Breaking Boundaries in Malaria Research: Design of a Genetic Tool for High-Throughput Gametocidal Drug Screening

Abstract

Malaria, a devastating illness remains a global health concern with an estimated 249 million malaria cases in 85 malaria-endemic countries around the world. Malaria elimination, challenged by drug resistance, requires strategic interventions that could be the implementation of antimalarials with selective actions on the different phases of the parasite life cycle. Of particular relevance is gametocytocidal drugs that could be used to prevent transmission of malaria infection to the mosquito. Finding drugs with gametocidal effect thus are limited by the technical challenges of large-scale production and quantification of parasite transmission stage, gametocytes. To surmount these obstacles, our study endeavors to design a genetic engineering strategy (a vector construct) to further deliver nucleic acid information through transfections-based systems in the form of a plasmid into Plasmodium falciparum. This approach will enable us to engineer a transgenic parasite line for multi-stage drug screening, targeting the symptomatic intra-erythrocyte parasite stage and gametocytes. Genetic engineering tools such as selected linked integration system and attB-attP site-specific recombination will be used in our vector construct aiming the genetic integration process into the P. falciparum genome. These systems will accommodate strategies for easy and accurate stage-specific quantification such as RFP-luciferase fusion cloned downstream stage-specific promoters leading to reporter products with optical outputs and for efficient production of gametocytes at large scale using a riboswitch-based inducible gene expression system. Such technology is of major need and will pave the way for scaling up the capacity for high-throughput drug screening, leading to improved strategies to find drugs capable of blocking malaria transmission.