title: Toxoplasma gondii exploits host low-density lipoprotein receptor-mediated endocytosis for cholesterol acquisition.
abstract: The obligate intracellular protozoan Toxoplasma gondii resides within a specialized parasitophorous vacuole (PV), isolated from host vesicular traffic. In this study, the origin of parasite cholesterol was investigated. T. gondii cannot synthesize sterols via the mevalonate pathway. Host cholesterol biosynthesis remains unchanged after infection and a blockade in host de novo sterol biosynthesis does not affect parasite growth. However, simultaneous limitation of exogenous and endogenous sources of cholesterol from the host cell strongly reduces parasite replication and parasite growth is stimulated 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. Interference with LDL endocytosis, with lysosomal degradation of LDL, or with cholesterol 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 lysosomes leads to a decrease of parasite cholesterol content and proliferation. This cholesterol trafficking to the PV is independent of the pathways involving the host Golgi or endoplasmic reticulum. Despite being segregated from the endocytic machinery of the host cell, the T. gondii vacuole actively accumulates LDL-derived cholesterol that has transited through host lysosomes.
authors.affiliation: Infectious Diseases Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8022, USA.
authors.forename: I
authors.initials: I
authors.lastname: Coppens
authors.forename: A P
authors.initials: AP
authors.lastname: Sinai
authors.forename: K A
authors.initials: KA
authors.lastname: Joiner
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012098:Reproduction / Q000187:drug effects; D014122:Toxoplasma / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D008798:Mevalonic Acid