Elucidation of artemisinin resistance mechanism by multidisciplinary fusion research based on genetics and big data analysis using endemic Plasmodium strains

The worldwide reported emergence of artemisinin-resistant parasites poses the greatest obstacle to malaria control. Therefore, elucidation of the resistance mechanism is urgently needed. In this fiscal year, using the life cycle reproduction system using Plasmodium falciparum vector mosquitoes and human hepatic mice established in the previous fiscal year, the project will genetically hybridize resistant strains and susceptible strains by simultaneous artificial blood sucking, and make mosaic genome protozoa. Establish a library. Using this protozoan library, whole genome analysis, artemisinin IC50 value acquisition, and gene expression data analysis will be performed. In addition, the project will simultaneously proceed with genomic DNA library screening of resistant strains using artificial chromosome vectors as a transcoding method to identify candidate resistant genes. When candidate genes are obtained, modified strains will be created and analyzed by genome editing, and attempts will be made to identify resistance genes or elucidate resistance-related gene networks. On the other hand, a functional analysis of the mdr1 gene will be performed, which was suggested to be related to artemisinin resistance in the previous year. The worldwide reported emergence of artemisinin-resistant parasites poses the greatest obstacle to malaria control. Therefore, elucidation of the resistance mechanism is urgently needed. As soon as stable acquisition of malaria parasite sporozoites by an artificial blood sucking system becomes possible, simultaneous artificial blood sucking of artemisinin-resistant strains and susceptible strains will be carried out, and genetic crossing will be carried out in the vector mosquito body. Subsequently, a mosaic-genome protozoan library is established from erythrocyte-invasive protozoa recovered from human hepatic mice infected with sporozoites carrying hybrid genomes. Using this protozoan library, whole genome analysis, artemisinin IC50 value acquisition, and gene expression data analysis will be performed. Once candidate genes are obtained, modified strains will be created and analyzed by genome editing. The worldwide reported emergence of artemisinin-resistant parasites poses the greatest obstacle to malaria control. Therefore, elucidation of the resistance mechanism is urgently needed. In addition, artemisinin treatment methods and IC50 determination methods will be examined for clearly distinguishing artemisinin-resistant strains. Furthermore, we will acquire NGS data of resistant and susceptible strains for bioinformatics analysis.

Drug Resistance

Apr 2020 — Mar 2023

$91,164

Japan