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

doi:10.1083/jcb.149.1.167

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© The Rockefeller University Press, 0021-9525/2000/4/167/ $5.00
The Journal of Cell Biology, Volume 149, Number 1, April 3, 2000 167-180

Original Article

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

Isabelle Coppens^a, Anthony P. Sinai^a, and Keith A. Joiner^a
^a Infectious Diseases Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8022

Correspondence to: Keith A. Joiner, Infectious Diseases Section, Department of Internal Medicine, 808 LCI, 333 Cedar Street, New Haven, CT 06520-8022. Tel:(203) 785-4140 Fax:(203) 785-3864 E-mail:keith.joiner{at}yale.edu.

The obligate intracellular protozoan Toxoplasma gondii resideswithin a specialized parasitophorous vacuole (PV), isolatedfrom host vesicular traffic. In this study, the origin of parasitecholesterol was investigated. T. gondii cannot synthesize sterolsvia the mevalonate pathway. Host cholesterol biosynthesis remainsunchanged after infection and a blockade in host de novo sterolbiosynthesis does not affect parasite growth. However, simultaneouslimitation of exogenous and endogenous sources of cholesterolfrom the host cell strongly reduces parasite replication andparasite growth is stimulated by exogenously supplied cholesterol.Intracellular parasites acquire host cholesterol that is endocytosedby the low-density lipoprotein (LDL) pathway, a process thatis specifically increased in infected cells. Interference withLDL endocytosis, with lysosomal degradation of LDL, or withcholesterol translocation from lysosomes blocks cholesteroldelivery to the PV and significantly reduces parasite replication.Similarly, incubation of T. gondii in mutant cells defectivein mobilization of cholesterol from lysosomes leads to a decreaseof parasite cholesterol content and proliferation. This cholesteroltrafficking to the PV is independent of the pathways involvingthe host Golgi or endoplasmic reticulum. Despite being segregatedfrom the endocytic machinery of the host cell, the T. gondiivacuole actively accumulates LDL-derived cholesterol that hastransited through host lysosomes.

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

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