The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background

Area of Science:

• Malariology and Parasitology
• Genomics and Transcriptomics
• Drug Resistance Mechanisms

Background:

• The mechanisms driving artemisinin resistance in Plasmodium falciparum remain incompletely understood, extending beyond Pfk13 gene mutations and unfolded protein response pathways.
• Artemisinin-based combination therapies are vital for malaria treatment, making the elucidation of resistance factors a global health priority.

Purpose of the Study:

• To investigate the genetic and regulatory underpinnings of artemisinin resistance in Plasmodium falciparum parasites.
• To identify novel genetic backgrounds and molecular players involved in artemisinin resistance within the Greater Mekong Subregion (GMS).

Main Methods:

• Reanalysis of 773 Plasmodium falciparum isolates from the TRACI-study.
• Integration of Transcriptome-Wide Association Studies (TWAS), Genome-Wide Association Studies (GWAS), and expression Quantitative Trait Loci (eQTL) analyses.
• Comparative analysis of parasite transcriptomic profiles and genetic variations across different geographic sites in the GMS.

Main Results:

• Parasites exhibit transcriptomic convergence within geographic sites, displaying two distinct physiological profiles across the GMS.
• Significant differences in SNP-expression linkages were observed between eastern (8720 linkages) and western (4537 linkages) GMS parasites, indicating divergent gene regulatory networks.
• Two genetic and physiological backgrounds associated with artemisinin resistance were identified, alongside a farnesyltransferase protein and a thioredoxin-like protein as potential mediators of resistance.

Conclusions:

• Differential gene regulatory networks contribute to Plasmodium falciparum adaptation and artemisinin resistance in unique host environments within the GMS.
• Specific proteins, including farnesyltransferase and thioredoxin-like proteins, may serve as critical intermediaries linking the Pfk13 C580Y mutation to prolonged parasite clearance times.
• These findings provide new insights into the complex etiology of artemisinin resistance, informing future therapeutic strategies and resistance monitoring.