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ItemNo Preview AvailableCorrection: Does Malaria Affect Placental Development? Evidence from In Vitro Models(Public Library of Science (PLoS), 2013)
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ItemAcquisition of Antibodies Against Endothelial Protein C Receptor-Binding Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 in Children with Severe Malaria(OXFORD UNIV PRESS INC, 2019-03-01)BACKGROUND: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration in postcapillary venules in P. falciparum malaria. PfEMP1 types can be classified based on their cysteine-rich interdomain region (CIDR) domains. Antibodies to different PfEMP1 types develop gradually after repeated infections as children age, and antibodies to specific CIDR types may confer protection. METHODS: Levels of immunoglobulin G to 35 recombinant CIDR domains were measured by means of Luminex assay in acute-stage (baseline) and convalescent-stage plasma samples from Papua New Guinean children with severe or uncomplicated malaria and in healthy age-matched community controls. RESULTS: At baseline, antibody levels were similar across the 3 groups. After infection, children with severe malaria had higher antibody levels than those with uncomplicated malaria against the endothelial protein C receptor (EPCR) binding CIDRα1 domains, and this difference was largely confined to older children. Antibodies to EPCR-binding domains increased from presentation to follow-up in severe malaria, but not in uncomplicated malaria. CONCLUSIONS: The acquisition of antibodies against EPCR-binding CIDRα1 domains of PfEMP1 after a severe malaria episode suggest that EPCR-binding PfEMP1 may have a role in the pathogenesis of severe malaria in Papua New Guinea.
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ItemAntibody Targets on the Surface of Plasmodium falciparum-Infected Erythrocytes That Are Associated With Immunity to Severe Malaria in Young Children(Oxford University Press, 2019-03-01)BACKGROUND: Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature contributes to pathogenesis of severe malaria in children. This mechanism is mediated by antigens expressed on the IE surface. However, knowledge of specific targets and functions of antibodies to IE surface antigens that protect against severe malaria is limited. METHODS: Antibodies to IE surface antigens were examined in a case-control study of young children in Papua New Guinea presenting with severe or uncomplicated malaria (n = 448), using isolates with a virulent phenotype associated with severe malaria, and functional opsonic phagocytosis assays. We used genetically modified isolates and recombinant P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains to quantify PfEMP1 as a target of antibodies associated with disease severity. RESULTS: Antibodies to the IE surface and recombinant PfEMP1 domains were significantly higher in uncomplicated vs severe malaria and were boosted following infection. The use of genetically modified P. falciparum revealed that PfEMP1 was a major target of antibodies and that PfEMP1-specific antibodies were associated with reduced odds of severe malaria. Furthermore, antibodies promoting the opsonic phagocytosis of IEs by monocytes were lower in those with severe malaria. CONCLUSIONS: Findings suggest that PfEMP1 is a dominant target of antibodies associated with reduced risk of severe malaria, and function in part by promoting opsonic phagocytosis.
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ItemSulphadoxine-pyrimethamine plus azithromycin may improve birth outcomes through impacts on inflammation and placental angiogenesis independent of malarial infection(NATURE PORTFOLIO, 2019-02-19)Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) and SP plus azithromycin (SPAZ) reduces low birthweight (<2,500 g) in women without malarial and reproductive tract infections. This study investigates the impact of SPAZ on associations between plasma biomarkers of inflammation and angiogenesis and adverse pregnancy outcomes in 2,012 Papua New Guinean women. Concentrations of C-reactive protein (CRP), α-1-acid glycoprotein (AGP), soluble endoglin (sEng), soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured at enrolment and delivery in a trial comparing SPAZ to SP plus chloroquine (SPCQ). At antenatal enrolment higher CRP (adjusted odds ratio 1.52; 95% confidence interval [CI] 1.03-2.25), sEng (4.35; 1.77, 10.7) and sFlt1 (2.21; 1.09, 4.48) were associated with preterm birth, and higher sEng with low birthweight (1.39; 1.11,3.37), in SPCQ recipients only. Increased enrolment sFlt1:PlGF ratios associated with LBW in all women (1.46; 1.11, 1.90). At delivery, higher AGP levels were strongly associated with low birthweight, preterm birth and small-for-gestational age babies in the SPCQ arm only. Restricting analyses to women without malaria infection did not materially alter these relationships. Women receiving SPAZ had lower delivery AGP and CRP levels (p < 0.001). SPAZ may protect against adverse pregnancy outcomes by reducing inflammation and preventing its deleterious consequences, including dysregulation of placental angiogenesis, in women with and without malarial infection.
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ItemIntermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial(PUBLIC LIBRARY SCIENCE, 2012-03)BACKGROUND: Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv). METHODS AND FINDINGS: In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10-43, p ≤ 0.001) in children receiving SP-AQ and 12% (95% CI, -11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9-54, p = 0.012) and Pv incidence was 23% (95% CI, 0-41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4-51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, -24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p > 0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%-2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention. CONCLUSIONS: IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.
