable advance planning is therefore needed—preferably well ahead of the consolidation phase. The author gives several examples of the need for flexibility in effecting the changeover and of the problems likely to arise after the completion of malaria eradication programmes. He recommends that epidemiological studies should be extended to vector-borne diseases other than malaria while eradication programmes are still in progress and that vector control programmes should be integrated into the basic health services of the country as soon as possible. He also underlines the importance of water management and other aspects of environmental sanitation in vector control programmes. PMID:20604169

  19. 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

  20. A simple pond parametrization for malaria transmission models

    NASA Astrophysics Data System (ADS)

    Tompkins, A. M.; Asare, E.; Amekudzi, L. K.

    2012-04-01

    In order to model malaria effectively using a dynamical modelling approach, a realistic representation of the surface hydrology is required. Achieving this goal is hindered by the fact that key vector breeding sites are small in spatial scale, ranging from small permanent ponds to temporary puddles. This small spatial scale confounds modelling efforts as the topography on such small scales is unknown, and also renders detection by remote sensing techniques difficult implying a requirement of in-situ measurements. Results from ongoing measurements of breeding sites in Kumasi (Ghana) are shown, along with attempts to reproduce these using a simple pond 'parametrization'. The significant impact of the pond model implementation and settings on malaria simulations using the new VECTRI dynamical disease model is demonstrated.

  1. Generation of Transgenic Rodent Malaria Parasites Expressing Human Malaria Parasite Proteins.

    PubMed

    Salman, Ahmed M; Mogollon, Catherin Marin; Lin, Jing-Wen; van Pul, Fiona J A; Janse, Chris J; Khan, Shahid M

    2015-01-01

    We describe methods for the rapid generation of transgenic rodent Plasmodium berghei (Pb) parasites that express human malaria parasite (HMP) proteins, using the recently developed GIMO-based transfection methodology. Three different genetic modifications are described resulting in three types of transgenic parasites. (1) Additional Gene (AG) mutants. In these mutants the HMP gene is introduced as an "additional gene" into a silent/neutral locus of the Pb genome under the control of either a constitutive or stage-specific Pb promoter. This method uses the GIMO-transfection protocol and AG mutants are generated by replacing the positive-negative selection marker (SM) hdhfr::yfcu cassette in a neutral locus of a standard GIMO mother line with the HMP gene expression cassette, resulting in SM free transgenic parasites. (2) Double-step Replacement (DsR) mutants. In these mutants the coding sequence (CDS) of the Pb gene is replaced with the CDS of the HMP ortholog in a two-step GIMO-transfection procedure. This process involves first the replacement of the Pb CDS with the hdhfr::yfcu SM, followed by insertion of the HMP ortholog at the same locus thereby replacing hdhfr::yfcu with the HMP CDS. These steps use the GIMO-transfection protocol, which exploits both positive selection for Pb orthologous gene-deletion and negative selection for HMP gene-insertion, resulting in SM free transgenic parasites. (3) Double-step Insertion (DsI) mutants. When a Pb gene is essential for blood stage development the DsR strategy is not possible. In these mutants the HMP expression cassette is first introduced into the neutral locus in a standard GIMO mother line as described for AG mutants but under the control elements of the Pb orthologous gene; subsequently, the Pb ortholog CDS is targeted for deletion through replacement of the Pb CDS with the hdhfr::yfcu SM, resulting in transgenic parasites with a new GIMO locus permissive for additional gene-insertion modifications.The different

  2. [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

  3. Exploiting the behaviour of wild malaria vectors to achieve high infection with fungal biocontrol agents

    PubMed Central

    2012-01-01

    Background Control of mosquitoes that transmit malaria has been the mainstay in the fight against the disease, but alternative methods are required in view of emerging insecticide resistance. Entomopathogenic fungi are candidate alternatives, but to date, few trials have translated the use of these agents to field-based evaluations of their actual impact on mosquito survival and malaria risk. Mineral oil-formulations of the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana were applied using five different techniques that each exploited the behaviour of malaria mosquitoes when entering, host-seeking or resting in experimental huts in a malaria endemic area of rural Tanzania. Results Survival of mosquitoes was reduced by 39-57% relative to controls after forcing upward house-entry of mosquitoes through fungus treated baffles attached to the eaves or after application of fungus-treated surfaces around an occupied bed net (bed net strip design). Moreover, 68 to 76% of the treatment mosquitoes showed fungal growth and thus had sufficient contact with fungus treated surfaces. A population dynamic model of malaria-mosquito interactions shows that these infection rates reduce malaria transmission by 75-80% due to the effect of fungal infection on adult mortality alone. The model also demonstrated that even if a high proportion of the mosquitoes exhibits outdoor biting behaviour, malaria transmission was still significantly reduced. Conclusions Entomopathogenic fungi strongly affect mosquito survival and have a high predicted impact on malaria transmission. These entomopathogens represent a viable alternative for malaria control, especially if they are used as part of an integrated vector management strategy. PMID:22449130

  4. 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

  5. WHO Expert Committee on Malaria. Seventeenth report.

    PubMed

    1979-01-01

    This publication consists of guidelines to assist health administrators and planners in planning, implementing, and evaluating malaria control programs that reflect the reorientation of the World Health Organization malaria control strategy endorsed by the World Health Assembly. The report stresses approaches to malaria control, describing the recent resurgence of malaria and present constraints on malaria control; prerequisites for implementation of the revised antimalaria strategy; objectives of a malaria control program; factors affecting planning of control programs including epidemiological factors related to the environment, man, the vector, and the parasite; socioeconomic factors; and the use of antimalaria measures in 4 different situations for reduction and prevention of mortality due to malaria, reduction and prevention of mortality and morbidity particularly in high risk groups, reduction of prevalence and endemicity of malaria, or countrywide malaria control aimed ultimately at eradication; program implementation, including definition of targets, interrelationship of the malaria services, general health services, and community, and program implementation in relation to each of the 4 tactical variants; and general principles, operational and epidemiological criteria, and socioeconomic indicators for program evaluation. Factors determining malaria epidemics, outbreaks of malaria during eradication or control campaigns, forecasting and detection of malaria epidemics, and control of epidemics are then discussed. Training in malaria control and advances in antimalaria measures including drugs, immunological methods, antimosquito measures, and biological and genetic approaches to vector control and their potential value are assessed. Program coordination between countries and at regional and global levels and data collection and dissemination for international surveillance are discussed. A series of recommendations is offered for various aspects of malaria

  6. 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

  7. Defining the protein interaction network of human malaria parasite Plasmodium falciparum.

    PubMed

    Ramaprasad, Abhinay; Pain, Arnab; Ravasi, Timothy

    2012-02-01

    Malaria, caused by the protozoan parasite Plasmodium falciparum, affects around 225 million people yearly and a huge international effort is directed towards combating this grave threat to world health and economic development. Considerable advances have been made in malaria research triggered by the sequencing of its genome in 2002, followed by several high-throughput studies defining the malaria transcriptome and proteome. A protein-protein interaction (PPI) network seeks to trace the dynamic interactions between proteins, thereby elucidating their local and global functional relationships. Experimentally derived PPI network from high-throughput methods such as yeast two hybrid (Y2H) screens are inherently noisy, but combining these independent datasets by computational methods tends to give a greater accuracy and coverage. This review aims to discuss the computational approaches used till date to construct a malaria protein interaction network and to catalog the functional predictions and biological inferences made from analysis of the PPI network.

  8. Effect of agricultural activities on prevalence rates, and clinical and presumptive malaria episodes in central Côte d'Ivoire.

