Plasmodium berghei liver stages establish a damage-mimicking vacuole to hijack host ER membrane contact site machinery for lipid uptake

Abstract

Plasmodium liver stage parasites undergo massive intracellular replication and therefore require extensive acquisition of host-derived lipids. How parasites coordinate lipid supply at the host-parasite interface, however, remains poorly understood. Here, we show that the Plasmodium berghei parasitophorous vacuole membrane (PVM) selectively mimics features of damaged endolysosomal membranes, including dynamic LC3-positive membrane tubules and PI4K2A-dependent PI(4)P accumulation, while lacking canonical damage markers including ESCRT components and galectins. This damage-mimicking membrane state drives OSBP recruitment and is associated with formation of VAPA/B-positive ER-PVM membrane contact sites. Disruption of VAPA/B or OSBP impaired PVM integrity and parasite survival, while OSBP depletion reduced cholesterol accumulation at the PVM. Together, our findings suggest that liver stage parasites exploit host lysosome repair-like pathways to redirect host lipids toward parasite growth and intracellular survival. These results redefine the PVM as an active metabolic interface that enables host lipid acquisition rather than merely serving as a protective barrier.