Association analyses of NCR3 polymorphisms with P. falciparum mild malaria

Plasmodium falciparum malaria is a major cause of morbidity and mortality in many developing countries especially in sub-Saharan Africa. A susceptibility locus for mild malaria has been mapped to the MHC region, and TNF polymorphisms have been associated with mild malaria. The Natural Cytotoxicity-triggering Receptor 3 (NCR3) gene is located in the peak region of linkage, and is 15kb distal to TNF. In this study, we considered NCR3 as a candidate gene, and we genotyped ten NCR3 single nucleotide polymorphisms (SNPs). Here, we report evidence of an association between mild malaria and NCR3 -412G>C polymorphism located within the promoter. Population-based association analysis showed that NCR3 -412C carriers had more frequent mild malaria attacks than NCR3 -412GG individuals (P=0.001). Using the family-based association test (FBAT) program and its phenotype (PBAT) option, we further found that NCR3 -412C (P=0.0009) and a haplotype containing NCR3 -412C (P=0.008) were significantly associated with increased risk of mild malaria, and that the association was not due to the association of TNF with mild malaria. These observations suggest that there are at least two genes located on the central region of MHC involved in genetic control of human malaria. The association of NCR3 with malaria should provide new insights into the role of Natural Killer cells in this common disease.     

Interleukin-21 is associated with IgG1 and IgG3 antibodies to erythrocyte-binding antigen-175 peptide 4 of Plasmodium falciparum in Gabonese children with acute falciparum malaria

Interleukin-21 (IL-21) is a newly described, typical, four-helix cytokine showing significant homology with IL-2, IL-4 and IL-15. It regulates IgG1 production and co-operates with IL-4 in the production of multiple antibody classes in vivo. IgG1 and IgG3 are critically involved in the development of clinical immunity to Plasmodium falciparum malaria. However, the mechanisms driving class-switch recombination towards these specific isotypes remain to be elucidated. Seventy-three children with P. falciparum-positive, thick blood smears were recruited from the pediatric wards of the Albert Schweitzer Hospital and the General Hospital in Lambaréné. Children were grouped into two categories according to age: group A (1 to 5 years old) and group B (6 to 16 years old). Patients with severe (severe anemia and/or hyperparasitemia) and mild malaria were enrolled. Prevalence and level of IL-21, total IgG and subclass (IgG1, IgG2, IgG3 and IgG4) titers were determined in plasma by enzyme-linked immunosorbent assay (ELISA). Plasma IL-21 levels correlated with IgG1 and IgG3 levels. Additionally, plasma IL-21 levels correlated with hemoglobin levels in younger children and with parasite density. Here we describe the relationship between IL-21 and antibodies for erythrocyte-binding antigen-175 (EBA-175) peptide 4, a malaria vaccine candidate in Gabonese children with acute falciparum malaria. This study provides new insights into the field of malaria.     

Testing a biochemical model of human genetic resistance to falciparum malaria by the analysis of variation at protein and microsatellite loci.

We recently proposed a biochemical model of genetic resistance to falciparum malaria based on the role of oxidant stress (of parasitic origin) in inducing the irreversible oxidation of hemoglobin and its binding to the erythrocyte membrane (Destro-Bisol et al. 1996). To test the model, we analyzed the relationships between the polymorphisms at the hemoglobin beta chain (HBB) and red cell glutathione peroxidase (GPX1) loci in 18 populations that had been subjected to endemic malaria (Cameroon and Central African Republic). The erythrocytes of GPX1*2 heterozygotes should be more efficient in sheltering the cell membrane from irreversible oxidation and binding of hemoglobin caused by the oxidant stress exerted by Plasmodium falciparum. According to our model, the GPX1*2 allele has an epistatic effect on the HBB*A/*S genotype by lowering its protection against falciparum malaria. In turn, this should decrease the fitness of the HBB*A/*S-GPX1*2/*1 genotype. Our predictions were confirmed. In fact, we observed a clear trend toward a dissociation between the HBB*A/*S and GPX1*2/*1 genotypes in the overall data. To test alternative hypotheses, we also analyzed the genetic variation at 9 protein and 10 autosomal microsatellite loci at both the single- and the 2-locus level. We also discuss the possible relevance of an alternative biochemical pathway. The results further support the conclusions of our study because the dissociation between the GPX1*2/*1 and HBB*A/*S genotypes does not appear to be related either to a general decrease in heterozygosity or to an increased risk of sudden death in HBB*A/*S individuals.     

