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Jean Langhorne - One of the best experts on this subject based on the ideXlab platform.

  • icam 1 is a key receptor mediating cytoadherence and pathology in the Plasmodium chabaudi malaria model
    Malaria Journal, 2017
    Co-Authors: Deirdre Cunningham, William Jarra, Thibaut Brugat, Jingwen Lin, Irene Tumwine, Garikai Kushinga, Jai Ramesar, Blandine Frankefayard, Jean Langhorne
    Abstract:

    Parasite cytoadherence within the microvasculature of tissues and organs of infected individuals is implicated in the pathogenesis of several malaria syndromes. Multiple host receptors may mediate sequestration. The identity of the host receptor(s), or the parasite ligand(s) responsible for sequestration of Plasmodium species other than Plasmodium falciparum is largely unknown. The rodent malaria parasites may be useful to model interactions of parasite species, which lack the var genes with their respective hosts, as other multigene families are shared between the species. The role of the endothelial receptors ICAM-1 and CD36 in cytoadherence and in the development of pathology was investigated in a Plasmodium chabaudi infection in C57BL/6 mice lacking these receptors. The schizont membrane-associated cytoadherence (SMAC) protein of Plasmodium berghei has been shown to exhibit reduced CD36-associated cytoadherence in P. berghei ANKA-infected mice. Parasite tissue sequestration and the development of acute stage pathology in P. chabaudi infections of mice lacking CD36 or ICAM-1, their respective wild type controls, and in infections with mutant P. chabaudi parasites lacking the smac gene were compared. Peripheral blood parasitaemia, red blood cell numbers and weight change were monitored throughout the courses of infection. Imaging of bioluminescent parasites in isolated tissues (spleen, lungs, liver, kidney and gut) was used to measure tissue parasite load. This study shows that neither the lack of CD36 nor the deletion of the smac gene from P. chabaudi significantly impacted on acute-stage pathology or parasite sequestration. By contrast, in the absence of ICAM-1, infected animals experience less anaemia and weight loss, reduced parasite accumulation in both spleen and liver and higher peripheral blood parasitaemia during acute stage malaria. The reduction in parasite tissue sequestration in infections of ICAM-1 null mice is maintained after mosquito transmission. These results indicate that ICAM-1-mediated cytoadherence is important in the P. chabaudi model of malaria and suggest that for rodent malarias, as for P. falciparum, there may be multiple host and parasite molecules involved in sequestration.

  • Characterization of the Plasmodium Interspersed Repeats (PIR) proteins of Plasmodium chabaudi indicates functional diversity
    Scientific reports, 2016
    Co-Authors: Xue Yan Yam, Jean Langhorne, Jennifer Lawton, Thibaut Brugat, Anthony Siau, Daniel S. Wong, Abdirahman Farah, Jing Shun Twang, Xiaohong Gao, Peter R. Preiser
    Abstract:

    Plasmodium multigene families play a central role in the pathogenesis of malaria. The Plasmodium interspersed repeat (pir) genes comprise the largest multigene family in many Plasmodium spp. However their function(s) remains unknown. Using the rodent model of malaria, Plasmodium chabaudi, we show that individual CIR proteins have differential localizations within infected red cell (iRBC), suggesting different functional roles in a blood-stage infection. Some CIRs appear to be located on the surface of iRBC and merozoites and are therefore well placed to interact with host molecules. In line with this hypothesis, we show for the first time that a subset of recombinant CIRs bind mouse RBCs suggesting a role for CIR in rosette formation and/or invasion. Together, our results unravel differences in subcellular localization and ability to bind mouse erythrocytes between the members of the cir family, which strongly suggest different functional roles in a blood-stage infection.

  • sequestration and histopathology in Plasmodium chabaudi malaria are influenced by the immune response in an organ specific manner
    Cellular Microbiology, 2014
    Co-Authors: Thibaut Brugat, William Jarra, Philip J Spence, Deirdre Cunningham, Joanne Thompson, Jan Sodenkamp, Stephanie M Coomes, Mark S Wilson, Cheryl L Scudamore, Jean Langhorne
    Abstract:

