Apolipoprotein E is a monomeric protein secreted by the liver and responsible for the transport of plasma cholesterol and triglycerides. The APOE gene encodes 3 isoforms latin_open_E4, latin_open_E3 ...and latin_open_E2 with APOE latin_open_E4 associated with higher plasma cholesterol levels and increased pathogenesis in several infectious diseases (HIV, HSV). Given that cholesterol is an important nutrient for malaria parasites, we examined whether APOE latin_open_E4 was a risk factor for Plasmodium infection, in terms of prevalence or parasite density. A cross sectional survey was performed in 508 children aged 1 to 12 years in Gabon during the wet season. Children were screened for Plasmodium spp. infection, APOE and hemoglobin S (HbS) polymorphisms. Median parasite densities were significantly higher in APOE latin_open_E4 children for Plasmodium spp. densities compared to non-APOE latin_open_E4 children. When stratified for HbS polymorphisms, median Plasmodium spp. densities were significantly higher in HbAA children if they had an APOE latin_open_E4 allele compared to those without an APOE latin_open_E4 allele. When considering non-APOE latin_open_E4 children, there was no quantitative reduction of Plasmodium spp. parasite densities for HbAS compared to HbAA phenotypes. No influence of APOE latin_open_E4 on successful Plasmodium liver cell invasion was detected by multiplicity of infection. These results show that the APOE latin_open_E4 allele is associated with higher median malaria parasite densities in children likely due to the importance of cholesterol availability to parasite growth and replication. Results suggest an epistatic interaction between APOE and HbS genes such that sickle cell trait only had an effect on parasite density in APOE latin_open_E4 children. This suggests a linked pathway of regulation of parasite density involving expression of these genes. These findings have significance for understanding host determinants of regulation of malaria parasite density, the design of clinical trials as well as studies of co-infection with Plasmodium and other pathogens.
Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria. With alternative antimalarial drugs not yet available, improving our understanding of how ...artemisinin-based drugs act and how resistance manifests is essential to enable optimisation of dosing regimens in order to prolong the lifespan of current first-line treatment options. Here, through introduction of a novel model of the dynamics of the parasites' response to drug, we explore how artemisinin-based therapies may be adjusted to maintain efficacy and how artemisinin resistance may manifest and be overcome. We introduce a dynamic mathematical model, extending on the traditional pharmacokinetic-pharmacodynamic framework, to capture the time-dependent development of a stress response in parasites. We fit the model to in vitro data and establish that the parasites' stress response explains the recently identified complex interplay between drug concentration, exposure time and parasite viability. Our model demonstrates that the previously reported hypersensitivity of early ring stage parasites of the 3D7 strain to dihydroartemisinin (DHA) is primarily due to the rapid development of stress, rather than any change in the maximum achievable killing rate. Of direct clinical relevance, we demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions of in vivo parasite clearance using PK-PD models. Given the important role that such models play in the design and evaluation of clinical trials for alternative drug dosing regimens, our model contributes an enhanced predictive platform for the continued efforts to minimise the burden of malaria.
Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple ...polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.
The heritable haemoglobinopathy alpha.sup.+-thalassaemia is caused by the reduced synthesis of alpha-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for ...alpha.sup.+-thalassaemia have microcytosis and an increased erythrocyte count. alpha.sup.+-Thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration, 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with alpha.sup.+-thalassaemia homozygosity provide a haematological benefit during acute malaria. Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by alpha.sup.+-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of ~1.5 x 10.sup.12/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for alpha.sup.+-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 x 10.sup.12/l as a result of the reduced mean cell Hb in homozygous alpha.sup.+-thalassaemia. In addition, children homozygous for alpha.sup.+-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for alpha.sup.+-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval CI 0.24-1.12, p = 0.09). The increased erythrocyte count and microcytosis in children homozygous for alpha.sup.+-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.
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