Abstract
Genetic variations in toll-like receptors and cytokine genes of the innate immune pathways have been implicated in controlling parasite growth and the pathogenesis of Plasmodium falciparum mediated malaria. We previously published genetic association of TLR4 non-synonymous and TNF-α promoter polymorphisms with P.falciparum blood infection level and here we extend the study considerably by (i) investigating genetic dependence of parasite-load on interleukin-12B polymorphisms, (ii) reconstructing gene-gene interactions among candidate TLRs and cytokine loci, (iii) exploring genetic and functional impact of epistatic models and (iv) providing mechanistic insights into functionality of disease-associated regulatory polymorphisms. Our data revealed that carriage of AA (P = 0.0001) and AC (P = 0.01) genotypes of IL12B 3′UTR polymorphism was associated with a significant increase of mean log-parasitemia relative to rare homozygous genotype CC. Presence of IL12B+1188 polymorphism in five of six multifactor models reinforced its strong genetic impact on malaria phenotype. Elevation of genetic risk in two-component models compared to the corresponding single locus and reduction of IL12B (2.2 fold) and lymphotoxin-α (1.7 fold) expressions in patients'peripheral-blood-mononuclear-cells under TLR4Thr399Ile risk genotype background substantiated the role of Multifactor Dimensionality Reduction derived models. Marked reduction of promoter activity of TNF-α risk haplotype (C-C-G-G) compared to wild-type haplotype (T-C-G-G) with (84%) and without (78%) LPS stimulation and the loss of binding of transcription factors detected in-silico supported a causal role of TNF-1031. Significantly lower expression of IL12B+1188 AA (5 fold) and AC (9 fold) genotypes compared to CC and under-representation (P = 0.0048) of allele A in transcripts of patients' PBMCs suggested an Allele-Expression-Imbalance. Allele (A+1188C) dependent differential stability (2 fold) of IL12B-transcripts upon actinomycin-D treatment and observed structural modulation (P = 0.013) of RNA-ensemble were the plausible explanations for AEI. In conclusion, our data provides functional support to the hypothesis that de-regulated receptor-cytokine axis of innate immune pathway influences blood infection level in P. falciparum malaria.
Highlights
Infection with Plasmodium falciparum is still a major health problem worldwide, causing about 225 million new malaria cases each year [1]
A large body of the literature has demonstrated that protection against severe P. falciparum malaria is provided by distinct genetic traits, while relatively less is known about the mild events which clearly constitute a substantial fraction of global socioeconomic burden of malaria [72,73,74]
Over the past several years, genetic epidemiology studies technologically have progressed from investigating few candidate markers to interrogating thousands of variants in genome-wide association studies (GWAS) while the data analysis mostly focuses on detecting single single nucleotide polymorphisms (SNPs) effects [75,76]
Summary
Infection with Plasmodium falciparum is still a major health problem worldwide, causing about 225 million new malaria cases each year [1]. Malaria parasitemia which affects disease severity and transmission is controlled by a balance between depletion of red blood cells and immune clearance by T-helper cells, B lymphocytes, and cytokines as shown in murine model of Plasmodium chabaudi infection [2,3,4]. Two important functions of innate immunity in the defense against the parasite are (i) it triggers a battery of pro-inflammatory cytokines inhibiting rapid parasite growth and thereby limiting the onset of malaria pathology and (ii) it determines the type and efficiency of subsequent parasite specific adaptive immune responses through the cytokine mediators at later stages of infection [8,9,10]. An account of the etiological components of innate immunity and the mechanistic framework of their interactions will offer the much needed therapeutic alternatives for control of the global burden of malaria
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