Abstract
The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia (72 miRNAs, B-H FDR 5%). Integrative miRNA-mRNA analysis implicates several infection-responsive miRNAs (e.g., miR-16-5p, miR-15a-5p and miR-181c-5p) promoting lymphocyte cell death. miRNA cis-eQTL analysis using whole-genome sequencing data identified 1,376 genetic variants associated with the expression of 34 miRNAs (B-H FDR 5%). We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression. These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria.
Highlights
The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination
We report the first genome-wide miRNA-mRNA gene expression profiling study of children naturally infected with P. falciparum
Follow-up profiling allowed for the integration of primary quantitative clinical trait data, mRNA and whole genome sequencing (WGS) data to help identify differentially expressed miRNAs associated with parasitemia, under host regulatory genetic control and/or with potential downstream effects on mRNA regulation
Summary
The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria. The search for effective and sustainable therapeutic strategies for malaria is hampered by limited understanding of the sources of variation in host immune response to natural P. falciparum infection Several factors such as host and parasite genetics, state of immunity, and environment contribute to the observed variation. Genetic mapping of miRNAs using WGS data identified 1,376 genetic variants associated with the expression levels of 34 miRNAs (B–H FDR 5%) Together, these findings suggest that the mechanisms involved in controlling P. falciparum infection are under host genetic control at both the transcriptional and post-transcriptional levels
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