    Summary Infection with the malaria parasite, Plasmodium ,i s associated with a strong inflammatory response and parasite cytoadhesion (sequestration) in several organs. Here, we have carried out a sys- tematic study of sequestration and histopathology during infection of C57Bl/6 mice with Plasmodium chabaudi AS and determined the influence of the immune response. This parasite sequesters pre- dominantly in liver and lung, but not in the brain, kidney or gut. Histopathological changes occur in multiple organs during the acute infection, but are not restricted to the organs where sequestration takes place. Adaptive immunity, and signalling through the IFNγ receptor increased sequestration and histopathology in the liver, but not in the lung, suggesting that there are differences in the adhe- sion molecules and/or parasite ligands utilized and mechanisms of pathogenesis in these two organs. Exacerbation of pro-inflammatory responses during infection by deletion of the il10 gene results in the aggravation of damage to lung and kidney irrespective of the degree of sequestration. The immune response therefore affected both seques- tration and histopathology in an organ-specific manner. P. chabaudi AS provides a good model to investigate the influence of the host response on the sequestration and specific organ pathology, which is applicable to human malaria.

  • Transformation of the rodent malaria parasite Plasmodium chabaudi
    Nature Protocols, 2011
    Co-Authors: Philip J Spence, William Jarra, Jean Langhorne, Deirdre Cunningham, Jennifer Lawton, Joanne Thompson
    Abstract:

    The rodent malaria parasite Plasmodium chabaudi chabaudi shares many features with human malaria species, including P. falciparum , and is the in vivo model of choice for many aspects of malaria research in the mammalian host, from sequestration of parasitized erythrocytes, to antigenic variation and host immunity and immunopathology. This protocol describes an optimized method for the transformation of mature blood-stage P.c. chabaudi and a description of a vector that targets efficient, single crossover integration into the P.c. chabaudi genome. Transformed lines are reproducibly generated and selected within 14–20 d, and show stable long-term protein expression even in the absence of drug selection. This protocol, therefore, provides the scientific community with a robust and reproducible method to generate transformed P.c. chabaudi parasites expressing fluorescent, bioluminescent and model antigens that can be used in vivo to dissect many of the fundamental principles of malaria infection.

  • distinct kinetics of memory b cell and plasma cell responses in peripheral blood following a blood stage Plasmodium chabaudi infection in mice
    PLOS ONE, 2010
    Co-Authors: Eunice Nduati, Francis M Ndungu, Peter Gardner, Britta C Urban, Jean Langhorne
    Abstract:

    B cell and plasma cell responses take place in lymphoid organs, but because of the inaccessibility of these organs, analyses of human responses are largely performed using peripheral blood mononuclear cells (PBMC). To determine whether PBMC are a useful source of memory B cells and plasma cells in malaria, and whether they reflect Plasmodium-specific B cell responses in spleen or bone marrow, we have investigated these components of the humoral response in PBMC using a model of Plasmodium chabaudi blood-stage infections in C57BL/6 mice. We detected memory B cells, defined as isotype-switched IgD− IgM− CD19+ B cells, and low numbers of Plasmodium chabaudi Merozoite Surface Protein-1 (MSP1)-specific memory B cells, in PBMC at all time points sampled for up to 90 days following primary or secondary infection. By contrast, we only detected CD138+ plasma cells and MSP1-specific antibody-secreting cells within a narrow time frame following primary (days 10 to 25) or secondary (day 10) infection. CD138+ plasma cells in PBMC at these times expressed CD19, B220 and MHC class II, suggesting that they were not dislodged bone-marrow long-lived plasma cells, but newly differentiated migratory plasmablasts migrating to the bone marrow; thus reflective of an ongoing or developing immune response. Our data indicates that PBMC can be a useful source for malaria-specific memory B cells and plasma cells, but extrapolation of the results to human malaria infections suggests that timing of sampling, particularly for plasma cells, may be critical. Studies should therefore include multiple sampling points, and at times of infection/immunisation when the B-cell phenotypes of interest are likely to be found in peripheral blood.

Andrew F. Read - One of the best experts on this subject based on the ideXlab platform.

  • relevance of undetectably rare resistant malaria parasites in treatment failure experimental evidence from Plasmodium chabaudi
    American Journal of Tropical Medicine and Hygiene, 2015
    Co-Authors: Silvie Huijben, Brian H K Chan, Andrew F. Read
    Abstract:

    Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance.

