Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria Resistance

Abstract

SUMMARY Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease, resist infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic lifecycle of P. falciparum, a subset of erythrocyte microRNAs translocate into the parasite. Two microRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes and these miRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451 and let-7i integrated into essential parasite mRNAs and, via impaired ribosomal loading, resulted in translational inhibition. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical microRNA activity which may represent a unique host defense strategy against complex eukaryotic pathogens.

Immunological Characterization in Malaria Patients with and without the Sickle-Cell Trait

“…falciparum parasites induced sickling of HbAS red blood cells in vitro, by increase in the polymerized hemoglobin or a reduction of intracellular pH [49] leading to enhanced phagocytosis of infected cells and reduced parasitaemia compared to that in HbAA individuals. Other specific intra-erythrocytic conditions of HbAS red blood cells, such as low intracellular potassium, high concentrations of hemoglobin or osmotic shrinkage of the red blood cell cause an inhospitable environment for parasites [50].…”

RNA-based disease control as a complementary measure to fight Fusarium fungi through silencing of the azole target Cytochrome P450 Lanosterol C-14 α-Demethylase

“…Moreover, the fungal mutants vdclp-1 and vdhic-15 were reduced in virulence, confirming that these genes contribute to pathogenicity. Animal hosts also export sRNAs into interacting parasite cells to suppress their virulence (LaMonte et al 2012). Sickle cell erythrocytes of anemia patients accumulate higher levels of miR-451 and lethal-7i (let-7i), which are transferred into the parasite Plasmodium falciparum.…”

Wolbachia small noncoding RNAs and their role in cross-kingdom communications

“…miRNA and siRNAs have been reported to have cross-kingdom effects in a fungal plant pathogen and also in Plasmodium, the malaria parasite (2,22). The discovery of these regulatory small RNAs that can affect bacterial and host gene expression opens up an exciting avenue to better understand and manipulate host-pathogen interactions, in particular, the epigenetic effect endosymbionts may have on vector-borne pathogens, leading to better control of diseases that have global impact on human and animal health.…”

“…Recently, it was shown that miRNAs from sickle cell erythrocytes are translocated and enriched in the malaria parasite, Plasmodium falciparum, when they infect the cells. Consequently, the translocated miRNAs suppress the cAMP-dependent protein kinase (PKA-R), resulting in inhibition of translation in the parasite, contributing to the resistance of the sickle cells to malaria infection (2). This example demonstrates the role of snRNAs in regulation of gene expression across kingdoms.…”