Toxoplasma gondii exploits host low-density lipoprotein receptor-mediated endocytosis for cholesterol acquisition

The obligate intracellular protozoan Toxoplasma gondii resides within a spe cialized parasitophorous vacuole (PV), isolated from host vesicular traffic . In this study, the origin of parasite cholesterol was investigated, T. go ndii cannot synthesize sterols via the mevalonate pathway. Host cholesterol biosynthesis remains unchanged after infection and a blockade in host de n ovo sterol biosynthesis does not affect parasite growth, However, simultane ous limitation of exogenous and endogenous sources of cholesterol from the host cell strongly reduces parasite replication and parasite growth is stim ulated by exogenously supplied cholesterol. Intracellular parasites acquire host cholesterol that is endocytosed by the low-density lipoprotein (LDL) pathway, a process that is specifically increased in infected cells. Interf erence with LDL endocytosis, with lysosomal degradation of LDL, or with cho lesterol translocation from lysosomes blocks cholesterol delivery to the PV and significantly reduces parasite replication. Similarly, incubation of T . gondii in mutant cells defective in mobilization of cholesterol from lyso somes leads to a decrease of parasite cholesterol content and proliferation . This cholesterol trafficking to the PV is independent of the pathways inv olving the host Golgi or endoplasmic reticulum. Despite being segregated fr om the endocytic machinery of the host cell, the T. gondii vacuole actively accumulates LDL-derived cholesterol that has transited through host lysoso mes.