  • the effect of immunodeficiency on the evolution of virulence an experimental test with the rodent malaria Plasmodium chabaudi
    The American Naturalist, 2014
    Co-Authors: Victoria C. Barclay, Derek G Sim, David A Kennedy, Veronika Weaver, James O Lloydsmith, Andrew F. Read
    Abstract:

    AbstractHost immunity plays an important role in the evolution of pathogen virulence and disease emergence. There is increasing theoretical and empirical evidence that enhanced immunity through vaccination may have the unfortunate side effect of selecting for more virulent parasites, but the effect of host immune suppression on pathogen evolution is less clear. Here, we use serial passage experiments in mice to test how immune-suppressed hosts may alter pathogen virulence evolution. We passaged Plasmodium chabaudi through CD4+ T cell–depleted or control mice every 7 days for 20 weeks and then measured virulence differences during infection of immunologically normal mice. We found that those parasites that had been selected through CD4+ T cell–depleted mice were more virulent than parasites selected through control mice. Virulence increases during serial passage are believed to be caused by pathogen adaptation to the passage host. These data suggest that immune-suppressed hosts could provide a within-host ...

  • rapid response to selection competitive release and increased transmission potential of artesunate selected Plasmodium chabaudi malaria parasites
    PLOS Pathogens, 2014
    Co-Authors: Laura C Pollitt, Derek G Sim, Silvie Huijben, Rahel M Salathe, Matthew J Jones, Andrew F. Read
    Abstract:

    The evolution of drug resistance, a key challenge for our ability to treat and control infections, depends on two processes: de-novo resistance mutations, and the selection for and spread of resistant mutants within a population. Understanding the factors influencing the rates of these two processes is essential for maximizing the useful lifespan of drugs and, therefore, effective disease control. For malaria parasites, artemisinin-based drugs are the frontline weapons in the fight against disease, but reports from the field of slower parasite clearance rates during drug treatment are generating concern that the useful lifespan of these drugs may be limited. Whether slower clearance rates represent true resistance, and how this provides a selective advantage for parasites is uncertain. Here, we show that Plasmodium chabaudi malaria parasites selected for resistance to artesunate (an artemisinin derivative) through a step-wise increase in drug dose evolved slower clearance rates extremely rapidly. In single infections, these slower clearance rates, similar to those seen in the field, provided fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. In mixed infections, removal of susceptible parasites by drug treatment led to substantial increases in the densities and transmission potential of resistant parasites (competitive release). Our results demonstrate the double-edged sword for resistance management: in our initial selection experiments, no parasites survived aggressive chemotherapy, but after selection, the fitness advantage for resistant parasites was greatest at high drug doses. Aggressive treatment of mixed infections resulted in resistant parasites dominating the pool of gametocytes, without providing additional health benefits to hosts. Slower clearance rates can evolve rapidly and can provide a strong fitness advantage during drug treatment in both single and mixed strain infections.

  • quantifying variation in the potential for antibody mediated apparent competition among nine genotypes of the rodent malaria parasite Plasmodium chabaudi
    Infection Genetics and Evolution, 2013
    Co-Authors: Karen Fairlieclarke, Judith E Allen, Andrew F. Read, Andrea L. Graham
    Abstract:

    Within-host competition among parasite genotypes affects epidemiology as well as the evolution of vir- ulence. In the rodent malaria Plasmodium chabaudi, competition among genotypes, as well as clone-spe- cific and clone-transcending immunity are well documented. However, variation among genotypes in the induction of antibodies is not well understood, despite the important role of antibodies in the clearance of malaria infection. Here, we quantify the potential for antibodies induced by one clone to bind another (i.e., to cause antibody-mediated apparent competition) for nine genetically distinct P. chabaudi clones. We hypothesised that clones would vary in the strength of antibody induction, and that the propensity for clone-transcending immunity between a pair of clones would increase with increasing genetic relat- edness at key antigenic loci. Using serum collected from mice 35 days post-infection, we measured titres of antibody to an unrelated antigen, Keyhole Limpet Haemocyanin (KLH), and two malaria antigens: recombinant Apical Membrane Antigen-1 (AMA-1) and Merozoite Surface Protein-119 (MSP-119). Amino acid sequence homology within each antigenic locus was used as a measure of relatedness. We found sig- nificant parasite genetic variation for the strength of antibody induction. We also found that relatedness at MSP-119 but not AMA-1 predicted clone-transcending binding. Our results help explain the outcome of chronic-phase mixed infections and generate testable predictions about the pairwise competitive ability of P. chabaudi clones.