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ItemIron deficiency during pregnancy is associated with a reduced risk of adverse birth outcomes in a malaria-endemic area in a longitudinal cohort study(BMC, 2018-09-20)BACKGROUND: Low birth weight (LBW) and preterm birth (PTB) are major contributors to infant mortality and chronic childhood morbidity. Understanding factors that contribute to or protect against these adverse birth outcomes is an important global health priority. Anaemia and iron deficiency are common in malaria-endemic regions, but there are concerns regarding the value of iron supplementation among pregnant women in malaria-endemic areas due to reports that iron supplementation may increase the risk of malaria. There is a lack of evidence on the impact of iron deficiency on pregnancy outcomes in malaria-endemic regions. METHODS: We determined iron deficiency in a cohort of 279 pregnant women in a malaria-endemic area of Papua New Guinea. Associations with birth weight, LBW and PTB were estimated using linear and logistic regression. A causal model using sequential mediation analyses was constructed to assess the association between iron deficiency and LBW, either independently or mediated through malaria and/or anaemia. RESULTS: Iron deficiency in pregnant women was common (71% at enrolment) and associated with higher mean birth weights (230 g; 95% confidence interval, CI 118, 514; p < 0.001), and reduced odds of LBW (adjusted odds ratio, aOR = 0.32; 95% CI 0.16, 0.64; p = 0.001) and PTB (aOR = 0.57; 95% CI 0.30, 1.09; p = 0.089). Magnitudes of effect were greatest in primigravidae (birth weight 351 g; 95% CI 188, 514; p < 0.001; LBW aOR 0.26; 95% CI 0.10, 0.66; p = 0.005; PTB aOR = 0.39, 95% CI 0.16, 0.97; p = 0.042). Sequential mediation analyses indicated that the protective association of iron deficiency on LBW was mainly mediated through mechanisms independent of malaria or anaemia. CONCLUSIONS: Iron deficiency was associated with substantially reduced odds of LBW predominantly through malaria-independent protective mechanisms, which has substantial implications for understanding risks for poor pregnancy outcomes and evaluating the benefit of iron supplementation in pregnancy. This study is the first longitudinal study to demonstrate a temporal relationship between antenatal iron deficiency and improved birth outcomes. These findings suggest that iron supplementation needs to be integrated with other strategies to prevent or treat infections and undernutrition in pregnancy to achieve substantial improvements in birth outcomes.
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ItemP. falciparum infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission(PUBLIC LIBRARY SCIENCE, 2017-10-13)INTRODUCTION: During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. Plasmodium falciparum infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear. METHODS: Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four P. falciparum antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral P. falciparum infection during pregnancy or placental P. falciparum infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between P. falciparum infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG. RESULTS: Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental P. falciparum infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log2 units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed. DISCUSSION: Primigravid women may be at risk of impaired maternofetal antibody transport with placental P. falciparum infection. Direct effects of P. falciparum on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.
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ItemDoes Malaria Affect Placental Development? Evidence from In Vitro Models(PUBLIC LIBRARY SCIENCE, 2013-01-31)BACKGROUND: Malaria in early pregnancy is difficult to study but has recently been associated with fetal growth restriction (FGR). The pathogenic mechanisms underlying malarial FGR are poorly characterized, but may include impaired placental development. We used in vitro methods that model migration and invasion of placental trophoblast into the uterine wall to investigate whether soluble factors released into maternal blood in malaria infection might impair placental development. Because trophoblast invasion is enhanced by a number of hormones and chemokines, and is inhibited by pro-inflammatory cytokines, many of which are dysregulated in malaria in pregnancy, we further compared concentrations of these factors in blood between malaria-infected and uninfected pregnancies. METHODOLOGY/PRINCIPAL FINDINGS: We measured trophoblast invasion, migration and viability in response to treatment with serum or plasma from two independent cohorts of Papua New Guinean women infected with Plasmodium falciparum or Plasmodium vivax in early pregnancy. Compared to uninfected women, serum and plasma from women with P. falciparum reduced trophoblast invasion (P = .06) and migration (P = .004). P. vivax infection did not alter trophoblast migration (P = .64). The P. falciparum-specific negative effect on placental development was independent of trophoblast viability, but associated with high-density infections. Serum from P. falciparum infected women tended to have lower levels of trophoblast invasion promoting hormones and factors and higher levels of invasion-inhibitory inflammatory factors. CONCLUSION/SIGNIFICANCE: We demonstrate that in vitro models of placental development can be adapted to indirectly study the impact of malaria in early pregnancy. These infections could result in impaired trophoblast invasion with reduced transformation of maternal spiral arteries due to maternal hormonal and inflammatory disturbances, which may contribute to FGR by limiting the delivery of maternal blood to the placenta. Future prevention strategies for malaria in pregnancy should include protection in the first half of pregnancy.
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ItemA single point in protein trafficking by Plasmodium falciparum determines the expression of major antigens on the surface of infected erythrocytes targeted by human antibodies(SPRINGER BASEL AG, 2016-11)Antibodies to blood-stage antigens of Plasmodium falciparum play a pivotal role in human immunity to malaria. During parasite development, multiple proteins are trafficked from the intracellular parasite to the surface of P. falciparum-infected erythrocytes (IEs). However, the relative importance of different proteins as targets of acquired antibodies, and key pathways involved in trafficking major antigens remain to be clearly defined. We quantified antibodies to surface antigens among children, adults, and pregnant women from different malaria-exposed regions. We quantified the importance of antigens as antibody targets using genetically engineered P. falciparum with modified surface antigen expression. Genetic deletion of the trafficking protein skeleton-binding protein-1 (SBP1), which is involved in trafficking the surface antigen PfEMP1, led to a dramatic reduction in antibody recognition of IEs and the ability of human antibodies to promote opsonic phagocytosis of IEs, a key mechanism of parasite clearance. The great majority of antibody epitopes on the IE surface were SBP1-dependent. This was demonstrated using parasite isolates with different genetic or phenotypic backgrounds, and among antibodies from children, adults, and pregnant women in different populations. Comparisons of antibody reactivity to parasite isolates with SBP1 deletion or inhibited PfEMP1 expression suggest that PfEMP1 is the dominant target of acquired human antibodies, and that other P. falciparum IE surface proteins are minor targets. These results establish SBP1 as part of a critical pathway for the trafficking of major surface antigens targeted by human immunity, and have key implications for vaccine development, and quantifying immunity in populations.