Cerebral malaria is associated with IgG2 and IgG4 antibody responses to recombinant Plasmodium falciparum RIFIN antigen

RIFIN proteins belong to the largest Plasmodium falciparum multicopy family of variant surface antigens (VSA) expressed by infected erythrocytes. VSA antibodies have been shown to be associated with protection against malaria. Here, antibody subclass responses to a recombinant RIFIN protein (RIF-29) in 116 Ghanaian children were determined by ELISA to investigate the relationship between severe malaria and anti-RIF-29 antibodies. The study group was composed of 23 children diagnosed exclusively for cerebral malaria and 35 children who had non-cerebral severe malaria. The remaining 58 individuals were age-, gender- and area-matched asymptomatic controls. The finding that IgG1 and IgG3 responses predominated in severe malaria patients compared to matched controls suggests that these antibodies are not protective, but are most probably induced by a current infection, an observation substantiated by the equally high reactivity to both recombinant RIF-29 protein and to P. falciparum crude lysate proteins. The exclusive detection of IgG2 and IgG4 antibodies to RIF-29 protein only in cerebral malaria children brings to mind the possibility that these antibodies are pathogenic. This is a new finding that may go some way towards explaining why these children are at risk of developing the life-threatening form of cerebral malaria.     

Investigation of host candidate malaria-associated risk/protective SNPs in a Brazilian Amazonian population

The Brazilian Amazon is a hypo-endemic malaria region with nearly 300,000 cases each year. A variety of genetic polymorphisms, particularly in erythrocyte receptors and immune response related genes, have been described to be associated with susceptibility and resistance to malaria. In order to identify polymorphisms that might be associated with malaria clinical outcomes in a Brazilian Amazonian population, sixty-four human single nucleotide polymorphisms in 37 genes were analyzed using a Sequenom massARRAY iPLEX platform. A total of 648 individuals from two malaria endemic areas were studied, including 535 malaria cases (113 individuals with clinical mild malaria, 122 individuals with asymptomatic infection and 300 individuals with history of previous mild malaria) and 113 health controls with no history of malaria. The data revealed significant associations (p<0.003) between one SNP in the IL10 gene (rs1800896) and one SNP in the TLR4 gene (rs4986790) with reduced risk for clinical malaria, one SNP in the IRF1 gene (rs2706384) with increased risk for clinical malaria, one SNP in the LTA gene (rs909253) with protection from clinical malaria and one SNP in the TNF gene (RS1800750) associated with susceptibility to clinical malaria. Also, a new association was found between a SNP in the CTL4 gene (rs2242665), located at the major histocompatibility complex III region, and reduced risk for clinical malaria. This study represents the first association study from an Amazonian population involving a large number of host genetic polymorphisms with susceptibility or resistance to Plasmodium infection and malaria outcomes. Further studies should include a larger number of individuals, refined parameters and a fine-scale map obtained through DNA sequencing to increase the knowledge of the Amazonian population genetic diversity.     

Impact of red blood cell polymorphisms on the antibody response to Plasmodium falciparum in Senegal

The evidence of protection afforded by red blood cell polymorphisms against either clinical malaria or Plasmodium falciparum blood levels varies with the study site and the type of malaria transmission. Nevertheless, no clear implication of an antibody-related effect has yet been established in the protection related to red blood cell polymorphisms. We performed a prospective study, where plasma IgG and IgG subclasses directed to recombinant proteins from the merozoite surface protein 2 (MSP2/3D7 and MSP2/FC27) and the ring-infected erythrocyte surface antigen (RESA) were determined in a cohort of 413 Senegalese children before the annual malaria transmission season. The antibody response was dependent on age, and to a lesser extent, on the village of residence. IgG3 responders to all proteins, IgG responders to RESA and MSP2/3D7, as well as IgG2 to RESA and IgG1 responders to MSP2/3D7, presented enhanced mean values of parasite density, as evaluated during an 18-month follow-up. The levels of IgG and IgG3 to MSP2/3D7 were negatively associated with the risk of occurrence of a malaria attack during the following transmission season. Compared to normal children, sickle cell trait carriers presented lower levels of IgG to MSP2/3D7. Similarly, G6PD A- girls had lower levels of IgG and IgG3 to MSP2/FC27 than did G6PD normal girls. The impact of these particular genetic polymorphisms on the modulation of the antibody response is discussed.     