    PubMed

    Koudou, Benjamin G; Tano, Yao; Keiser, Jennifer; Vounatsou, Penelope; Girardin, Olivier; Klero, Kouassi; Koné, Mamadou; N'goran, Eliézer K; Cissé, Guéladio; Tanner, Marcel; Utzinger, Jürg

    2009-09-01

    Agricultural activities, among other factors, can influence the transmission of malaria. In two villages of central Côte d'Ivoire (Tiémélékro and Zatta) with distinctively different agro-ecological characteristics, we assessed Plasmodium prevalence rates, fever and clinically confirmed malaria episodes among children aged 15 years and below by means of repeated cross-sectional surveys. Additionally, presumptive malaria cases were monitored in dispensaries for a 4-year period. In Tiémélékro, we observed a decrease in malaria prevalence rates from 2002 to 2005, which might be partially explained by changes in agricultural activities from subsistence farming to cash crop production. In Zatta, where an irrigated rice perimeter is located in close proximity to human habitations, malaria prevalence rates in 2003 were significantly lower than in 2002 and 2005, which coincided with the interruption of irrigated rice farming in 2003/2004. Although malaria transmission differed by an order of magnitude in the two villages in 2003, there was no statistically significant difference between the proportions of severe malaria episodes (i.e. axillary temperature>37.5 degrees C plus parasitaemia>5000 parasites/microl blood). Our study underscores the complex relationship between malaria transmission, prevalence rate and the dynamics of malaria episodes. A better understanding of local contextual determinants, including the effect of agricultural activities, will help to improve the local epidemiology and control of malaria.

  9. Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar.

    PubMed

    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; Cui, Liwang

    2015-02-01

    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.

  10. 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

  11. 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

  12. 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

  13. New malaria parasites of the subgenus Novyella in African rainforest birds, with remarks on their high prevalence, classification and diagnostics.

    PubMed

    Valkiūnas, Gediminas; Iezhova, Tatjana A; Loiseau, Claire; Smith, Thomas B; Sehgal, Ravinder N M

    2009-04-01

    Blood samples from 655 passerine birds were collected in rainforests of Ghana and Cameroon and examined both by microscopy and polymerase chain reaction (PCR)-based techniques. The overall prevalence of Plasmodium spp. was 46.6%, as determined by combining the results of both these diagnostic methods. In comparison to PCR-based diagnostics, microscopic examination of blood films was more sensitive in determining simultaneous infection of Plasmodium spp., but both detection methods showed similar trends of prevalence of malaria parasites in the same study sites. Plasmodium (Novyella) lucens n. sp., Plasmodium (Novyella) multivacuolaris n. sp. and Plasmodium (Novyella) parahexamerium n. sp. were found in the olive sunbird Cyanomitra olivacea (Nectariniidae), yellow-whiskered greenbul Andropadus latirostris (Picnonotidae), and white-tailed alethe Alethe diademata (Turdidae), respectively. These parasites are described based on the morphology of their blood stages and a segment of the mitochondrial cytochrome b (cyt b) gene, which can be used for molecular identification and diagnosis of these species. Illustrations of blood stages of new species are given, and phylogenetic analysis identifies DNA lineages closely related to these parasites. Malaria parasites of the subgenus Novyella with small erythrocytic meronts clearly predominate in African passerines. It is probable that the development of such meronts is a characteristic feature of evolution of Plasmodium spp. in African rainforest birds. Subgeneric taxonomy of avian Plasmodium spp. is discussed based on the recent molecular phylogenies of these parasites. It is concluded that a multi-genome phylogeny is needed before revising the current subgeneric classification of Plasmodium. We supported a hypothesis by Hellgren, Krizanauskiene, Valkiūnas, Bensch (J Parasitol 93:889-896, 2007), according to which, haemosporidian species with a genetic differentiation of over 5% in mitochondrial cyt b gene are expected to be

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. Malaria: prevention in travellers

    PubMed Central

    2010-01-01

    Introduction Malaria transmission occurs most frequently in environments with humidity greater than 60% and ambient temperature of 25 °C to 30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10 to 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 non-pregnant adult travellers? What are the effects of drug prophylaxis in non-pregnant adult travellers? What are the effects of antimalaria vaccines in adult and child 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 November 2009 (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 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone–proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), dietary supplementation, doxycycline, electronic mosquito repellents, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vapourising mats, primaquine, pyrimethamine–dapsone, pyrimethamine–sulfadoxine, smoke

  1. [Malaria in the Rostov Region: retrospective analysis of the malaria situation in 1952-2007].

    PubMed

    Kormilenko, I V; Aĭdinov, G T; Shvager, M M

    2009-01-01

    In the Rostov Region, no cases of local malaria transmission have been notified since 1958, but cases of import malaria are recorded every year. The region is one of malaria-susceptible areas in the Russian Federation, which is characterized by intensive migration, the malariogenic potential sufficient for local transmission (malariogenic index 1.2), and the optimum conditions for resurgence of malaria when it is imported. The prevention of undesirable consequences of malaria importation requires the strict monitoring of feverish patients, cohorts of high-risk patients who go for trips to malaria-endemic countries.

  2. Passive immunoprotection of Plasmodium falciparum-infected mice designates the CyRPA as candidate malaria vaccine antigen.

    PubMed

    Dreyer, Anita M; Matile, Hugues; Papastogiannidis, Petros; Kamber, Jolanda; Favuzza, Paola; Voss, Till S; Wittlin, Sergio; Pluschke, Gerd

    2012-06-15

    An effective malaria vaccine could prove to be the most cost-effective and efficacious means of preventing severe disease and death from malaria. In an endeavor to identify novel vaccine targets, we tested predicted Plasmodium falciparum open reading frames for proteins that elicit parasite-inhibitory Abs. This has led to the identification of the cysteine-rich protective Ag (CyRPA). CyRPA is a cysteine-rich protein harboring a predicted signal sequence. The stage-specific expression of CyRPA in late schizonts resembles that of proteins known to be involved in merozoite invasion. Immunofluorescence staining localized CyRPA at the apex of merozoites. The entire protein is conserved as shown by sequencing of the CyRPA encoding gene from a diverse range of P. falciparum isolates. CyRPA-specific mAbs substantially inhibited parasite growth in vitro as well as in a P. falciparum animal model based on NOD-scid IL2Rγ(null) mice engrafted with human erythrocytes. In contrast to other P. falciparum mouse models, this system generated very consistent results and evinced a dose-response relationship and therefore represents an unprecedented in vivo model for quantitative comparison of the functional potencies of malaria-specific Abs. Our data suggest a role for CyRPA in erythrocyte invasion by the merozoite. Inhibition of merozoite invasion by CyRPA-specific mAbs in vitro and in vivo renders this protein a promising malaria asexual blood-stage vaccine candidate Ag.

  3. Wheat Germ Cell-Free System-Based Production of Malaria Proteins for Discovery of Novel Vaccine Candidates▿ †

    PubMed Central

    Tsuboi, Takafumi; Takeo, Satoru; Iriko, Hideyuki; Jin, Ling; Tsuchimochi, Masateru; Matsuda, Shusaku; Han, Eun-Taek; Otsuki, Hitoshi; Kaneko, Osamu; Sattabongkot, Jetsumon; Udomsangpetch, Rachanee; Sawasaki, Tatsuya; Torii, Motomi; Endo, Yaeta

    2008-01-01

    One of the major bottlenecks in malaria research has been the difficulty in recombinant protein expression. Here, we report the application of the wheat germ cell-free system for the successful production of malaria proteins. For proof of principle, the Pfs25, PfCSP, and PfAMA1 proteins were chosen. These genes contain very high A/T sequences and are also difficult to express as recombinant proteins. In our wheat germ cell-free system, native and codon-optimized versions of the Pfs25 genes produced equal amounts of proteins. PfCSP and PfAMA1 genes without any codon optimization were also expressed. The products were soluble, with yields between 50 and 200 μg/ml of the translation mixture, indicating that the cell-free system can be used to produce malaria proteins without any prior optimization of their biased codon usage. Biochemical and immunocytochemical analyses of antibodies raised in mice against each protein revealed that every antibody retained its high specificity to the parasite protein in question. The development of parasites in mosquitoes fed patient blood carrying Plasmodium falciparum gametocytes and supplemented with our mouse anti-Pfs25 sera was strongly inhibited, indicating that both Pfs25-3D7/WG and Pfs25-TBV/WG retained their immunogenicity. Lastly, we carried out a parallel expression assay of proteins of blood-stage P. falciparum. The PCR products of 124 P. falciparum genes chosen from the available database were used directly in a small-scale format of transcription and translation reactions. Autoradiogram testing revealed the production of 93 proteins. The application of this new cell-free system-based protocol for the discovery of malaria vaccine candidates will be discussed. PMID:18268027

  4. Malaria: developing an action programme.

    PubMed

    Seadzi, G K; Nyonator, F K

    1995-03-01

    Malaria is the most common reason that people seek medical care in Ghana. This situation is taken for granted by the people, and there is no organized prevention effort. A World Health Organization-sponsored pilot malaria eradication program (1958-64) was abandoned after a peak period of activity in 1963 when vector control included indoor spraying with DDT. Recently there has been an upward trend in the incidence of malaria, with 15% of all cases becoming complicated. The main vector species are A. gambiae, A. melas, and A. funestus, and the predominant parasite species is Plasmodium falciparum. Treatment of choice is chloroquine phosphate, and although drug resistance has been suspected, it has not been documented. All health facilities are stretched to the limit with regard to the diagnosis and treatment of malaria. Field research is needed to provide a more accurate picture of the current situation. The clinical ability to deliver prompt diagnoses and treatment must be strengthened, and public health education must be instituted. The regional health management system must be improved, and personnel must be taught to use collected data. The use of bed nets, which is common in the south, should be encouraged, and impregnated nets should be introduced.

