Abstract
Cerebral malaria (CM) is the most severe manifestation of infection with Plasmodium, however its pathogenesis is still not completely understood. microRNA (miRNA) have been an area of focus in infectious disease research, due to their ability to affect normal biological processes, and have been shown to play roles in various viral, bacterial and parasitic infections, including malaria. The expression of miRNA was studied following infection of CBA mice with either Plasmodium berghei ANKA (causing CM), or Plasmodium yoelii (causing severe but non-cerebral malaria (NCM)). Using microarray analysis, miRNA expression was compared in the brains of non-infected (NI), NCM and CM mice. Six miRNA were significantly dysregulated between NCM and CM mice, and four of these, miR-19a-3p, miR-19b-3p, miR-142-3p and miR-223-3p, were further validated by qPCR assays. These miRNA are significantly involved in several pathways relevant to CM, including the TGF-β and endocytosis pathways. Dysregulation of these miRNA during CM specifically compared with NCM suggests that these miRNA, through their regulation of downstream targets, may be vitally involved in the neurological syndrome. Our data implies that, at least in the mouse model, miRNA may play a regulatory role in CM pathogenesis.
Highlights
Malaria is a serious and sometimes life-threatening disease transmitted by the bite of female Anopheles mosquitoes
The pathogenicity associated with Cerebral malaria (CM) is understood to involve parasitised red blood cells (PRBCs), endothelial cells, various adhesion molecules and cytokines, platelets, monocytes, and microvesicles released from many different cell types, including several involved in the pathogenesis of CM5–8
This study provides the first large-scale analysis of miRNA expression in experimental malaria and reveals that Plasmodium infection induces the dysregulation of a specific set of miRNA in the brain, among which are several miRNA that are more abundant in CM compared with Non-cerebral malaria (NCM) mice
Summary
The abundance of those miRNAs that showed a differential expression between the NCM and the CM group with the OpenArray platform was further validated by TaqMan MicroRNA assays, following the manufacturer’s instructions To this end, five NCM four CM brain samples were included in this analysis. The results were calculated using the ΔΔCt method[33], and fold change (FC) was calculated using the 2−ΔΔCt method, and data were log2-transformed Those miRNA with expression differences among the three study groups (as determined by Kruskal-Wallis test and corresponding post-hoc tests) were included in hierarchical clustering, which was performed using Euclidean distance, complete linkage and z-score normalisation. The datasets generated and analysed during the current study are available from the corresponding author on reasonable request
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