Family-based association of a low producing lymphotoxin-alpha allele with reduced Plasmodium falciparum parasitemia

Tumor necrosis factor (TNF)-related genes are thought to play a role in human malaria. TNF polymorphisms have been associated with severe malaria, mild malaria, and parasitemia. Lymphotoxin-alpha gene (LTA) that belongs to the TNF family is one such candidate gene. Here we report the family-based association analysis of a cis-regulatory lymphotoxin-alpha polymorphism with parasitemia in two independent populations living in Burkina Faso. Analysis of 199 subjects (34 families) living in an urban endemic area revealed the association of the low producing LTA+80A allele with reduced parasitemia. Furthermore, there was evidence of significant LTA+80-by-age and LTA+80-by-gender interactions. In another set of 318 residents (55 families) in a rural endemic area, we found both the association of the low producing LTA+80A allele with reduced parasitemia and LTA+80-by-age and LTA+80-by-gender interactions. This study suggests that LTA+80 polymorphism influences parasitemia and acts in an age- and gender-dependent manner.     

Anti-malaria humoral responses in children exposed to Plasmodium falciparum and Schistosoma haematobium

Antibody responses directed against the Plasmodium falciparum antigens, total extract, anti-merozoite surface protein-3 (MSP3b) and glutamate-rich protein (Glurp-R0) were studied in 42 children exposed to both Schistosoma haematobium and P. falciparum infections. The association between levels of the anti-malaria IgG subclasses and IgM with host age, sex, schistosome infection intensity and schistosome specific antibodies was studied before chemotherapeutic treatment of schistosome infections. This showed a significant negative association between schistosome infection intensity and levels of IgG1, IgG3, and IgG4 directed against malaria total extract antigen, and a positive association between levels of anti-schistosome soluble egg antigen IgG2, IgG3, and IgG4 and levels of the same subclasses directed against malaria total extract antigens. The effect of treating schistosome infections with praziquantel on malaria specific responses was also studied. This treatment resulted in increases in significant IgG4 levels against MSP3b and IgM against Glurp R0. Treatment also resulted in a significant decrease in IgG4 levels against Glurp R0. Host age, sex or pre-treatment infection intensity was not associated with the magnitude of change in the two IgG4 responses while males showed a significantly higher increase in levels of IgM. The results suggest cross reactivity between schistosome and malaria antigens in this population.     

The Plasmodium falciparum Erythrocyte Invasion Ligand Pfrh4 as a Target of Functional and Protective Human Antibodies against Malaria

Background

Acquired antibodies are important in human immunity to malaria, but key targets remain largely unknown. Plasmodium falciparum reticulocyte-binding-homologue-4 (PfRh4) is important for invasion of human erythrocytes and may therefore be a target of protective immunity.

Methods

IgG and IgG subclass-specific responses against different regions of PfRh4 were determined in a longitudinal cohort of 206 children in Papua New Guinea (PNG). Human PfRh4 antibodies were tested for functional invasion-inhibitory activity, and expression of PfRh4 by P. falciparum isolates and sequence polymorphisms were determined.

Results

Antibodies to PfRh4 were acquired by children exposed to P. falciparum malaria, were predominantly comprised of IgG1 and IgG3 subclasses, and were associated with increasing age and active parasitemia. High levels of antibodies, particularly IgG3, were strongly predictive of protection against clinical malaria and high-density parasitemia. Human affinity-purified antibodies to the binding region of PfRh4 effectively inhibited erythrocyte invasion by P. falciparum merozoites and antibody levels in protected children were at functionally-active concentrations. Although expression of PfRh4 can vary, PfRh4 protein was expressed by most isolates derived from the cohort and showed limited sequence polymorphism.

Conclusions

Evidence suggests that PfRh4 is a target of antibodies that contribute to protective immunity to malaria by inhibiting erythrocyte invasion and preventing high density parasitemia. These findings advance our understanding of the targets and mechanisms of human immunity and evaluating the potential of PfRh4 as a component of candidate malaria vaccines.     