  5. Malaria parasite development in mosquitoes.

    PubMed

    Beier, J C

    1998-01-01

    Mosquitoes of the genus Anopheles transmit malaria parasites to humans. Anopheles mosquito species vary in their vector potential because of environmental conditions and factors affecting their abundance, blood-feeding behavior, survival, and ability to support malaria parasite development. In the complex life cycle of the parasite in female mosquitoes, a process termed sporogony, mosquitoes acquire gametocyte-stage parasites from blood-feeding on an infected host. The parasites carry out fertilization in the midgut, transform to ookinetes, then oocysts, which produce sporozoites. Sporozoites invade the salivary glands and are transmitted when the mosquito feeds on another host. Most individual mosquitoes that ingest gametocytes do not support development to the sporozoite stage. Bottle-necks occur at every stage of the cycle in the mosquito. Powerful new techniques and approaches exist for evaluating malaria parasite development and for identifying mechanisms regulating malaria parasite-vector interactions. This review focuses on those interactions that are important for the development of new approaches for evaluating and blocking transmission in nature.

  6. Malaria in Sucre State, Venezuela.

    PubMed

    Zimmerman, R H

    2000-01-01

    The author reviews the malaria research program in Sucre State, Venezuela, taking an ecosystem approach. The goal was to determine which methods could have been introduced at the onset that would have made the study more ecological and interdisciplinary. Neither an ecosystem approach nor integrated disease control were in place at the time of the study. This study began to introduce an ecosystem approach when two contrasting ecosystems in Sucre State were selected for study and vector control methods were implemented based on research results. The need to have a health policy in place with an eco-health approach is crucial to the success of research and control. The review suggests that sustainability is low when not all the stakeholders are involved in the design and implementation of the research and control strategy development. The lack of community involvement makes sustainability doubtful. The author concludes that there were two interdependent challenges for malaria control: development of an ecosystem approach for malaria research and control, and the implementation of an integrated disease control strategy, with malaria as one of the important health issues.

  7. Genetic Control Of Malaria Mosquitoes.

    PubMed

    McLean, Kyle Jarrod; Jacobs-Lorena, Marcelo

    2016-03-01

    Experiments demonstrating the feasibility of genetically modifying mosquito vectors to impair their ability to transmit the malaria parasite have been known for well over a decade. However, means to spread resistance or population control genes into wild mosquito populations remains an unsolved challenge. Two recent reports give hope that CRISPR technology may allow such challenge to be overcome.

  8. Microfluidic approaches to malaria detection.

    PubMed

    Gascoyne, Peter; Satayavivad, Jutamaad; Ruchirawat, Mathuros

    2004-02-01

    Microfluidic systems are under development to address a variety of medical problems. Key advantages of micrototal analysis systems based on microfluidic technology are the promise of small size and the integration of sample handling and measurement functions within a single, automated device having low mass-production costs. Here, we review the spectrum of methods currently used to detect malaria, consider their advantages and disadvantages, and discuss their adaptability towards integration into small, automated micro total analysis systems. Molecular amplification methods emerge as leading candidates for chip-based systems because they offer extremely high sensitivity, the ability to recognize malaria species and strain, and they will be adaptable to the detection of new genotypic signatures that will emerge from current genomic-based research of the disease. Current approaches to the development of chip-based molecular amplification are considered with special emphasis on flow-through PCR, and we present for the first time the method of malaria specimen preparation by dielectrophoretic field-flow-fractionation. Although many challenges must be addressed to realize a micrototal analysis system for malaria diagnosis, it is concluded that the potential benefits of the approach are well worth pursuing.

  9. 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

  10. 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...

  11. Genetic Control Of Malaria Mosquitoes

    PubMed Central

    McLean, Kyle Jarrod; Jacobs-Lorena, Marcelo

    2016-01-01

    Experiments demonstrating the feasibility of genetically modifying mosquito vectors to impair their ability to transmit the malaria parasite have been known for well over a decade. However, means to spread resistance or population control genes into wild mosquito populations remains an unsolved challenge. Two recent reports give hope that CRISPR technology may allow such challenge to be overcome. PMID:26809567

  12. Selection and identification of malaria vaccine target molecule using bioinformatics and DNA vaccination.

    PubMed

    Shuaibu, M N; Kikuchi, M; Cherif, M S; Helegbe, G K; Yanagi, T; Hirayama, K

    2010-10-04

    Following a genome-wide search for a blood stage malaria DNA-based vaccine using web-based bioinformatic tools, 29 genes from the annotated Plasmodium yoelii genome sequence (www.PlasmoDB.org and www.tigr.org) were identified as encoding GPI-anchored proteins. Target genes were those with orthologues in P. falciparum, containing an N-terminal signal sequence containing hydrophobic amino acid stretch and signal P criteria, a transmembrane-like domain and GPI anchor motif. Focusing on the blood stage, we extracted mRNA from pRBCs, PCR-amplified 22 out of the 29 selected genes, and eventually cloned nine of these into a DNA vaccine plasmid, pVAX 200-DEST. Biojector-mediated delivery of the nine DNA vaccines was conducted using ShimaJET to C57BL/6 mice at a dose of 4 μg/mouse three times at an interval of 3 weeks. Two weeks after the second booster, immunized mice were challenged with P. y. yoelii 17XL-parasitized RBCs and the level of parasitaemia, protection and survival was assessed. Immunization with one gene (PY03470) resulted in 2-4 days of delayed onset and level of parasitaemia and was associated with increased survival compared to non-immunized mice. Antibody production was, however, low following DNA vaccination, as determined by immunofluorescence assay. Recombinant protein from this gene, GPI8p transamidase-related protein (rPyTAM) in PBS or emulsified with GERBU adjuvant was also used to immunize another set of C57BL/6 mice with 10-20 μg/mouse three times at 3-week interval. Higher antibody response was obtained as determined by ELISA with similar protective effects as observed after DNA vaccination.

  13. Ethical aspects of malaria control and research.

    PubMed

    Jamrozik, Euzebiusz; de la Fuente-Núñez, Vânia; Reis, Andreas; Ringwald, Pascal; Selgelid, Michael J

    2015-12-22

    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.

  14. Genetic polymorphisms linked to susceptibility to malaria.

    PubMed

    Driss, Adel; Hibbert, Jacqueline M; Wilson, Nana O; Iqbal, Shareen A; Adamkiewicz, Thomas V; Stiles, Jonathan K

    2011-09-19

    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.

  15. 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

  16. Population Density, Climate Variables and Poverty Synergistically Structure Spatial Risk in Urban Malaria in India

    PubMed Central

    Santos-Vega, Mauricio; Bouma, Menno J; Kohli, Vijay; Pascual, Mercedes

    2016-01-01

    Background The world is rapidly becoming urban with the global population living in cities projected to double by 2050. This increase in urbanization poses new challenges for the spread and control of communicable diseases such as malaria. In particular, urban environments create highly heterogeneous socio-economic and environmental conditions that can affect the transmission of vector-borne diseases dependent on human water storage and waste water management. Interestingly India, as opposed to Africa, harbors a mosquito vector, Anopheles stephensi, which thrives in the man-made environments of cities and acts as the vector for both Plasmodium vivax and Plasmodium falciparum, making the malaria problem a truly urban phenomenon. Here we address the role and determinants of within-city spatial heterogeneity in the incidence patterns of vivax malaria, and then draw comparisons with results for falciparum malaria. Methodology/principal findings Statistical analyses and a phenomenological transmission model are applied to an extensive spatio-temporal dataset on cases of Plasmodium vivax in the city of Ahmedabad (Gujarat, India) that spans 12 years monthly at the level of wards. A spatial pattern in malaria incidence is described that is largely stationary in time for this parasite. Malaria risk is then shown to be associated with socioeconomic indicators and environmental parameters, temperature and humidity. In a more dynamical perspective, an Inhomogeneous Markov Chain Model is used to predict vivax malaria risk. Models that account for climate factors, socioeconomic level and population size show the highest predictive skill. A comparison to the transmission dynamics of falciparum malaria reinforces the conclusion that the spatio-temporal patterns of risk are strongly driven by extrinsic factors. Conclusion/significance Climate forcing and socio-economic heterogeneity act synergistically at local scales on the population dynamics of urban malaria in this city. The

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. Designing malaria vaccines to circumvent antigen variability.

