Parasite-Related Genetic and Epigenetic Aspects and Host Factors Influencing Plasmodium falciparum Invasion of Erythrocytes

Abstract

Malaria, a disease caused by Plasmodium parasites, is widespread throughout tropical and sub-tropical regions worldwide; it mostly affects children and pregnant woman. Eradication has stalled despite effective prevention measures and medication being available for this disease; this has mainly been due to the parasite's resistance to medical treatment and the mosquito vector's resistance to insecticides. Tackling such resistance involves using renewed approaches and techniques for accruing a deep understanding of the parasite's biology, and developing new drugs and vaccines. Studying the parasite's invasion of erythrocytes should shed light on its ability to switch between invasion phenotypes related to the expression of gene sets encoding proteins acting as ligands during target cell invasion, thereby conferring mechanisms for evading a particular host's immune response and adapting to changes in target cell surface receptors. This review considers some factors influencing the expression of such phenotypes, such as Plasmodium's genetic, transcriptional and epigenetic characteristics, and explores some host-related aspects which could affect parasite phenotypes, aiming at integrating knowledge regarding this topic and the possible relationship between the parasite's biology and host factors playing a role in erythrocyte invasion.

Keywords: Plasmodium falciparum; invasion factors; malaria; phenotype change; regulatory mechanism.

Figure 1

A hypothesis of the relation between ligand-receptor binding failure and a signal transduction pathway. The ligand-receptor binding failure between Pf EBA175 and glycophorin A may induce, inside the merozoite, an increase in the expression of calcineurin B (Pf CnB) which could be associated (by its possible relation with class I histone deacetylase inhibitors) with suppression of H3K9-methylation, allowing Pf Rh4 transcription.

Figure 2

Factors affecting invasion. (1) Merozoites in the blood stream when the erythrocyte cycle takes place are exposed to host antibodies which recognize and inactivate merozoite having higher surface antigen expression in patients exposed to malaria. (2) Merozoites which are not inactivated by antibodies use their surface ligand proteins for erythrocyte sensing and attachment, thereby initiating invasion. Ligand/receptor (L-R) binding may activate signaling pathways, improving these ligands transcription and triggering their selection. (3) The parasite develops to ring state and then trophozoite stage. (4) Most transcription take place during the trophozoite stage; this begins with the opening of the nucleosomes and recruitment of transcription factors acting as transcription activators or repressors, which are related to “in time” expression. (5) The parasite develops into a schizont, invasion genes transcription occurs since transcription repression of them becomes halted. Receptor-ligand interactions between the merozoite and the erythrocyte could be related to the selection of the genes expressed during this phase.