Asymptomatic Plasmodium infection carriers represent a major threat to malaria control worldwide as they are silent natural reservoirs and do not seek medical care. There are no standard criteria for asymptomaticPlasmodium infection; therefore, its diagnosis relies on the presence of the parasite during a specific period of symptomless infection. The antiparasitic immune response can result in reducedPlasmodium sp. load with control of disease manifestations, which leads to asymptomatic infection. Both the innate and adaptive immune responses seem to play major roles in asymptomatic Plasmodiuminfection; T regulatory cell activity (through the production of interleukin-10 and transforming growth factor-β) and B-cells (with a broad antibody response) both play prominent roles. Furthermore, molecules involved in the haem detoxification pathway (such as haptoglobin and haeme oxygenase-1) and iron metabolism (ferritin and activated c-Jun N-terminal kinase) have emerged in recent years as potential biomarkers and thus are helping to unravel the immune response underlying asymptomatic Plasmodium infection. The acquisition of large data sets and the use of robust statistical tools, including network analysis, associated with well-designed malaria studies will likely help elucidate the immune mechanisms responsible for asymptomatic infection.

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Immunoregulation in human malaria: the challenge of understanding asymptomatic infection

Overview of human genetic susceptibility to malaria: From parasitemia control to severe disease

Recent research efforts to identify genes involved in malaria susceptibility using genome-wide approaches have focused on severe malaria. Here, we present the first GWAS on non-severe malaria designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Our study was performed on two cohorts of infants from southern Benin (525 and 250 individuals used as discovery and replication cohorts, respectively) closely followed from birth to 18–24 months of age, with an assessment of a space- and time-dependent environmental risk of exposure. Both the recurrence of mild malaria attacks and the recurrence of malaria infections as a whole (symptomatic and asymptomatic) were considered. Post-GWAS functional analyses were performed using positional, eQTL, and chromatin interaction mapping to identify the genes underlying association signals. Our study highlights a role of PTPRT, a tyrosine phosphatase receptor involved in STAT3 pathway, in the protection against both mild malaria attacks and malaria infections (p = 9.70 × 10−8 and p = 1.78 × 10−7, respectively, in the discovery cohort). Strong statistical support was also found for a role of MYLK4 (meta-analysis, p = 5.29 × 10−8 with malaria attacks), and for several other genes, whose biological functions are relevant in malaria infection. Results shows that GWAS on non-severe malaria can successfully identify new candidate genes and inform physiological mechanisms underlying natural protection against malaria.

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First genome-wide association study of non-severe malaria in two birth cohorts in Benin

Several studies have provided evidence of both helpful and harmful effects of TNF on the outcome of Plasmodium falciparum malaria infection. Several TNF polymorphisms that are located within non-coding regions have been associated with parasitaemia, mild malaria or severe malaria. We investigated the association of TNF1304 (rs3093664), TNF-308 (rs1800629), TNF-238 (rs361525) and TNF-244 (rs673) with mild malaria and symptomatic maximum parasitaemia in a population-based design (n=310). We obtained nominal evidence for an association between symptomatic maximum parasitaemia and TNF-308, TNF-238, and TNF-244 on the one hand, and between the number of mild malaria attacks and TNF-244 on the other hand. After accounting for multiple tests, we confirmed the association of symptomatic maximum parasitaemia with TNF-244. We further provide bioinformatics and experimental evidence that TNF-244 has a cis-regulatory effect. This is the first report that emphasizes the potential role of TNF-244 in malaria.

Association of a functional TNF variant with Plasmodium falciparum parasitaemia in a congolese population.

BACKGROUND Estimating single nucleotide polymorphism (SNP)-heritability (h2g) of severe malaria resistance and its distribution across the genome might shed new light in to the underlying biology. METHOD We investigated h2g of severe malaria resistance from a genome-wide association study (GWAS) dataset (sample size = 11 657). We estimated the h2g and partitioned in to chromosomes, allele frequencies and annotations using the genetic relationship-matrix restricted maximum likelihood approach. We further examined non-cell type-specific and cell type-specific enrichments from GWAS-summary statistics. RESULTS The h2g of severe malaria resistance was estimated at 0.21 (se = 0.05, P = 2.7 × 10-5), 0.20 (se = 0.05, P = 7.5 × 10-5) and 0.17 (se = 0.05, P = 7.2 × 10-4) in Gambian, Kenyan and Malawi populations, respectively. A comparable range of h2g [0.21 (se = 0.02, P < 1 × 10-5)] was estimated from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in genic SNPs while summary statistics analysis suggests evidences of enrichment in multiple categories. Supporting the polygenic inheritance, the h2g of severe malaria resistance is distributed across the chromosomes and allelic frequency spectrum. However, the h2g is disproportionately concentrated on three chromosomes (chr 5, 11 and 20), suggesting cost-effectiveness of targeting these chromosomes in future malaria genomic sequencing studies. CONCLUSION We report for the first time that the heritability of malaria resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Further studies with larger sample sizes are needed to better understand the underpinning genetics of severe malaria resistance.

Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance.

Genome-wide studies have mapped several loci controlling Plasmodium falciparum mild malaria and parasitaemia, only two of them being significant at the genome level. The objective of the present study was to identify malaria resistance loci in individuals living in Burkina Faso. A genome scan that involved 314 individuals belonging to 63 families was performed. Markers located within chromosomes 6p21.3 and 17p12 were genotyped in 247 additional individuals belonging to 55 families. The linkage and the association of markers with parasitaemia and mild malaria were assessed by using the maximum-likelihood binomial method extended to quantitative trait linkage and the quantitative trait disequilibrium test, respectively. Multipoint linkage analysis showed a significant linkage of mild malaria to chromosome 6p21.3 (LOD score 3.73, P = 1.7 10−5), a suggestive linkage of mild malaria to chromosome 19p13.12 (LOD score 2.50, P = 3.5 10−4), and a suggestive linkage of asymptomatic parasitaemia to chromosomes 6p21.3 (LOD score 2.36, P = 4.9 10−4) and 17p12 (LOD score 2.87, P = 1.4 10−4). Genome-wide family-based association analysis revealed a significant association between three chromosome 5q31 markers and asymptomatic parasitaemia, whereas there was no association with mild malaria. When taking into account 247 additional individuals, a significant linkage of asymptomatic parasitaemia to chromosome 17p12 (LOD score 3.6, P = 2 10−5) was detected. A new genome-wide significant malaria locus on chromosome 17p12 and a new suggestive locus on chromosome 19p13.12 are reported. Moreover, there was evidence that confirmed the influence of chromosomes 5q31 and 6p21.3 as loci controlling mild malaria or asymptomatic parasitaemia.

https://hal-amu.archives-ouvertes.fr/hal-01461374/document

Brice Kumulungui

Papers

A genome scan for Plasmodium falciparum malaria identifies quantitative trait loci on chromosomes 5q31, 6p21.3, 17p12, and 19p13