  • virulence drug sensitivity and transmission success in the rodent malaria Plasmodium chabaudi
    Proceedings of The Royal Society B: Biological Sciences, 2012
    Co-Authors: Petra Schneider, Simon Blanford, Andrew F. Read, Andrew S Bell, Derek G Sim, Aidan J Odonnell, Krijn P Paaijmans, Sarah E Reece
    Abstract:

    Here, we test the hypothesis that virulent malaria parasites are less susceptible to drug treatment than less virulent parasites. If true, drug treatment might promote the evolution of more virulent parasites (defined here as those doing more harm to hosts). Drug-resistance mechanisms that protect parasites through interactions with drug molecules at the sub-cellular level are well known. However, parasite phenotypes associated with virulence might also help parasites survive in the presence of drugs. For example, rapidly replicating parasites might be better able to recover in the host if drug treatment fails to eliminate parasites. We quantified the effects of drug treatment on the in-host survival and between-host transmission of rodent malaria (Plasmodium chabaudi) parasites which differed in virulence and had never been previously exposed to drugs. In all our treatment regimens and in single- and mixed-genotype infections, virulent parasites were less sensitive to pyrimethamine and artemisinin, the two antimalarial drugs we tested. Virulent parasites also achieved disproportionately greater transmission when exposed to pyrimethamine. Overall, our data suggest that drug treatment can select for more virulent parasites. Drugs targeting transmission stages (such as artemisinin) may minimize the evolutionary advantage of virulence in drug-treated infections.

Filip C Castberg - One of the best experts on this subject based on the ideXlab platform.

  • increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short term adjunctive iron supplementation
    Malaria Journal, 2018
    Co-Authors: Filip C Castberg, Lasse Maretty, Trine Staalsoe, Casper Hempel, Erik Clasenlinde, Lars Hviid, Jorogen A L Kurtzhals
    Abstract:

    Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial. The effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed. Nutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores. Blood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered.

  • Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Filip C Castberg, Lasse Maretty, Trine Staalsoe, Casper Hempel, Lars Hviid, Erik Clasen-linde, Jorogen A L Kurtzhals
    Abstract:

    Abstract Background Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial. Methods The effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed. Results Nutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores. Conclusions Blood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered

Richard Carter - One of the best experts on this subject based on the ideXlab platform.

  • Strain-specific immunity induced by immunization with pre-erythrocytic stages of Plasmodium chabaudi
    Parasite immunology, 2010
    Co-Authors: Richard Culleton, Sandra Cheesman, Sarah E Reece, Megumi Inoue, Richard Carter
    Abstract:

    One of the most promising approaches in the efforts to produce a malaria vaccine involves the use of attenuated whole sporozoite immunizations. Attenuation may be achieved by the use of genetic modification, irradiation, chemical attenuation, or by the contemporaneous administration of antimalarial drugs that target only the erythrocytic stages of the parasite. Most research to date has focused on the efficacy of these approaches upon challenge with parasites homologous to those used for the initial immunizations. We, as have others, have previously shown that a component of the immunity achieved against the erythrocytic stages of the rodent malaria parasite Plasmodium chabaudi chabaudi is strain-specific, with a stronger immune response targeting the immunizing strain than genetically distinct strains. Here, we show that the immunity induced by infection with the pre-erythrocytic stages of these parasites, achieved via inoculation of sporozoites contemporaneously with mefloquine, also has a strain-specific component.

  • a study on pathogenicity and mosquito transmission success in the rodent malaria parasite Plasmodium chabaudi adami
    International Journal for Parasitology, 2009
    Co-Authors: Naomi Gadsby, Richard Lawrence, Richard Carter
    Abstract:

    We investigated the parasitology, pathogenicity (virulence) and infectivity to mosquitoes of blood infections in mice, of two strains, DS and DK, of the rodent malaria parasite Plasmodium chabaudi adami. Blood infections of DS were found to be highly pathogenic; the asexual parasites in these infections were fast-growing and showed no evidence of selectivity in their infection of host erythrocytes. In contrast to DS, blood infections of DK were much less pathogenic; the asexual parasites were slower-growing and showed a moderate degree of selectivity to a subset of erythrocytes which were not reticulocytes. In both DS and DK infections, infectivity to mosquitoes was highest before the peak of asexual parasitaemia had occurred; usually this did not coincide with the time when gametocyte numbers in the blood were highest. Infections with the pathogenic DS strain in CBA mice produced fewer gametocytes than did the less pathogenic DK strain. The DS strain infections in both CBA and C57 mice were also significantly much less infective to mosquitoes than the DK strain. Investigations by others on the related rodent malaria parasite subspecies, Plasmodium chabaudi chabaudi, have indicated that the mosquito infectivity of blood infections in mice tended to be higher in the more pathogenic (virulent) and lower in the less pathogenic strains of this parasite subspecies. This is the converse of the finding of the present investigation of blood infections of P. c. adami in mice in which a more pathogenic, or virulent, strain (DS) of these parasites was significantly much less infective to mosquitoes than was a less pathogenic strain (DK).

