Targeted repression of Plasmodium apicortin by host microRNA impairs malaria parasite growth and invasion

Abstract

Mature human erythrocytes contain a rich pool of microRNAs (miRNAs), which result from differentiation of the erythrocytes during the course of haematopoiesis. Recent studies have described the effect of erythrocytic miRNAs on the invasion and growth of the malaria parasite Plasmodium falciparum during the asexual blood stage of its life cycle. In this work, we have identified two erythrocytic miRNAs, miR-150-3p and miR-197-5p, that show favourable in silico hybridization with Plasmodium apicortin, a protein with putative microtubule-stabilizing properties. Co-expression of P. falciparum apicortin and these two miRNAs in a cell line model resulted in downregulation of apicortin at both the RNA and protein level. To create a disease model of erythrocytes containing miRNAs, chemically synthesized mimics of miR-150-3p and miR-197-5p were loaded into erythrocytes and subsequently used for invasion by the parasite. Growth of the parasite was hindered in miRNA-loaded erythrocytes, followed by impaired invasion; micronemal secretion was also reduced, especially in the case of miR-197-5p. Apicortin expression was found to be reduced in miRNA-loaded erythrocytes. To interpret the effect of downregulation of apicortin on parasite invasion to host erythrocytes, we investigated the secretion of the invasion-related microneme protein apical membrane antigen 1 (AMA1). AMA1 secretion was found to be reduced in miRNA-treated parasites. Overall, this study identifies apicortin as a novel target within the malaria parasite and establishes miR-197-5p as its miRNA inhibitor. This miRNA represents an unconventional nucleotide-based therapeutic and provides a new host factor-inspired strategy for the design of antimalarial molecular medicine. This article has an associated First Person interview with the first author of the paper.

A Southeast Asian Perspective on the COVID-19 Pandemic: Hemoglobin E (HbE)-Trait Confers Resistance Against COVID-19

“…The genetic and molecular mechanisms of this hypothesized protection are as yet elusive, but biological evidence is suggestive. Hemoglobinopathy-induced red blood cell structural modifications hinder invasion, growth, and migration of plasmodium [ 42 , 45 ]. Recent studies in thalassemias have pointed to the involvement of microRNAs (miRNAs) in malarial pathogenesis and anti-plasmodial defense [ 45 ].…”

“…Hemoglobinopathy-induced red blood cell structural modifications hinder invasion, growth, and migration of plasmodium [ 42 , 45 ]. Recent studies in thalassemias have pointed to the involvement of microRNAs (miRNAs) in malarial pathogenesis and anti-plasmodial defense [ 45 ]. MicroRNAs (miRNAs) are 18–25 nucleotide long, small, non-coding RNA molecules whose production is strictly regulated and abundant in all human cells [ 46 ].…”

Apicortin, a Constituent of Apicomplexan Conoid/Apical Complex and Its Tentative Role in Pathogen—Host Interaction

“…Two human erythrocytic miRNAs, miR-150-3p and miR-197-5p, showed favorable in silico hybridization with both P. falciparum and Plasmodium vivax apicortins ( Table 1 ). This finding was strengthened experimentally: co-expression of P. falciparum apicortin and either of these two miRNAs in a cell line model (HEK 293T cells) resulted in about 10-fold downregulation of apicortin at both the RNA and the protein levels [ 45 ]. A similar phenomenon was observed when mature schizonts were incubated with chemically synthesized mimics of miR-150-3p or miR-197-5p.…”

“…Immuno-localization of apicortin was monitored in various stages of P. falciparum [ 44 , 45 ]. Apicortin was localized on the surface of the parasite in the subpellicular region of both the trophozoites and the schizonts, where apicortin was co-localized with merozoite surface protein 1 (MSP1) and myosin A tail interacting protein (MTIP).…”

“…It was co-localized with both α- and β-tubulin. The localization of apicortin was confirmed in the nuclear and cytoplasmic extracts of the parasite with a major occurrence in the cytoplasm [ 44 , 45 ] ( Table 1 ).…”