Host metabolic pathways essential for malaria and related hemoparasites in the infection of nucleated cells

Abstract

SUMMARYApicomplexan parasite diseases, including malaria (Plasmodium) and theileriosis (Theileria), pose a significant threat to global health and the socioeconomic well-being of low-income countries. Despite recent advances, the common host metabolic proteins essential for these highly auxotrophic pathogens remain elusive. Here, we present a comprehensive investigation integrating a metabolic model ofP. falciparumparasites in hepatocytes and a genome-wide CRISPR screen targetingTheileriaschizont-infected macrophages. We reveal unifying host metabolic enzymes critical for the intracellular survival of these related hematozoa. We show that pathways such as host purine and heme biosynthesis are essential for bothTheileriasurvival andPlasmodiumliver development, while genes involved in glutathione and polyamine biosynthesis are predicted to be essential forPlasmodiumonly under certain metabolic conditions. Our work highlights the importance of host porphyrins for the viability of liver-stagePlasmodium. Shared parasite vulnerabilities provide a resource for exploring alternative therapeutic approaches to combat these crippling diseases.