Low antibodies against Plasmodium falciparum and imbalanced pro-inflammatory cytokines are associated with severe malaria in Mozambican children: a case-control study

ABSTRACT: BACKGROUND: The factors involved in the progression from Plasmodium falciparum infection to severe malaria (SM) are still incompletely understood. Altered antibody and cellular immunity against P. falciparum might contribute to increase the risk of developing SM. METHODS: To identify immune responses associated with SM, a sex- and age-matched case-control study was carried out in 134 Mozambican children with SM (cerebral malaria, severe anaemia, acidosis and/or respiratory distress, prostration, hypoglycaemia, multiple seizures) or uncomplicated malaria (UM). IgG and IgM against P. falciparum lysate, merozoite antigens (MSP-119, AMA-1 and EBA-175), a Duffy binding like (DBL)-alpha rosetting domain and antigens on the surface of infected erythrocytes were measured by ELISA or flow cytometry. Plasma concentrations of IL-12p70, IL-2, IFN-gamma, IL-4, IL-5, IL-10, IL-8, IL-6, IL- 1beta, TNF, TNF-beta and TGF-beta1 were measured using fluorescent bead immunoassays. Data was analysed using McNemar's and Signtest. RESULTS: Compared to UM, matched children with SM had reduced levels of IgG against DBLalpha (P < 0.001), IgM against MSP-119 (P = 0.050) and AMA-1 (P = 0.047), TGF-beta1 (P <0.001) and IL-12 (P = 0.039). In addition, levels of IgG against P. falciparum lysate and IL-6 concentrations were increased (P = 0.004 and P = 0.047, respectively). Anti-DBLalpha IgG was the only antibody response associated to reduced parasite densities in a multivariate regression model (P = 0.026). CONCLUSIONS: The lower levels of antibodies found in children with SM compared to children with UM were not attributable to lower exposure to P. falciparum in the SM group. IgM against P. falciparum and specific IgG against a rosetting PfEMP1 domain may play a role in the control of SM, whereas an imbalanced pro-inflammatory cytokine response may exacerbate the severity of infection. A high overlap in symptoms together with a limited sample size of different SM clinical groups reduced the power to identify immunological correlates for particular forms of SM.     

Evidence that invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein-1 (MSP-1 19) can play a protective role against blood-stage Plasmodium falciparum infection in individuals in a malaria endemic area of Africa

The C-terminal 19-kDa fragment of Plasmodium falciparum merozoite surface protein-1 (MSP-1(19)) is a target of protective Abs against blood-stage infection and a leading candidate for inclusion in a human malaria vaccine. However, the precise role, relative importance, and mechanism of action of Abs that target this protein remain unclear. To examine the potential protective role of Abs to MSP-1(19) in individuals naturally exposed to malaria, we conducted a treatment time to infection study over a 10-wk period in 76 residents of a highland area of western Kenya during a malaria epidemic. These semi-immune individuals were not all equally susceptible to reinfection with P. falciparum following drug cure. Using a new neutralization assay based on transgenic P. falciparum expressing the P. chabaudi MSP-1(19) orthologue, individuals with high-level MSP-1(19)-specific invasion-inhibitory Abs (>75th percentile) had a 66% reduction in the risk of blood-stage infection relative to others in the population (95% confidence interval, 3-88%). In contrast, high levels of MSP-1(19) IgG or IgG subclass Abs measured by enzyme immunoassay with six different recombinant MSP-1(19) Ags did not correlate with protection from infection. IgG Abs measured by serology and functional invasion-inhibitory activity did not correlate with each other. These findings implicate an important protective role for MSP-1(19)-specific invasion inhibitory Abs in immunity to blood-stage P. falciparum infection, and suggest that the measurement of MSP-1(19) specific inhibitory Abs may serve as an accurate correlate of protection in clinical trials of MSP-1-based vaccines.     

Atypical IgG subclass antibody responses to Plasmodium falciparum asexual stage antigens

The ability of Plasmodium falciparum to induce long-term immunity in the absence of continual restimulation has often been questioned. Recently it has been shown that, while a high proportion of individuals living in areas of high malaria endemicity have antibodies to merozoite surface antigen 2 (MSA2; MSP2) of P. falciparum, these antibodies are primarily of the IgG3 subclass. In this article, Antonio Ferrante and Christine Rzepczyk discuss how such atypical antibody responses may in part explain why immunity to malaria has been widely perceived to be short-lived.     

