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© The Rockefeller University Press, 0021-9525/2000//167 $5.00
The Journal of Cell Biology, Volume 149, Number 1, , 2000 167-180

Toxoplasma gondii Exploits Host Low-Density Lipoprotein Receptor-Mediated Endocytosis for Cholesterol Acquisition

^a Infectious Diseases Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8022
Infectious Diseases Section, Department of Internal Medicine, 808 LCI, 333 Cedar Street, New Haven, CT 06520-8022.(203) 785-3864(203) 785-4140

keith.joiner{at}yale.edu

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.

Key Words: Toxoplasma gondii • parasitophorous vacuole • somatic cell mutant • LDL endocytic pathway • cholesterol transport

© 2000 The Rockefeller University Press

Abbreviations used in this paper: CO, cholesteryl oleate; HFF, human foreskin fibroblast; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; LP, total lipoproteins; LPDS, LP-deficient serum; NBD-C, 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)23,24-bisnor-5-cholen-3β)-ol; NPC, Niemann-Pick type C; PV, parasitophorous vacuole; PVM, PV membrane; SRD cells, mutant CHO cells with a sterol regulatory defective phenotype; SSD cells, mutant CHO cells with a squalene synthase deficiency; [³H-CO]-LDL, LDL that is labeled with [³H-CO]; [NBD-C]-LDL, LDL that is labeled with [NBD-C].

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