  • mixed strain infections and strain specific protective immunity in the rodent malaria parasite Plasmodium chabaudi chabaudi in mice
    Infection and Immunity, 2006
    Co-Authors: Sandra Cheesman, Ahmed Raza, Richard Carter
    Abstract:

    Important to malaria vaccine design is the phenomenon of "strain-specific" immunity. Using an accurate and sensitive assay of parasite genotype, real-time quantitative PCR, we have investigated protective immunity against mixed infections of genetically distinct cloned "strains" of the rodent malaria parasite Plasmodium chabaudi chabaudi in mice. Four strains of P. c. chabaudi, AS, AJ, AQ, and CB, were studied. One round of blood infection and drug cure with a single strain resulted in a partial reduction in parasitemia, compared with levels for naive mice, in challenge infections with mixed inocula of the immunizing (homologous) strain and a heterologous strain. In all cases, the numbers of blood-stage parasites of each genotype were reduced to similar degrees. After a second, homologous round of infection and drug cure followed by challenge with homologous and heterologous strains, the parasitemias were reduced even further. In these circumstances, moreover, the homologous strain was reduced much faster than the heterologous strain in all of the combinations tested. That the immunity induced by a single infection did not show "strain specificity," while the immunity following a second, homologous infection did, suggests that the "strain-specific" component of protective immunity in malaria may be dependent upon immune memory. The results show that strong, protective immunity induced by and effective against malaria parasites from a single parasite species has a significant "strain-specific" component and that this immunity operates differentially against genetically distinct parasites within the same infection.

  • An AFLP-based genetic linkage map of Plasmodium chabaudi chabaudi
    Malaria Journal, 2005
    Co-Authors: Axel Martinelli, Richard Fawcett, Pedro Cravo, Paul Hunt, David Walliker, Richard Carter
    Abstract:

    Background Plasmodium chabaudi chabaudi can be considered as a rodent model of human malaria parasites in the genetic analysis of important characters such as drug resistance and immunity. Despite the availability of some genome sequence data, an extensive genetic linkage map is needed for mapping the genes involved in certain traits.

  • gene synteny and chloroquine resistance in Plasmodium chabaudi
    Molecular and Biochemical Parasitology, 2004
    Co-Authors: Paul Hunt, Axel Martinelli, Richard Fawcett, Richard Carter, Jane M Carlton, David Walliker
    Abstract:

    Abstract Chloroquine resistance in the rodent malaria parasite Plasmodium chabaudi has been shown to be caused by a gene on chromosome 11, and is not linked to orthologues of the Plasmodium falciparum chloroquine resistance transporter ( pfcrt ) or Pgh-1 ( pfmdr1 ) genes. In the current work, the progeny of crosses between chloroquine-resistant and sensitive clones of P. chabaudi have been analysed for the inheritance of 658 AFLP markers. Markers linked to the chloroquine responses of the progeny, including two which are completely linked, have been genetically mapped, sequenced and their homologues, or closely linked loci, identified in P. falciparum . The chromosome 11 markers most closely linked to chloroquine resistance in P. chabaudi map to loci which are also closely linked in P. falciparum , although in two linkage groups on chromosomes 6 and 13 of this species. The P. falciparum orthologue of the gene conferring chloroquine resistance in P. chabaudi is predicted to lie within a 250 kb region of P. falciparum chromosome 6, containing approximately 50 genes. The genetic order of the markers in P. chabaudi is co-linear with the physical linkage represented in the P. falciparum genome database. The findings provide evidence for extensive conservation of synteny between the two species.

Jorogen A L Kurtzhals - One of the best experts on this subject based on the ideXlab platform.

  • increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short term adjunctive iron supplementation
    Malaria Journal, 2018
    Co-Authors: Filip C Castberg, Lasse Maretty, Trine Staalsoe, Casper Hempel, Erik Clasenlinde, Lars Hviid, Jorogen A L Kurtzhals
    Abstract:

    Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial. The effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed. Nutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores. Blood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered.

  • Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Filip C Castberg, Lasse Maretty, Trine Staalsoe, Casper Hempel, Lars Hviid, Erik Clasen-linde, Jorogen A L Kurtzhals
    Abstract:

    Abstract Background Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial. Methods The effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed. Results Nutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores. Conclusions Blood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered