title: Host cholesterol synthesis contributes to growth of intracellular Toxoplasma gondii in macrophages.
abstract: The intracellular protozoan Toxoplasma gondii lacks the ability to synthesize sterol and scavenges cholesterol from the low-density lipoprotein receptor (LDLR) pathway of its host to facilitate replication. Sterol biosynthesis inhibitors, however, have a demonstrated anti-Toxoplasma effect. In this study, we examined the host mevalonate pathway as a novel source of cholesterol for T. gondii and its effects on parasite growth in macrophages. Parasite growth did not significantly change in the absence of LDLR or when LDL was exogenously supplemented. Lovastatin and compactin, both inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase in the mevalonate pathway, significantly inhibited T. gondii growth in both wild-type and LDLR-knockout macrophages. Parasite growth was also suppressed by squalestatin, an inhibitor of squalene synthase, despite mevalonate producing isoprenoid intermediates in host cells. The present study demonstrates that lovastatin, compactin and squalestatin have anti-Toxoplasma activities and that the host cholesterol synthesis may contribute to parasite growth in macrophages.
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro,Hokkaido 080–8555, Japan. nisikawa@obihiro.ac.jp
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Hany M
authors.initials: HM
authors.lastname: Ibrahim
authors.forename: Kyohko
authors.initials: K
authors.lastname: Kameyama
authors.forename: Ikumi
authors.initials: I
authors.lastname: Shiga
authors.forename: Jun
authors.initials: J
authors.lastname: Hiasa
authors.forename: Xuenan
authors.initials: X
authors.lastname: Xuan
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology*; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000235:genetics; D014122:Toxoplasma / Q000254:growth & development*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; C012258:mevastatin; D002784:Cholesterol; D008148:Lovastatin; D008798:Mevalonic Acid