Evidence that the erythrocyte invasion ligand PfRh2 is a target of protective immunity against Plasmodium falciparum malaria

Abs targeting blood-stage Ags of Plasmodium falciparum are important in acquired immunity to malaria, but major targets remain unclear. The P. falciparum reticulocyte-binding homologs (PfRh) are key ligands used by merozoites during invasion of erythrocytes. PfRh2a and PfRh2b are functionally important members of this family and may be targets of protective immunity, but their potential role in human immunity has not been examined. We expressed eight recombinant proteins covering the entire PfRh2 common region, as well as PfRh2a- and PfRh2b-specific regions. Abs were measured among a cohort of 206 Papua New Guinean children who were followed prospectively for 6 mo for reinfection and malaria. At baseline, Abs were associated with increasing age and active infection. High levels of IgG to all PfRh2 protein constructs were strongly associated with protection from symptomatic malaria and high-density parasitemia. The predominant IgG subclasses were IgG1 and IgG3, with little IgG2 and IgG4 detected. To further understand the significance of PfRh2 as an immune target, we analyzed PfRh2 sequences and found that polymorphisms are concentrated in an N-terminal region of the protein and seem to be under diversifying selection, suggesting immune pressure. Cluster analysis arranged the sequences into two main groups, suggesting that many of the haplotypes identified may be antigenically similar. These findings provide evidence suggesting that PfRh2 is an important target of protective immunity in humans and that Abs act by controlling blood-stage parasitemia and support its potential for vaccine development.     

Fc Gamma Receptor IIIB (FcγRIIIB) Polymorphisms Are Associated with Clinical Malaria in Ghanaian Children

Plasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from clinical malaria. Human neutrophils constitutively express Fc gamma receptor-FcγRIIA and FcγRIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding FcγRIIA and FcγRIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding FcγRIIA p.H166R and FcγRIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. FcγRIIA-p.166H/R was genotyped by gene specific polymerase chain reaction followed by allele specific restriction enzyme digestion. FCGR3B-exon 3 was sequenced in 585 children, aged 1 to 12 years living in a malaria endemic region of Ghana. Multivariate logistic regression analysis found no association between FcγRIIA-166H/R polymorphism and clinical malaria. The A-allele of FCGR3B-c.233C>A (rs5030738) was significantly associated with protection from clinical malaria under two out of three genetic models (additive: p = 0.0061; recessive: p = 0.097; dominant: p = 0.0076) of inheritance. The FcγRIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p = 0.049). The FcγRIIIB-NA2*03 allotype (CTGCGA), a variant of the classical FcγRIIIB-NA2 (CTGCAA) was associated with susceptibility to clinical malaria (p = 0.0092). The present study is the first to report an association between a variant of FcγRIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical FcγRIIIB allotypes. This would be crucial to the improvement of neutrophil mediated functional assays such as the ADRB assay aimed at assessing the functionality of antibodies induced by candidate malaria vaccines.     

Serum levels of interleukin-18 in patients with uncomplicated Plasmodium falciparum malaria

Interleukin (IL)-18, a newly discovered cytokine produced primarily by macrophages, has been shown to induce gamma interferon (IFN-gamma) production by natural killer cells, to induce the T helper type 1 response. To further elucidate the role of this cytokine in uncomplicated malaria caused by Plasmodium falciparum, serum levels of IL-18, and gamma interferon (IFN-gamma), determined by an immunoenzymatic assay, were analyzed in 40 adult patients, and in 15 healthy control subjects. A significant increase in serum levels of IL-18 was observed in patients with uncomplicated P. falciparum malaria on admission, whereas serum levels of IFN-gamma tended to increase although not significantly. Serum levels of IL-18 decreased three days later, but still remained significantly high, whereas IFN-gamma levels returned to normal levels compared to the controls. No significant correlation was found between parasitemia and serum levels of IL-18 and IFN-gamma. The increase of IL-18 levels during acute and recovery phases of uncomplicated P. falciparum malaria may reflect a proinflammatory role of IL-18 in these patients. An early and effective immune response regulated by proinflammatory Th1 cytokines, including tumor necrosis factor (TNF), interleukin (IL)-12, and possibly IFN-gamma may limit the progression from uncomplicated malaria to severe and life-threatening complications.     

IgG1 and IgG2 antibody responses to Plasmodium falciparum exoantigens correlate inversely and positively, respectively, to the number of malaria attacks

Abstract In Manarintsoa, near Antananarivo, Madagascar, two groups of patients were defined in terms of malaria clinical immune status: Group MA⁺ consisted of 36 patients who suffered from between one to four malaria attacks (MA) during the 20-week study, and Group MA⁻ who comprised of 48 persons who did not have any malaria attacks during this time. In group MA⁺, IgM and IgG antibody levels to Plasmodium falciparum exoantigens (E-Ag) were inversely related to the number of malaria attacks. The level of IgM antibodies were significantly higher in group MA⁺. In contrast, IgG, IgG1, IgG2, IgG3 and IgG4 antibodies to E-Ag were significantly higher in group MA⁻. The level of IgG1 antibodies was inversely correlated, and IgG2 antibodies were positively correlated to the number of malaria attacks.     

