Abstract
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 Ɛ4, Ɛ3 and Ɛ2 with APOE Ɛ4 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 Ɛ4 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 Ɛ4 children for Plasmodium spp. densities compared to non-APOE Ɛ4 children. When stratified for HbS polymorphisms, median Plasmodium spp. densities were significantly higher in HbAA children if they had an APOE Ɛ4 allele compared to those without an APOE Ɛ4 allele. When considering non-APOE Ɛ4 children, there was no quantitative reduction of Plasmodium spp. parasite densities for HbAS compared to HbAA phenotypes. No influence of APOE Ɛ4 on successful Plasmodium liver cell invasion was detected by multiplicity of infection. These results show that the APOE Ɛ4 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 Ɛ4 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.
Highlights
Children in malaria endemic areas experience multiple clinical episodes of malaria
We investigated the association of APOE polymorphisms with Plasmodium spp. infection in children living in an area of seasonal malaria transmission in Southeastern Gabon
Most children were infected with P. falciparum (46.0%, n=234), and a few were infected with P. malariae (2.8%, n=14) and the prevalence of mixed P. falciparum/ P. malariae infection was only 1.8% (n=9)
Summary
Children in malaria endemic areas experience multiple clinical episodes of malaria. They eventually develop acquired immunity that protects against clinical disease rather than infection. Clinical episodes occur against a background of chronic infections with multiple Plasmodium spp. and genotypes that can persist for months [1]. These chronic infections represent a significant burden of disease as they contribute to anemia and can become symptomatic. The progression from asymptomatic infection to high parasite densities and associated clinical disease is determined by the interplay between a number of biological factors including acquired immunity, parasite virulence and host genetics
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