Discovery of Druggable Host Factors Critical to Plasmodium Liver-Stage Infection

Abstract

Plasmodium parasites undergo an obligatory and asymptomatic developmental stage within the liver before infecting red blood cells to cause malaria. The hijacked host pathways critical to parasite infection during this hepatic phase remain poorly understood. Here, we implemented a forward genetic screen to identify over 100 host factors within the human druggable genome that are critical to P. berghei infection in hepatoma cells. Notably, we found knockdown of genes involved in protein trafficking pathways to be detrimental to parasite infection. The disruption of protein trafficking modulators, including COPB2 and GGA1 decreases P. berghei parasite size and an immunofluorescence study indicates that these proteins are recruited to the Plasmodium parasitophorous vacuole in infected hepatocytes. These findings reveal that various host intracellular protein trafficking pathways are subverted by Plasmodium parasites during the liver stage and provide new insights into their manipulation for growth and development. Raphemot et al. use a genomic screen to provide insights into host-pathogen interactions during Plasmodium development within hepatocytes. Molecular and chemical approaches highlight that the host vesicular trafficking pathway is subverted by Plasmodium for growth in liver cells.