Plasmodium falciparum: IgG subclass antibody response to merozoite surface protein-1 among Amazonian gold miners, in relation to infection status and disease expression

The merozoite surface protein-1 (MSP-1) of Plasmodium falciparum comprises two major targets of antibody-mediated immunity: the polymorphic block 2 and the 19-kDa C-terminal domain MSP-1(19). Here, we measured antibodies to three block 2 variants and MSP-1(19) among Amazonian gold miners and examined the repertoire of block 2 variants in local parasites. Main findings were as follows: (1) Only seven different block 2 variants were found in 18 DNA sequences analyzed. (2) No major difference was observed in IgG subclass distribution of antibodies from symptomatic P. falciparum-infected patients, asymptomatic parasite carriers, and non-infected subjects. (3) Antibodies to all block 2 antigens, but not to MSP-1(19), were biased towards IgG3 across different strata of cumulative malaria exposure. (4) Similar proportions of symptomatic and asymptomatic subjects failed to recognize the block 2 variant expressed by infecting parasites. These negative results underscore the limits of conventional antibody assays to evaluate clinical immunity to malaria.     

Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria

The pathogenesis of two of the most severe complications of Plasmodium falciparum malaria, cerebral malaria (CM) and severe malarial anaemia (SA) both appear to involve dysregulation of the immune system. We have measured plasma levels of TNF and its two receptors in Ghanaian children with strictly defined cerebral malaria (CM), severe malarial anaemia (SA), or uncomplicated malaria (UM) in two independent studies in an area of seasonal, hyperendemic transmission of P. falciparum. Levels of TNF, soluble TNF receptor 1 (sTNF-R1) and 2 (sTNF-R2) were found to be significantly higher in CM than in the other clinical categories of P. falciparum malaria patients. Levels of both receptors depended on clinical category, whereas only sTNF-R1 levels were significantly dependent on parasitemia. Detailed analysis of the interrelationship between these variables resolved this pattern further, and identified marked differences between the patient categories. While levels of TNF, sTNF-R1 and sTNF-R2 correlated with parasitemia in UM, this was not the case in CM and SA. Rather, there was a tendency towards high levels of TNF and its receptors in CM and low levels in SA without significant correlation to parasitemia in either category. This, and the fact that malaria-induced increases in plasma levels of IL-10 are much lower in SA compared to CM, suggest that distinct forms of dysregulation of the immune response to infection contribute to the pathogenesis of CM and SA.     

Antibody to P. falciparum in pregnancy varies with intermittent preventive treatment regime and bed net use

BACKGROUND: Antibodies towards placental-binding P. falciparum are thought to protect against pregnancy malaria; however, environmental factors may affect antibody development. Methods and Findings: Using plasma from pregnant Malawian women, we measured IgG against placental-binding P. falciparum parasites by flow cytometry, and related results to intermittent preventive treatment (IPTp) regime, and bed net use. Bed net use was associated with decreased antibody levels at mid-pregnancy but not at 1 month post partum (1 mpp). At 1 mpp a more intensive IPTp regime was associated with decreased antibody levels in primigravidae, but not multigravidae. CONCLUSIONS/SIGNIFICANCE: Results suggest bed nets and IPTp regime influence acquisition of pregnancy-specific P. falciparum immunity.     

Distribution of IgG subclass antibodies specific for Plasmodium falciparum glutamate-rich-protein molecule in sickle cell trait children with asymptomatic infections

Polymorphism in the beta-globin gene (hemoglobin S) has been associated with protection against severe forms of malaria. In a cross-sectional study, 180 young Gabonese children with and without sickle cell trait and harboring asymptomatic Plasmodium falciparum infections, were assessed for the responses to recombinant protein containing the conserved region of glutamate-rich protein (GLURP). We reported increased age-dependence of antibody prevalence and levels of total IgG (p<0.0001), IgG1 (p=0.009), and IgG3 (p<0.03) antibodies to GLURP with a cut-off at 5 years of age. Whatever the hemoglobin type, cytophilic antibodies (IgG1 and IgG3) were prevalent, but GLURP-specific IgG4 antibodies were detected at significantly (p<0.05) lower levels in HbAS children. We showed that the distribution of non-cytophilic IgG antibodies differs according to the hemoglobin type and to the malaria antigens tested. This may have possible implication for the clearance of malaria parasites and for protection against severe malaria.