title: Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin.
abstract: Intracellular pathogens have complex metabolic interactions with their host cells to ensure a steady supply of energy and anabolic building blocks for rapid growth. Here we use the obligate intracellular parasite Toxoplasma gondii to probe this interaction for isoprenoids, abundant lipidic compounds essential to many cellular processes including signaling, trafficking, energy metabolism, and protein translation. Synthesis of precursors for isoprenoids in Apicomplexa occurs in the apicoplast and is essential. To synthesize longer isoprenoids from these precursors, T. gondii expresses a bifunctional farnesyl diphosphate/geranylgeranyl diphosphate synthase (TgFPPS). In this work we construct and characterize T. gondii null mutants for this enzyme. Surprisingly, these mutants have only a mild growth phenotype and an isoprenoid composition similar to wild type parasites. However, when extracellular, the loss of the enzyme becomes phenotypically apparent. This strongly suggests that intracellular parasite salvage FPP and/or geranylgeranyl diphosphate (GGPP) from the host. We test this hypothesis using inhibitors of host cell isoprenoid synthesis. Mammals use the mevalonate pathway, which is susceptible to statins. We document strong synergy between statin treatment and pharmacological or genetic interference with the parasite isoprenoid pathway. Mice can be cured with atorvastatin (Lipitor) from a lethal infection with the TgFPPs mutant. We propose a double-hit strategy combining inhibitors of host and parasite pathways as a novel therapeutic approach against Apicomplexan parasites.
authors.affiliation: Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: Zhu-Hong
authors.initials: ZH
authors.lastname: Li
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Boris
authors.initials: B
authors.lastname: Striepen
authors.forename: Silvia N J
authors.initials: SN
authors.lastname: Moreno
mesh_terms: D000818:Animals; D063546:Apicoplasts / Q000235:genetics / Q000378:metabolism; D000069059:Atorvastatin; D011756:Diphosphates / Q000378:metabolism*; D004224:Diterpenes / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000378:metabolism*; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism*; D014123:Toxoplasmosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D011756:Diphosphates; D004224:Diterpenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D015800:Protozoan Proteins; D011758:Pyrroles; D012717:Sesquiterpenes; C511282:geranyl diphosphate; C004808:farnesyl pyrophosphate; D000069059:Atorvastatin; D051231:Farnesyltranstransferase