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      Antibody responses to the full-length VAR2CSA and its DBL domains in Cameroonian children and teenagers

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          Abstract

          Background

          Antigenic variation of Plasmodium falciparum erythrocyte membrane protein 1 is a key parasite mechanism for immune evasion and parasite survival. It is assumed that the number of parasites expressing the same var gene must reach high enough numbers before the host can produce detectable levels of antibodies (Ab) to the variant. VAR2CSA is a protein coded for by one of 60 var genes that is expressed on the surface of infected erythrocytes (IE) and mediates IE binding to the placenta. The idea that Ab to VAR2CSA are pregnancy-associated was challenged when VAR2CSA-specific Ab were reported in children and men. However, the frequency and conditions under which Ab to VAR2CSA are produced outside pregnancy is unclear. This study sought to determine frequency, specificity and level of Ab to VAR2CSA produced in children and whether children with hyperparasitaemia and severe malaria are more likely to produce Ab to VAR2CSA compared to healthy children.

          Methods

          Antibody responses to a panel of recombinant proteins consisting of multiple VAR2CSA Duffy-binding-like domains (DBL) and full-length VAR2CSA (FV2) were characterized in 193 1–15 year old children from rural Cameroonian villages and 160 children with severe malaria from the city.

          Results

          Low Ab levels to VAR2CSA were detected in children; however, Ab levels to FV2 in teenagers were rare. Children preferentially recognized DBL2 (56–70%) and DBL4 (50–60%), while multigravidae produced high levels of IgG to DBL3, DBL5 and FV2. Sixty-seven percent of teenage girls (n = 16/24) recognized ID1–ID2a region of VAR2CSA. Children with severe forms of malaria had significantly higher IgG to merozoite antigens (all p < 0.05), but not to VAR2CSA (all p > 0.05) when compared to the healthy children.

          Conclusion

          The study suggests that children, including teenage girls acquire Ab to VAR2CSA domains and FV2, but Ab levels are much lower than those needed to protect women from placental infections and repertoire of Ab responses to DBL domains is different from those in pregnant women. Interestingly, children with severe malaria did not have higher Ab levels to VAR2CSA compared to healthy children.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12936-016-1585-y) contains supplementary material, which is available to authorized users.

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          Most cited references47

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          Maternal antibodies block malaria.

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            Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum.

            Members of the Plasmodium falciparum var gene family encode clonally variant adhesins, which play an important role in the pathogenicity of tropical malaria. Here we employ a selective panning protocol to generate isogenic P.falciparum populations with defined adhesive phenotypes for CD36, ICAM-1 and CSA, expressing single and distinct var gene variants. This technique has established the framework for examining var gene expression, its regulation and switching. It was found that var gene switching occurs in situ. Ubiquitous transcription of all var gene variants appears to occur in early ring stages. However, var gene expression is tightly regulated in trophozoites and is exerted through a silencing mechanism. Transcriptional control is mutually exclusive in parasites that express defined adhesive phenotypes. In situ var gene switching is apparently mediated at the level of transcriptional initiation, as demonstrated by nuclear run-on analyses. Our results suggest that an epigenetic mechanism(s) is involved in var gene regulation.
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              An analysis of anemia and child mortality.

              The relationship of anemia as a risk factor for child mortality was analyzed by using cross-sectional, longitudinal and case-control studies, and randomized trials. Five methods of estimation were adopted: 1) the proportion of child deaths attributable to anemia; 2) the proportion of anemic children who die in hospital studies; 3) the population-attributable risk of child mortality due to anemia; 4) survival analyses of mortality in anemic children; and 5) cause-specific anemia-related child mortality. Most of the data available were hospital based. For children aged 0-5 y the percentage of deaths due to anemia was comparable for reports from highly malarious areas in Africa (Sierra Leone 11.2%, Zaire 12.2%, Kenya 14.3%). Ten values available for hemoglobin values <50 g/L showed a variation in case fatality from 2 to 29.3%. The data suggested little if any dose-response relating increasing hemoglobin level (whether by mean value or selected cut-off values) with decreasing mortality. Although mortality was increased in anemic children with hemoglobin <50 g/L, the evidence for increased risk with less severe anemia was inconclusive. The wide variation for mortality with hemoglobin <50 g/L is related to methodological variation and places severe limits on causal inference; in view of this, it is premature to generate projections on population-attributable risk. A preliminary survival analysis of an infant cohort from Malawi indicated that if the hemoglobin decreases by 10 g/L at age 6 mo, the risk of dying becomes 1.72 times higher. Evidence from a number of studies suggests that mortality due to malarial severe anemia is greater than that due to iron-deficiency anemia. Data are scarce on anemia and child mortality from non-malarious regions. Primary prevention of iron-deficiency anemia and malaria in young children could have substantive effects on reducing child mortality from severe anemia in children living in malarious areas.
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                Author and article information

                Contributors
                fodjoyetgang@gmail.com
                atemnkeng.njika@gmail.com
                esemu_livo@yahoo.com
                yuosembome76@yahoo.com
                iaquakyi@yahoo.com
                vtchinda1@yahoo.com
                joe.smith@seattlebiomed.org
                salanti@sund.ku.dk
                jbigoga@gmail.com
                dwtaylor@hawaii.edu
                roseleke@yahoo.com
                annab8@hawaii.edu
                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                4 November 2016
                4 November 2016
                2016
                : 15
                : 532
                Affiliations
                [1 ]Department of Biochemistry, Faculty of Medicine and Biomedical Research, Biotechnology Centre, University of Yaoundé 1, Yaounde, Cameroon
                [2 ]School of Public Health, College of Health Sciences, University of Ghana, Legon, Ghana
                [3 ]Seattle Biomedical Research Institute, Seattle, WA 98109 USA
                [4 ]Department of Immunology and Microbiology, Centre for Medical Parasitology, University of Copenhagen, Copenhagen, Denmark
                [5 ]Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A Burns School of Medicine, 651 Ilalo Street, BSB 320, Honolulu, Hawaii 96813 USA
                Article
                1585
                10.1186/s12936-016-1585-y
                5097422
                27814765
                8458794a-a714-4c69-ae15-7c184c84df43
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 July 2016
                : 28 October 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000061, Fogarty International Center;
                Award ID: #R25 TW009345
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: UO1-AI-43888
                Award ID: RO1AI071160
                Award ID: 5D43 TWO1264
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006641, UNICEF;
                Award ID: A00769
                Award Recipient :
                Funded by: European Union STOPPAM
                Award ID: 355 #200889
                Award Recipient :
                Funded by: Institut de Recherches Médicales et d'Etudes des Plantes Médicinales
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Infectious disease & Microbiology
                malaria,var2csa,antibody,children
                Infectious disease & Microbiology
                malaria, var2csa, antibody, children

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