    PubMed

    Ouattara, Amed; Barry, Alyssa E; Dutta, Sheetij; Remarque, Edmond J; Beeson, James G; Plowe, Christopher V

    2015-12-22

    Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines.

  4. Current therapies and prophylaxis of malaria.

    PubMed

    Ehrich, R

    1994-09-01

    Malaria is a potentially life-threatening disease. Although not commonplace in the United States, malaria cases are occurring more frequently due to an influx of military personnel returning from duty in malarious areas, increased numbers of immigrants, and tourist and business travel to endemic areas. Careful history taking and proper laboratory diagnosis are essential in detecting malaria. Malaria should be considered in the differential diagnosis with any fever of unknown origin. Due to the increase in chloroquine resistant P. falciparum malaria worldwide it behooves the clinician to keep abreast of current therapies in the treatment and prophylaxis of malaria. The Centers for Disease Control and Prevention is one of the best resources for up-to-date recommended therapies.

  5. 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.

  6. Molecular basis of human cerebral malaria development.

    PubMed

    Wah, Saw Thu; Hananantachai, Hathairad; Kerdpin, Usanee; Plabplueng, Chotiros; Prachayasittikul, Virapong; Nuchnoi, Pornlada

    2016-01-01

    Cerebral malaria is still a deleterious health problem in tropical countries. The wide spread of malarial drug resistance and the lack of an effective vaccine are obstacles for disease management and prevention. Parasite and human genetic factors play important roles in malaria susceptibility and disease severity. The malaria parasite exerted a potent selective signature on the human genome, which is apparent in the genetic polymorphism landscape of genes related to pathogenesis. Currently, much genomic data and a novel body of knowledge, including the identification of microRNAs, are being increasingly accumulated for the development of laboratory testing cassettes for cerebral malaria prevention. Therefore, understanding of the underlying complex molecular basis of cerebral malaria is important for the design of strategy for cerebral malaria treatment and control.

  7. Rapid diagnostic tests for malaria ---Haiti, 2010.

    PubMed

    2010-10-29

    Plasmodium falciparum malaria is endemic to Haiti and remains a major concern for residents, including displaced persons, and emergency responders in the aftermath of the January 12, 2010 earthquake. Microscopy has been the only test approved in the national policy for the diagnosis and management of malaria in Haiti; however, the use of microscopy often has been limited by lack of equipment or trained personnel. In contrast, malaria rapid diagnostic tests (RDTs) require less equipment or training to use. To assist in the timely diagnosis and treatment of malaria in Haiti, the Ministry of Public Health and Population (MSPP), in collaboration with CDC, conducted a field assessment that guided the decision to approve the use of RDTs. This data-driven policy change greatly expands the opportunities for accurate malaria diagnosis across the country, allows for improved clinical management of febrile patients, and will improve the quality of malaria surveillance in Haiti.

  8. 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

  9. 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

  10. A simple method for defining malaria seasonality

    PubMed Central

    2009-01-01

    Background There is currently no standard way of defining malaria seasonality, resulting in a wide range of definitions reported in the literature. Malaria cases show seasonal peaks in most endemic settings, and the choice and timing for optimal malaria control may vary by seasonality. A simple approach is presented to describe the seasonality of malaria, to aid localized policymaking and targeting of interventions. Methods A series of systematic literature reviews were undertaken to identify studies reporting on monthly data for full calendar years on clinical malaria, hospital admission with malaria and entomological inoculation rates (EIR). Sites were defined as having 'marked seasonality' if 75% or more of all episodes occurred in six or less months of the year. A 'concentrated period of malaria' was defined as the six consecutive months with the highest cumulative proportion of cases. A sensitivity analysis was performed based on a variety of cut-offs. Results Monthly data for full calendar years on clinical malaria, all hospital admissions with malaria, and entomological inoculation rates were available for 13, 18, and 11 sites respectively. Most sites showed year-round transmission with seasonal peaks for both clinical malaria and hospital admissions with malaria, with a few sites fitting the definition of 'marked seasonality'. For these sites, consistent results were observed when more than one outcome or more than one calendar year was available from the same site. The use of monthly EIR data was found to be of limited value when looking at seasonal variations of malaria transmission, particularly at low and medium intensity levels. Conclusion The proposed definition discriminated well between studies with 'marked seasonality' and those with less seasonality. However, a poor fit was observed in sites with two seasonal peaks. Further work is needed to explore the applicability of this definition on a wide-scale, using routine health information system data

  11. 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.

  12. [Research progress on malaria vector control].

    PubMed

    Zhu, Guo-Ding; Cao, Jun; Zhou, Hua-Yun; Gao, Qi

    2013-06-01

    Vector control plays a crucial role in the stages of malaria control and elimination. Currently, it mainly relies on the chemical control methods for adult mosquitoes in malaria endemic areas, however, it is undergoing the serious threat by insecticide resistance. In recent years, the transgenic technologies of malaria vectors have made a great progress in the laboratory. This paper reviews the challenges of the traditional methods and the rapid developed genetic modified technology in the application of vector control.

  13. 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

  14. Low autochtonous urban malaria in Antananarivo (Madagascar)

    PubMed Central

    Rabarijaona, Léon Paul; Ariey, Frédéric; Matra, Robert; Cot, Sylvie; Raharimalala, Andrianavalona Lucie; Ranaivo, Louise Henriette; Le Bras, Jacques; Robert, Vincent; Randrianarivelojosia, Milijaona

    2006-01-01

    Background The study of urban malaria is an area undergoing rapid expansion, after many years of neglect. The problem of over-diagnosis of malaria, especially in low transmission settings including urban areas, is also receiving deserved attention. The primary objective of the present study was to assess the frequency of malaria among febrile outpatients seen in private and public primary care facilities of Antananarivo. The second aim was to determine, among the diagnosed malaria cases, the contribution of autochthonous urban malaria. Methods Two cross-sectional surveys in 43 health centres in Antananarivo in February 2003 (rainy season) and in July 2003 (dry season) were conducted. Consenting clinically suspected malaria patients with fever or history of fever in the past 48 hours were included. Malaria rapid diagnostic tests and microscopy were used to diagnose malaria. Basic information was collected from patients to try to identify the origin of the infection: autochthonous or introduced. Results In February, among 771 patients, 15 (1.9%) positive cases were detected. Three malaria parasites were implicated: Plasmodium. falciparum (n = 12), Plasmodium vivax (n = 2) and Plasmodium. ovale (n = 1). Only two cases, both P. falciparum, were likely to have been autochthonous (0.26%). In July, among 739 blood smears examined, 11 (1.5%) were positive: P. falciparum (n = 9) and P. vivax (n = 2). Three cases of P. falciparum malaria were considered to be of local origin (0.4%). Conclusion This study demonstrates that malaria cases among febrile episodes are low in Antananarivo and autochthonous malaria cases exist but are rare. PMID:16573843

  15. '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.

  16. Adult and child malaria mortality in India

    PubMed Central

    Dhingra, Neeraj; Jha, Prabhat; Sharma, Vinod P; Cohen, Alan A; Jotkar, Raju M; Rodriguez, Peter S; Bassani, Diego G; Suraweera, Wilson; Laxminaryan, Ramanan; Peto, Richard

    2010-01-01

    Summary Background Malaria, a non-fatal disease if detected promptly and treated properly, still causes many deaths in malaria-endemic countries with limited healthcare facilities. National malaria mortality rates are, however, particularly difficult to assess reliably in such countries, as any fevers reliably diagnosed as malaria are likely therefore to be cured. Hence, most malaria deaths are from undiagnosed malaria, which may be misattributed in retrospective enquiries to other febrile causes of death, or vice-versa. Aim To estimate plausible ranges of malaria mortality in India, the most populous country where it remains common. Methods Nationally representative retrospective study of 122,000 deaths during 2001-03 in 6671 areas. Full-time non-medical field workers interviewed families or other respondents about each death, obtaining a half-page narrative plus answers to specific questions about the severity and course of any fevers. Each field report was scanned and emailed to two of 130 trained physicians, who independently coded underlying causes, with discrepancies resolved either via anonymous reconciliation or, failing that, adjudication. Findings Of all coded deaths at ages 1 month to 70 years, 3.6% (2681/75,342) were attributed to malaria. Of these, 2419 (90%) were rural and 2311 (86%) were not in any healthcare facility. Malaria-attributed death rates correlated geographically with local malaria transmission rates derived independently from the Indian malaria control programme, and rose after the wet season began. The adjudicated results suggest 205,000 malaria deaths per year in India before age 70 (55,000 in early childhood, 30,000 at ages 5-14, 120,000 at ages 15-69); cumulative probability 1.8% of death from malaria before age 70. Plausible upper and lower bounds (based only on the initial coding) were 125,000 to 277,000. Interpretation Despite inevitable uncertainty as to which unattended febrile deaths are from malaria, even the lower bound

  17. Implementation workshop of WHO guidelines on evaluation of malaria vaccines: Current regulatory concepts and issues related to vaccine quality, Pretoria, South Africa 07 Nov 2014.

    PubMed

    Ho, Mei Mei; Baca-Estrada, Maria; Conrad, Christoph; Karikari-Boateng, Eric; Kang, Hye-Na

    2015-08-26

    The current World Health Organization (WHO) guidelines on the quality, safety and efficacy of recombinant malaria vaccines targeting the pre-erythrocytic and blood stages of Plasmodium falciparum were adopted by the WHO Expert Committee on Biological Standardization in 2012 to provide guidance on the quality, nonclinical and clinical aspects of recombinant malaria vaccines. A WHO workshop was organised to facilitate implementation into African (national/regional) regulatory practices, of the regulatory evaluation principles outlined in the guidelines regarding quality aspects. The workshop was used also to share knowledge and experience on regulatory topics of chemistry, manufacturing and control with a focus on vaccines through presentations and an interactive discussion using a case study approach. The basic principles and concepts of vaccine quality including consistency of production, quality control and manufacturing process were presented and discussed in the meeting. By reviewing and practicing a case study, better understanding on the relationship between consistency of production and batch release tests of an adjuvanted pre-erythrocytic recombinant malaria vaccine was reached. The case study exercise was considered very useful to understand regulatory evaluation principles of vaccines and a suggestion was made to WHO to provide such practices also through its Global Learning Opportunities for Vaccine Quality programme.

  18. Nonobese Diabetic (NOD) Mice Lack a Protective B-Cell Response against the “Nonlethal” Plasmodium yoelii 17XNL Malaria Protozoan

    PubMed Central

    Mendoza, Mirian; Qiu, Qi; Casares, Sofia

    2016-01-01

    Background. Plasmodium yoelii 17XNL is a nonlethal malaria strain in mice of different genetic backgrounds including the C57BL/6 mice (I-Ab/I-Enull) used in this study as a control strain. We have compared the trends of blood stage infection with the nonlethal murine strain of P. yoelii 17XNL malaria protozoan in immunocompetent Nonobese Diabetic (NOD) mice prone to type 1 diabetes (T1D) and C57BL/6 mice (control mice) that are not prone to T1D and self-cure the P. yoelii 17XNL infection. Prediabetic NOD mice could not mount a protective antibody response to the P. yoelii 17XNL-infected red blood cells (iRBCs), and they all succumbed shortly after infection. Our data suggest that the lack of anti-P. yoelii 17XNL-iRBCs protective antibodies in NOD mice is a result of parasite-induced, Foxp3+ T regulatory (Treg) cells able to suppress the parasite-specific antibody secretion. Conclusions. The NOD mouse model may help in identifying new mechanisms of B-cell evasion by malaria parasites. It may also serve as a more accurate tool for testing antimalaria therapeutics due to the lack of interference with a preexistent self-curing mechanism present in other mouse strains. PMID:28074170

  19. [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.

  20. [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.

  1. 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.

  2. Cellular Immune Mechanisms in Malaria.

    DTIC Science & Technology

    1979-08-31

    secondary to the fragmented red cells rather than causative of an autoimmune hemolytic process (25,27). Finally, increased levels of auto-antibodies directed...there is suppressed antibody production, reduced severity of autoimmune disease, and increased susceptibility to tumor viruses (25). Secondly, there is...the immunopathologic effect of antigen-antibody complexes causing nephrotic disease in young children with P. malariae (26,27). Thirdly, anemia due to

  3. How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?

    PubMed Central

    Kay, Katherine

    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

  4. Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies

    PubMed Central

    de Souza, Nicolli Bellotti; de Andrade, Isabel M; Carneiro, Paula F; Jardim, Guilherme AM; de Melo, Isadora MM; da Silva, Eufrânio N; Krettli, Antoniana Ursine

    2014-01-01

    Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC50) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC50. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study. PMID:25099332

  5. Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies.

    PubMed

    de Souza, Nicolli Bellotti; de Andrade, Isabel M; Carneiro, Paula F; Jardim, Guilherme A M; de Melo, Isadora M M; da Silva Júnior, Eufrânio N; Krettli, Antoniana Ursine

    2014-08-01

    Due to the recent advances of atovaquone, a naphthoquinone, through clinical trials as treatment for malarial infection, 19 quinone derivatives with previously reported structures were also evaluated for blood schizonticide activity against the malaria parasite Plasmodium falciparum. These compounds include 2-hydroxy-3-methylamino naphthoquinones (2-9), lapachol (10), nor-lapachol (11), iso-lapachol (12), phthiocol (13) and phenazines (12-20). Their cytotoxicities were also evaluated against human hepatoma and normal monkey kidney cell lines. Compounds 2 and 5 showed the highest activity against P. falciparum chloroquine-resistant blood-stage parasites (clone W2), indicated by their low inhibitory concentration for 50% (IC50) of parasite growth. The therapeutic potential of the active compounds was evaluated according to the selectivity index, which is a ratio of the cytotoxicity minimum lethal dose which eliminates 50% of cells and the in vitro IC50. Naphthoquinones 2 and 5, with activities similar to the reference antimalarial chloroquine, were also active against malaria in mice and suppressed parasitaemia by more than 60% in contrast to compound 11 which was inactive. Based on their in vitro and in vivo activities, compounds 2 and 5 are considered promising molecules for antimalarial treatment and warrant further study.

  6. Role of IL-10-producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice.

    PubMed

    Liu, Yunfeng; Chen, Yue; Li, Zhaotao; Han, Yingli; Sun, Yanxia; Wang, Qiong; Liu, Boyu; Su, Zhong

    2013-11-01

    Cerebral malaria (CM) is a neurological syndrome often occurring in severe malaria. Although CM is known as an immunopathology in brain tissue mediated by excessive proinflammatory cytokines, the immunoregulatory mechanism is poorly understood. Here, we investigated the role of IL-10-producing regulatory B (Breg) cells in modulating CM development in a murine model of Plasmodium berghei ANKA infection. We observed that blood-stage P. berghei induced expansion of IL-10-producing Breg cells in C57BL/6 mice. Adoptive transfer of IL-10(+) Breg cells to P. berghei infected mice significantly reduced the accumulation of NK and CD8(+) T cells and hemorrhage in brain tissue, and improved the survival of the mice compared with control groups, although parasitemia levels were not altered. Treatment of Breg-cell recipient mice with anti-IL-10 receptor mAb blocked the protective effect of Breg cells. Adoptive transfer of CD4(+) CD25(+) Treg cells failed to prevent CM in infected mice. Spleen cells from Breg-cell recipient mice produced increased levels of IL-10 in vitro. Cell co-culture showed that purified IL-10(+) B cells, but not IL-10(-) B cells, promoted IL-10 production by CD4(+) T cells. These results demonstrate that IL-10-producing Breg cells may represent an important mechanism for controlling the immunopathology and prevention of CM associated with P. berghei infection.

  7. Minimal role for the circumsporozoite protein in the induction of sterile immunity by vaccination with live rodent malaria sporozoites.

    PubMed

    Mauduit, Marjorie; Tewari, Rita; Depinay, Nadya; Kayibanda, Michèle; Lallemand, Eliette; Chavatte, Jean-Marc; Snounou, Georges; Rénia, Laurent; Grüner, Anne Charlotte

    2010-05-01

    Immunization with live Plasmodium sporozoites under chloroquine prophylaxis (Spz plus CQ) induces sterile immunity against sporozoite challenge in rodents and, more importantly, in humans. Full protection is obtained with substantially fewer parasites than with the classic immunization with radiation-attenuated sporozoites. The sterile protection observed comprised a massive reduction in the hepatic parasite load and an additional effect at the blood stage level. Differences in the immune responses induced by the two protocols occur but are as yet little characterized. We have previously demonstrated that in mice immunized with irradiated sporozoites, immune responses against the circumsporozoite protein (CSP), the major component of the sporozoite's surface and the leading malaria vaccine candidate, were not essential for sterile protection. Here, we have employed transgenic Plasmodium berghei parasites in which the endogenous CSP was replaced by that of Plasmodium yoelii, another rodent malaria species, to assess the role of CSP in the sterile protection induced by the Spz-plus-CQ protocol. The data demonstrated that this role was minor because sterile immunity was obtained irrespective of the origin of CSP expressed by the parasites in this model of protection. The immunity was obtained through a single transient exposure of the host to the immunizing parasites (preerythrocytic and erythrocytic), a dose much smaller than that required for immunization with radiation-attenuated sporozoites.

  8. Antigenicity, immunogenicity, and protective efficacy of Plasmodium vivax MSP1 PV200l: a potential malaria vaccine subunit.

    PubMed

    Valderrama-Aguirre, Augusto; Quintero, Gustavo; Gómez, Andrés; Castellanos, Alejandro; Pérez, Yobana; Méndez, Fabián; Arévalo-Herrera, Myriam; Herrera, Sócrates

    2005-11-01

    The merozoite surface protein 1 (MSP-1) is expressed in all Plasmodium species and is considered a major malaria vaccine candidate. We found that MSP-1 from Plasmodium vivax (PvMSP-1) contains a region of significant sequence homology with the 190L subunit vaccine derived from the P. falciparum MSP-1. The fragment, termed Pv200L, was expressed as a recombinant protein in Escherichia coli (rPv200L) and used to asses its immunologic relevance as a vaccine target. A cross-sectional, seroepidemiologic study conducted in Buenaventura, Colombia showed that 52.2% (95% confidence interval [CI] = 39.8-64.3) of individuals previously exposed to P. vivax and 72.8% (95% CI = 61.8-82.1) of P. vivax-infected patients had IgG antibodies to rPv200L. Immunization of BALB/c mice and Aotus monkeys induced IgG antibodies (titer > 10(6)) that cross-reacted with P. vivax parasites. Immunized monkeys displayed partial protection against a challenge with P. vivax blood stages. Our results suggest that Pv200L is a new malaria vaccine subunit and deserves further testing.

  9. A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119

    PubMed Central

    Fonseca, Jairo Andres; Cabrera-Mora, Monica; Singh, Balwan; Oliveira-Ferreira, Joseli; da Costa Lima-Junior, Josué; Calvo-Calle, J. Mauricio; Lozano, Jose Manuel; Moreno, Alberto

    2016-01-01

    The most widespread Plasmodium species, Plasmodium vivax, poses a significant public health threat. An effective vaccine is needed to reduce global malaria burden. Of the erythrocytic stage vaccine candidates, the 19 kDa fragment of the P. vivax Merozoite Surface Protein 1 (PvMSP119) is one of the most promising. Our group has previously defined several promiscuous T helper epitopes within the PvMSP1 protein, with features that allow them to bind multiple MHC class II alleles. We describe here a P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) that includes defined T cell epitopes genetically fused to PvMSP119. This vaccine candidate preserved structural elements of the native PvMSP119 and elicited cytophilic antibody responses, and CD4+ and CD8+ T cells capable of recognizing PvMSP119. Although CD8+ T cells that recognize blood stage antigens have been reported to control blood infection, CD8+ T cell responses induced by P. falciparum or P. vivax vaccine candidates based on MSP119 have not been reported. To our knowledge, this is the first time a protein based subunit vaccine has been able to induce CD8+ T cell against PvMSP119. The PvRMC-MSP1 protein was also recognized by naturally acquired antibodies from individuals living in malaria endemic areas with an antibody profile associated with protection from infection. These features make PvRMC-MSP1 a promising vaccine candidate. PMID:27708348

  10. Translational Repression in Malaria Sporozoites

    PubMed Central

    Turque, Oliver; Tsao, Tiffany; Li, Thomas; Zhang, Min

    2016-01-01

    Malaria is a mosquito-borne infectious disease of humans and other animals. It is caused by the parasitic protozoan, Plasmodium. Sporozoites, the infectious form of malaria parasites, are quiescent when they remain in the salivary glands of the Anopheles mosquito until transmission into a mammalian host. Metamorphosis of the dormant sporozoite to its active form in the liver stage requires transcriptional and translational regulations. Here, we summarize recent advances in the translational repression of gene expression in the malaria sporozoite. In sporozoites, many mRNAs that are required for liver stage development are translationally repressed. Phosphorylation of eukaryotic Initiation Factor 2α (eIF2α) leads to a global translational repression in sporozoites. The eIF2α kinase, known as Upregulated in Infectious Sporozoite 1 (UIS1), is dominant in the sporozoite. The eIF2α phosphatase, UIS2, is translationally repressed by the Pumilio protein Puf2. This translational repression is alleviated when sporozoites are delivered into the mammalian host.

  11. [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.

  12. A Randomized Controlled Phase Ib Trial of the Malaria Vaccine Candidate GMZ2 in African Children

    PubMed Central

    Hounkpatin, Aurore B.; Schaumburg, Frieder; Ngoa, Ulysse Ateba; Esen, Meral; Fendel, Rolf; de Salazar, Pablo Martinez; Mürbeth, Raymund E.; Milligan, Paul; Imbault, Nathalie; Imoukhuede, Egeruan Babatunde; Theisen, Michael; Jepsen, Søren; Noor, Ramadhani A.; Okech, Brenda; Kremsner, Peter G.; Mordmüller, Benjamin

    2011-01-01

    Background GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP) that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials. Methodology/Principal Findings Thirty children one to five years of age were randomized to receive three doses of either 30 µg or 100 µg of GMZ2, or rabies vaccine. GMZ2, adjuvanted in aluminum hydroxide, was administered on Days 0, 28 and 56. All participants received a full course of their respective vaccination and were followed up for one year. Both 30 µg and 100 µg GMZ2 vaccine doses were well tolerated and induced antibodies and memory B-cells against GMZ2 as well as its antigenic constituents MSP3 and GLURP. After three doses of vaccine, the geometric mean concentration of antibodies to GMZ2 was 19-fold (95%CI: 11,34) higher in the 30 µg GMZ2 group than in the rabies vaccine controls, and 16-fold (7,36) higher in the 100 µg GMZ2 group than the rabies group. Geometric mean concentration of antibodies to MSP3 was 2.7-fold (1.6,4.6) higher in the 30 µg group than in the rabies group and 3.8-fold (1.5,9.6) higher in the 100 µg group. Memory B-cells against GMZ2 developed in both GMZ2 vaccinated groups. Conclusions/Significance Both 30 µg as well as 100 µg intramuscular GMZ2 are immunogenic, well tolerated, and safe in young, malaria-exposed Gabonese children. This result confirms previous findings in naïve and malaria-exposed adults and supports further clinical development of GMZ2. Trial Registration ClinicalTrials.gov NCT00703066 PMID:21829466

  13. The company malaria keeps: how co-infection with Epstein-Barr virus leads to endemic Burkitt lymphoma

    PubMed Central

    Moormann, Ann M.; Snider, Cynthia J.; Chelimo, Kiprotich

    2012-01-01

    Purpose of review Co-infection with Plasmodium falciparum (Pf-) malaria and Epstein-Barr virus (EBV) are implicated in the etiology of endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in equatorial Africa. Although the causal association between EBV and eBL has been established, Pf-malaria’s role is not as clearly defined. This review focuses on how malaria may disrupt EBV persistence and immunity. Recent findings Two mutually-compatible theories have been proposed. One suggests that Pf-malaria induces polyclonal B-cell expansion and lytic EBV reactivation, leading to the expansion of latently infected B-cells and the likelihood of c-myc translocation; a hallmark of BL tumors. The other advocates that EBV-specific T-cell immunity is impaired during Pf-malaria co-infection, either as a cause or consequence of enhanced EBV replication, leading to loss of viral control. Advancements in our ability to query the complexity of human responses to infectious diseases have stimulated interest in eBL pathogenesis. Summary EBV is necessary but not sufficient to cause eBL. A more dynamic model encompasses incremental contributions from both chronic and acute Pf-malaria leading to alterations in EBV persistence and EBV-specific immunity that culminate in eBL. A better understanding of how Pf-malaria modifies EBV infections in children may allow us to anticipate reductions in eBL incidence coinciding with malaria control programs. PMID:21885920

  14. 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

  15. Climate change and the global malaria recession.

    PubMed

    Gething, Peter W; Smith, David L; Patil, Anand P; Tatem, Andrew J; Snow, Robert W; Hay, Simon I

    2010-05-20

    The current and potential future impact of climate change on malaria is of major public health interest. The proposed effects of rising global temperatures on the future spread and intensification of the disease, and on existing malaria morbidity and mortality rates, substantively influence global health policy. The contemporary spatial limits of Plasmodium falciparum malaria and its endemicity within this range, when compared with comparable historical maps, offer unique insights into the changing global epidemiology of malaria over the last century. It has long been known that the range of malaria has contracted through a century of economic development and disease control. Here, for the first time, we quantify this contraction and the global decreases in malaria endemicity since approximately 1900. We compare the magnitude of these changes to the size of effects on malaria endemicity proposed under future climate scenarios and associated with widely used public health interventions. Our findings have two key and often ignored implications with respect to climate change and malaria. First, widespread claims that rising mean temperatures have already led to increases in worldwide malaria morbidity and mortality are largely at odds with observed decreasing global trends in both its endemicity and geographic extent. Second, the proposed future effects of rising temperatures on endemicity are at least one order of magnitude smaller than changes observed since about 1900 and up to two orders of magnitude smaller than those that can be achieved by the effective scale-up of key control measures. Predictions of an intensification of malaria in a warmer world, based on extrapolated empirical relationships or biological mechanisms, must be set against a context of a century of warming that has seen marked global declines in the disease and a substantial weakening of the global correlation between malaria endemicity and climate.

  16. Uncertainty in Mapping Malaria Epidemiology: Implications for Control

    PubMed Central

    Sullivan, David

    2010-01-01

    Malaria is a location-specific, dynamic infectious disease transmitted by mosquitoes to humans and is influenced by environmental, vector, parasite, and host factors. The principal purposes of malarial epidemiology are 1) to describe the malarial distribution in space and time along with the physical, biologic, and social etiologic factors and 2) to guide control objectives for either modeling impact or measuring progress of control tactics. Mapping malaria and many of its causative factors has been achieved on many different levels from global distribution to biologic quantitative trait localization in humans, parasites, and mosquitoes. Despite these important achievements, a large degree of uncertainty still exists on the annual burden of malarial cases. Accurate, sensitive detection and treatment of asymptomatic reservoirs important to infectious transmission are additional components necessary for future control measures. Presently spurred by the leadership and funding of Bill and Melinda Gates, the malarial community is developing and implementing plans for elimination of malaria. The challenge for malariologists is to digitally integrate and map epidemiologic factors and intervention measures in space and time to target effective, sustainable control alongside research efforts. PMID:20581219

  17. Quantifying Transmission Investment in Malaria Parasites.

    PubMed

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

    2016-02-01

    Many microparasites infect new hosts with specialized life stages, requiring a subset of the parasite population to forgo proliferation and develop into transmission forms. Transmission stage production influences infectivity, host exploitation, and the impact of medical interventions like drug treatment. Predicting how parasites will respond to public health efforts on both epidemiological and evolutionary timescales requires understanding transmission strategies. These strategies can rarely be observed directly and must typically be inferred from infection dynamics. Using malaria as a case study, we test previously described methods for inferring transmission stage investment against simulated data generated with a model of within-host infection dynamics, where the true transmission investment is known. We show that existing methods are inadequate and potentially very misleading. The key difficulty lies in separating transmission stages produced by different generations of parasites. We develop a new approach that performs much better on simulated data. Applying this approach to real data from mice infected with a single Plasmodium chabaudi strain, we estimate that transmission investment varies from zero to 20%, with evidence for variable investment over time in some hosts, but not others. These patterns suggest that, even in experimental infections where host genetics and other environmental factors are controlled, parasites may exhibit remarkably different patterns of transmission investment.

  18. Quantifying Transmission Investment in Malaria Parasites

    PubMed Central

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

    2016-01-01

    Many microparasites infect new hosts with specialized life stages, requiring a subset of the parasite population to forgo proliferation and develop into transmission forms. Transmission stage production influences infectivity, host exploitation, and the impact of medical interventions like drug treatment. Predicting how parasites will respond to public health efforts on both epidemiological and evolutionary timescales requires understanding transmission strategies. These strategies can rarely be observed directly and must typically be inferred from infection dynamics. Using malaria as a case study, we test previously described methods for inferring transmission stage investment against simulated data generated with a model of within-host infection dynamics, where the true transmission investment is known. We show that existing methods are inadequate and potentially very misleading. The key difficulty lies in separating transmission stages produced by different generations of parasites. We develop a new approach that performs much better on simulated data. Applying this approach to real data from mice infected with a single Plasmodium chabaudi strain, we estimate that transmission investment varies from zero to 20%, with evidence for variable investment over time in some hosts, but not others. These patterns suggest that, even in experimental infections where host genetics and other environmental factors are controlled, parasites may exhibit remarkably different patterns of transmission investment. PMID:26890485

  19. Integrating Remote Sensing and Disease Surveillance to Forecast Malaria Epidemics

    NASA Astrophysics Data System (ADS)

    Wimberly, M. C.; Beyane, B.; DeVos, M.; Liu, Y.; Merkord, C. L.; Mihretie, A.

    2015-12-01

    Advance information about the timing and locations of malaria epidemics can facilitate the targeting of resources for prevention and emergency response. Early detection methods can detect incipient outbreaks by identifying deviations from expected seasonal patterns, whereas early warning approaches typically forecast future malaria risk based on lagged responses to meteorological factors. A critical limiting factor for implementing either of these approaches is the need for timely and consistent acquisition, processing and analysis of both environmental and epidemiological data. To address this need, we have developed EPIDEMIA - an integrated system for surveillance and forecasting of malaria epidemics. The EPIDEMIA system includes a public health interface for uploading and querying weekly surveillance reports as well as algorithms for automatically validating incoming data and updating the epidemiological surveillance database. The newly released EASTWeb 2.0 software application automatically downloads, processes, and summaries remotely-sensed environmental data from multiple earth science data archives. EASTWeb was implemented as a component of the EPIDEMIA system, which combines the environmental monitoring data and epidemiological surveillance data into a unified database that supports both early detection and early warning models. Dynamic linear models implemented with Kalman filtering were used to carry out forecasting and model updating. Preliminary forecasts have been disseminated to public health partners in the Amhara Region of Ethiopia and will be validated and refined as the EPIDEMIA system ingests new data. In addition to continued model development and testing, future work will involve updating the public health interface to provide a broader suite of outbreak alerts and data visualization tools that are useful to our public health partners. The EPIDEMIA system demonstrates a feasible approach to synthesizing the information from epidemiological

  20. Signatures of aestivation and migration in Sahelian malaria mosquito populations.

    PubMed

    Dao, A; Yaro, A S; Diallo, M; Timbiné, S; Huestis, D L; Kassogué, Y; Traoré, A I; Sanogo, Z L; Samaké, D; Lehmann, T

    2014-12-18

    During the long Sahelian dry season, mosquito vectors of malaria are expected to perish when no larval sites are available; yet, days after the first rains, mosquitoes reappear in large numbers. How these vectors persist over the 3-6-month long dry season has not been resolved, despite extensive research for over a century. Hypotheses for vector persistence include dry-season diapause (aestivation) and long-distance migration (LDM); both are facets of vector biology that have been highly controversial owing to lack of concrete evidence. Here we show that certain species persist by a form of aestivation, while others engage in LDM. Using time-series analyses, the seasonal cycles of Anopheles coluzzii, Anopheles gambiae sensu stricto (s.s.), and Anopheles arabiensis were estimated, and their effects were found to be significant, stable and highly species-specific. Contrary to all expectations, the most complex dynamics occurred during the dry season, when the density of A. coluzzii fluctuated markedly, peaking when migration would seem highly unlikely, whereas A. gambiae s.s. was undetected. The population growth of A. coluzzii followed the first rains closely, consistent with aestivation, whereas the growth phase of both A. gambiae s.s. and A. arabiensis lagged by two months. Such a delay is incompatible with local persistence, but fits LDM. Surviving the long dry season in situ allows A. coluzzii to predominate and form the primary force of malaria transmission. Our results reveal profound ecological divergence between A. coluzzii and A. gambiae s.s., whose standing as distinct species has been challenged, and suggest that climate is one of the selective pressures that led to their speciation. Incorporating vector dormancy and LDM is key to predicting shifts in the range of malaria due to global climate change, and to the elimination of malaria from Africa.

  1. Mass drug administration for malaria

    PubMed Central

    Poirot, Eugenie; Skarbinski, Jacek; Sinclair, David; Kachur, S Patrick; Slutsker, Laurence; Hwang, Jimee

    2013-01-01

    Background Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended. With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission. Objectives To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA-associated adverse events. Search methods We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013. We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings. Selection criteria Cluster-randomized trials and non-randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before-and-after studies comparing post-MDA to baseline data were selected. Studies administering intermittent preventive treatment (IPT) to sub-populations (for example, pregnant women, children or infants) were excluded. Data collection and analysis Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias. Studies were stratified by study design and then subgrouped by endemicity, by co-administration of 8-aminoquinoline plus schizonticide drugs and by plasmodium species. The quality of evidence was assessed using the GRADE approach. Main results Two cluster-randomized trials, eight non-randomized controlled studies and 22 uncontrolled before-and-after studies are included in this review. Twenty-two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were

  2. [The epidemic situation with malaria in Turkmenistan].

    PubMed

    Amangel'diev, K A; Morozova, K V; Medalieva, D O

    2000-01-01

    As a result of comprehensive research on the causative agents and vectors of malaria and wide use of synthetic antimalarials and highly effective residual insecticides, endemic malaria was eliminated in Turkmenistan by 1960. During the period 1965-1980, 23 local cases of malaria were recorded in Turkmenistan. These local cases were confined to the regions of Mary and Akhal, on the borders of neighbouring countries. In 1998 the epidemiological situation in the country worsened and local transmission of infection resumed. During the year the number of cases recorded was 137:134 being a first diagnosis of the disease and three being relapsed cases. In comparison with 1997, the previous year, incidence was up by 123 cases (a 9.7-fold increase), while the incidence of imported cases of malaria went up by 11 (a 2.2-fold increase), principally in Dashkhovuz and Lebar regions, being brought in from malaria foci in Gushgin district, Turkey, Azerbaijan and Tadjikistan. Local transmission of malaria went up by 111 cases (a 27.7 fold increase); 108 cases were recorded in Gushgin district, Mary region. The first case of malaria in Gushkin district was detected in June 1998. At that time there were five active foci. The approximate number of inhabitants in the active focus area was 10,000. The appearance of local malaria in border districts was caused by the periodic influx of infected mosquitos from neighbouring countries (Afghanistan).

  3. A Research Agenda for Malaria Eradication: Vaccines

    PubMed Central

    2011-01-01

    Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of “vaccines that interrupt malaria transmission” (VIMT), which includes not only “classical” transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented. PMID:21311586

  4. Acute renal failure in Plasmodium malariae infection.

    PubMed

    Neri, S; Pulvirenti, D; Patamia, I; Zoccolo, A; Castellino, P

    2008-04-01

    We report an unusual case of transfusion-transmitted malaria which remained undiagnosed for several months in an Italian woman splenectomised and polytransfused for thalassaemia major. The infecting species was Plasmodium malariae, and the patient developed acute renal failure, severe thrombocytopenia, and hepatic failure. Treatment with chlorochine was followed by a slow, but complete recovery of renal function.

  5. A research agenda for malaria eradication: vaccines.

    PubMed

    2011-01-25

    Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.

  6. Linking environmental variability to village-scale malaria transmission using a simple immunity model

    PubMed Central

    2013-01-01

    Background Individuals continuously exposed to malaria gradually acquire immunity that protects from severe disease and high levels of parasitization. Acquired immunity has been incorporated into numerous models of malaria transmission of varying levels of complexity (e.g. Bull World Health Organ 50:347, 1974; Am J Trop Med Hyg 75:19, 2006; Math Biosci 90:385–396, 1988). Most such models require prescribing inputs of mosquito biting rates or other entomological or epidemiological information. Here, we present a model with a novel structure that uses environmental controls of mosquito population dynamics to simulate the mosquito biting rates, malaria prevalence as well as variability in protective immunity of the population. Methods A simple model of acquired immunity to malaria is presented and tested within the framework of the Hydrology, Entomology and Malaria Transmission Simulator (HYDREMATS), a coupled hydrology and agent-based entomology model. The combined model uses environmental data including rainfall, temperature, and topography to simulate malaria prevalence and level of acquired immunity in the human population. The model is used to demonstrate the effect of acquired immunity on malaria prevalence in two Niger villages that are hydrologically and entomologically very different. Simulations are conducted for the year 2006 and compared to malaria prevalence observations collected from the two villages. Results Blood smear samples from children show no clear difference in malaria prevalence between the two villages despite pronounced differences in observed mosquito abundance. The similarity in prevalence is attributed to the moderating effect of acquired immunity, which depends on prior exposure to the parasite through infectious bites - and thus the hydrologically determined mosquito abundance. Modelling the level of acquired immunity can affect village vulnerability to climatic anomalies. Conclusions The model presented has a novel structure

  7. Avian malaria in Hawaiian forest birds: Infection and population impacts across species and elevations

    USGS Publications Warehouse

    Samuel, Michael D.; Woodworth, Bethany L.; Atkinson, Carter T.; Hart, P. J.; LaPointe, Dennis

    2015-01-01

    Wildlife diseases can present significant threats to ecological systems and biological diversity, as well as domestic animal and human health. However, determining the dynamics of wildlife diseases and understanding the impact on host populations is a significant challenge. In Hawai‘i, there is ample circumstantial evidence that introduced avian malaria (Plasmodium relictum) has played an important role in the decline and extinction of many native forest birds. However, few studies have attempted to estimate disease transmission and mortality, survival, and individual species impacts in this distinctive ecosystem. We combined multi-state capture-recapture (longitudinal) models with cumulative age-prevalence (cross-sectional) models to evaluate these patterns in Apapane, Hawai‘i Amakihi, and Iiwi in low-, mid-, and high-elevation forests on the island of Hawai‘i based on four longitudinal studies of 3–7 years in length. We found species-specific patterns of malaria prevalence, transmission, and mortality rates that varied among elevations, likely in response to ecological factors that drive mosquito abundance. Malaria infection was highest at low elevations, moderate at mid elevations, and limited in high-elevation forests. Infection rates were highest for Iiwi and Apapane, likely contributing to the absence of these species in low-elevation forests. Adult malaria fatality rates were highest for Iiwi, intermediate for Amakihi at mid and high elevations, and lower for Apapane; low-elevation Amakihi had the lowest malaria fatality, providing strong evidence of malaria tolerance in this low-elevation population. Our study indicates that hatch-year birds may have greater malaria infection and/or fatality rates than adults. Our study also found that mosquitoes prefer feeding on Amakihi rather than Apapane, but Apapane are likely a more important reservoir for malaria transmission to mosquitoes. Our approach, based on host abundance and infection rates, may be an

  8. Pulmonary manifestations of malaria : recognition and management.

    PubMed

    Taylor, Walter R J; Cañon, Viviam; White, Nicholas J

    2006-01-01

    Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar ca